IGFBP2 from a novel copper metabolism-associated biomarker promoted glioma progression and response to immunotherapy.

Introduction: Copper metabolism encompasses all cellular metabolic processes involving copper ions and plays a significant role in the pathogenesis of diseases, including cancer. Furthermore, copper is intricately involved in various processes related to nucleotide metabolism. However, a comprehensive analysis of copper metabolism in gliomas remains lacking despite its importance. Methods: To address this gap, glioma patients were stratified based on the expression levels of copper metabolism-related genes. By utilizing machine learning techniques, a novel copper metabolism-associated biomarker was developed. The potential of this biomarker in prognosis, mutation analysis, and predicting immunotherapy response efficiency in gliomas was systematically investigated. Results: Notably, IGFBP2, identified as a glioma tumor promoter, was found to promote disease progression and influence immunotherapy response. Additionally, glioma-derived IGFBP2 was observed to enhance microglial migration. High IGFBP2 expression in GBM cells facilitated macrophage interactions through the EGFR, CD63, ITGB1, and CD44 signaling pathways. Discussion: Overall, the copper metabolism-associated biomarker shows promising potential to enhance the clinical management of gliomas, offering valuable insights into disease prognosis and treatment strategies.

Magnetic resonance imaging findings of intracranial extraventricular ependymoma: A retrospective multi-center cohort study of 114 cases.

BACKGROUND: Intracranial extraventricular ependymoma (IEE) is an ependymoma located in the brain parenchyma outside the ventricles. IEE has overlapping clinical and imaging characteristics with glioblastoma multiforme (GBM) but different treatment strategy and prognosis. Therefore, an accurate preoperative diagnosis is necessary for optimizing therapy for IEE. METHODS: A retrospective multicenter cohort of IEE and GBM was identified. MR imaging characteristics assessed with the Visually Accessible Rembrandt Images (VASARI) feature set and clinicopathological findings were recorded. Independent predictors for IEE were identified using multivariate logistic regression, which was used to construct a diagnostic score for differentiating IEE from GBM. RESULTS: Compared to GBM, IEE tended to occur in younger patients. Multivariate logistic regression analysis identified seven independent predictors for IEE. Among them, 3 predictors including tumor necrosis rate (F7), age, and tumor-enhancing margin thickness (F11), demonstrated higher diagnostic performance with an Area Under Curve (AUC) of more than 70% in distinguishing IEE from GBM. The AUC was 0.85, 0.78, and 0.70, with sensitivity of 92.98%, 72.81%, and 96.49%, and specificity of 65.50%, 73.64%, and 43.41%, for F7, age, and F11, respectively. CONCLUSION: We identified specific MR imaging features such as tumor necrosis and thickness of enhancing tumor margins that could help to differentiate IEE from GBM. Our study results should be helpful to assist in diagnosis and clinical management of this rare brain tumor.

HABP2 Encapsulated by Peripheral Blood-Derived Exosomes Suppresses Astrocyte Autophagy to Exacerbate Neuroinflammatory Injury in Mice with Ischemic Stroke.

Exosomes are shown to be involved in the regulation of neuroinflammatory injury. The current study analyzed how peripheral blood-derived exosomes affected hyaluronan-binding protein 2 (HABP2) expression to regulate neuroinflammatory injury after ischemic stroke (IS). An IS animal model was stimulated by middle cerebral artery occlusion (MCAO), followed by injection of lentivirus. Peripheral blood samples were collected from MCAO mice after different treatments. The cerebral infarction volume, astrocyte activation, and neuroinflammation were observed by TTC staining, immunofluorescence, and ELISA, respectively. HABP2 was highly expressed in the brain tissues of MCAO mice. Also, an enhancement of HABP2 was noted in their peripheral blood-derived exosomes, while loss of HABP2 in peripheral blood-derived exosomes promoted the astrocyte autophagy and reduced the release of the inflammatory factors as well as the apoptosis of neuronal cells. PAR1 overexpression reversed the effect of HABP2 loss on autophagy and neuroinflammation in MCAO mice. Additionally, the agonist of the PI3K/AKT/mTOR pathway, SC79, could also reverse the effect of sh-PAR1 on neuroinflammation. Mechanistically, HABP2 enhanced PAR1 to activate the PI3K/AKT/mTOR pathway, thereby suppressing cell autophagy. Overall, HABP2 in peripheral blood-derived exosomes can activate the PAR1/PI3K/AKT/mTOR pathway to reduce autophagy and aggravate neuroinflammatory injury after IS.

Targeted Diagnosis, Therapeutic Monitoring, and Assessment of Atherosclerosis Based on Mesoporous Silica Nanoparticles Coated with cRGD-Platelets.

Objective: The off-target effects and severe side effects of PPARα and LXRα agonists greatly limit their application in atherosclerosis (AS). Therefore, this study intended to use mesoporous silica nanoparticles as carriers to generate MnO nanoparticles in situ with T1WI-MRI in mesoporous pores and simultaneously load PPARα and LXRα agonists. Afterward, cRGD-chelated platelet membranes can be used for coating to construct a new nanotheranostic agent. Methods: cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles were synthesized by a chemical method. Dynamic light scattering (DLS) was utilized to detect the size distribution and polydispersity index (PDI) of the nanoparticles. The safety of the nanoparticles was detected by CCK8 in vitro and HE staining and kidney function in vivo. Cell apoptosis was detected by flow cytometry detection and TUNEL staining. Oxidative stress responses (ROS, SOD, MDA, and NOX levels) were tested via a DCFH-DA assay and commercial kits. Immunofluorescence and phagocytosis experiments were used to detect the targeting of nanoparticles. Magnetic resonance imaging (MRI) was used to detect the imaging performance of cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles. Using western blotting, the expression changes in LXRα and ABCA1 were identified. Results: cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles were successfully established, with a particle size of approximately 150 nm and PDI less than 0.3, and showed high safety both in vitro and in vivo. cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles showed good targeting properties and better MRI imaging performance in AS. cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles showed better antioxidative capacities, MRI imaging performance, and diagnostic and therapeutic effects on AS by regulating the expression of LXRα and ABCA1. Conclusion: In the present study, cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles with high safety and the capacity to target vulnerable plaques of AS were successfully established. They showed better performance on MRI images and treatment effects on AS by promoting cholesterol efflux through the regulation of ABCA1. These findings might address the problems of off-target effects and side effects of nanoparticle-mediated drug delivery, which will enhance the efficiency of AS treatment and provide new ideas for the clinical treatment of AS.

miR-150-3p enhances neuroprotective effects of neural stem cell exosomes after hypoxic-ischemic brain injury by targeting CASP2.

Brains are vulnerable to ischemic/hypoxic damage, which are directly caused by stroke, hypoxic-ischemic encephalopathy and other cerebral diseases. Currently, therapeutic strategies against cerebral ischemia and hypoxia are extremely limited. Recent studies have indicated that stem cell-derived exosomes play a neuroprotective role in hypoxic-ischemic brain injury. However, the treatment mechanism remains unclear. In this study, we cultured neural stem cells (NSCs) in vitro successfully. Exosomes isolated from NSCs (NSCs-Ex) inhibited the apoptosis while promoting the proliferation of SH-SY5Y cells both in normal and oxygen-glucose deprivation (OGD) culture conditions. Moreover, in vivo studies demonstrated that NSCs-Ex significantly reduced the infarction area in the middle cerebral artery occlusion (MCAO) model and suppressed the apoptosis of neurons. Furthermore, miR-150-3p was identified as the most abundantly expressed miRNA in exosomes compared to their parent NSCs. The miR-150-3p mimic displayed neuroprotective effects while miR-150-3p inhibitor exacerbated nerve injury both in vivo and in vitro. We further identified CASP2 as a miR-150-3p target. Thus, our data indicate that NSC-Ex facilitate the neuroprotective effects via transfer of miR-150-3p which targets CASP2, thus suppressing neuronal apoptosis after brain injury. Our results suggest that NSCs-Ex prevent cerebral injury by transferring miR-150-3p which promotes neurons proliferation by inhibiting CASP2 signaling pathway.

Beclin­1 exerts protective effects against cerebral ischemia­reperfusion injury by promoting DNA damage repair through a non­autophagy­dependent regulatory mechanism.

Cerebral ischemia­reperfusion (I/R) can result in severe brain injury, for which there are no optimal treatment options. I/R is often accompanied by increased autophagy. Beclin­1, a central player in autophagy, has been extensively studied in I/R; however, to date, at least to the best of our knowledge, there are no definitive descriptions of its specific role. Thus, the aim of the present study was to explore the regulatory role played by Beclin­1 in I/R. In vivo experiments were performed using an animal model of brain I/R with male Sprague­Dawley rats. Brain tissue damage was observed using 2,3,5­triphenyltetrazolium chloride, and hematoxylin and eosin staining. Tissue apoptosis levels were evaluated using a TUNEL assay, as well as western blot analysis. Immunofluorescence together with western blot analysis was used to detect autophagy in the tissues. Immunohistochemistry and western blot analysis were used to analyze DNA double­stranded breaks (DSBs). Moreover, HT22 cells overexpressing Beclin­1 were subjected to oxygen glucose deprivation/reoxygenation injury to simulate I/R pathological damage in vitro. Apoptosis was assessed using TUNEL and flow cytometric assays in this in vitro model, and autophagy was assessed using immunofluorescence and western blot analysis. The DSBs of the cells were analyzed using western blot analysis. I/R activated autophagy and induced DSBs. Autophagy inhibitors decreased brain tissue damage and reduced cell apoptosis; however, the degree of decrease in damage and apoptosis was not highly associated with the change in autophagy, and the frequency of DSBs slightly increased. The overexpression of Beclin­1 in neurons significantly attenuated I/R­induced damage and promoted DSB repair. On the whole, the present study demonstrates that Beclin­1 protects neurons from ischemic damage through the non­autophagy­dependent regulation of DNA repair processes.

circ_PTN contributes to -cisplatin resistance in glioblastoma via PI3K/AKT signaling through the miR-542-3p/PIK3R3 pathway.

Glioblastoma has been identified as the most common and aggressive primary brain tumor in adults. Recently, it has been found that cisplatin (DDP) treatment is a common chemotherapeutic method for GBM patients. circ_PTN (ID number: hsa_circ_0003949) is a newly found circular (circRNA) which has been proved to be highly expressed in GBM cells, while its role in GBM remains unclear. Therefore, our study focused on investigating the role of circ_PTN in the DDP resistance of GBM cells. The expression of circ_PTN in DDP-sensitive and DDP-resistant GBM cells was detected in our assay. Functional experiments were utilized to unveil the effects of circ_PTN on the DDP resistance of GBM cells. Moreover, mechanism assays were conducted to confirm the mechanism of how circ_PTN affected the DDP resistance of GBM cells. According to the results, we found that circ_PTN promoted the DDP resistance of GBM cells through activation of the PI3K/AKT pathway. Moreover, circ_PTN silencing inhibited the DDP resistance of GBM tumors in vivo. To conclude, our study unveiled the influence of circ_PTN on the DDP resistance of GBM cells, which might provide a therapeutic target for GBM treatment via DDP.

New Enhancement beyond Radiation Field Improves Survival Prediction in Patients with Post-Treatment High-Grade Glioma.

The imaging signs which can accurately predict survival prognosis after standard treatment of high-grade glioma (HGG) are highly desirable. This study aims to explore the role of new enhancement beyond radiation field (NERF) in the survival prediction in patients with post-treatment HGG. The present study included 142 pathologically confirmed HGG patients who had received standard treatment. NERF, as well as other conventional MR findings and clinical variables, were included in univariate and multivariate analyses for evaluating their impactions on progression-free survival (PFS) and overall survival (OS). Univariate analysis showed that histological grade (p=0.008) and NERF (p=0.001) were the prognostic variables for poor PFS, whereas histological grade (p=0.017), NERF (p=0.001), and new subventricular zone enhancement (nSVZE) (p=0.001) were prognostic variables for poor OS. The multivariate analysis showed that NERF (HR 3.93; 95% CI 1.93-8.01; p=0.001) and nSVZE (HR 3.92; 95% CI 1.95-7.89; p=0.001) were the prognostic variables for poor OS. However, only nSVZE was (HR 3.29; 95% CI 2.04-5.28; p=0.001) the prognostic variable for poor PFS. When combining the NERF with the clinical and other MR variables, the highest AUC (0.924) and specificity (0.899) for predicting poor OS were achieved. The location of new developed enhancements relevant to high dose radiation field appears to be the main determinant of their prognostic value. Our results suggest that the new enhancement beyond radiation field can improve the survival prediction in patients with HGG after standard treatment.

Role of Dynamic Susceptibility Contrast Perfusion MRI in Glioma Progression Evaluation.

Accurately and quickly differentiating true progression from pseudoprogression in glioma patients is still a challenge. This study aims to explore if dynamic susceptibility contrast- (DSC-) MRI can improve the evaluation of glioma progression. We enrolled 65 glioma patients with suspected gadolinium-enhancing lesion. Longitudinal MRI follow-up (mean 590 days, range: 210-2670 days) or re-operation (n = 3) was used to confirm true progression (n = 51) and pseudoprogression (n = 14). We assessed the diagnostic performance of each MRI variable and the different combinations. Our results showed that the relative cerebral blood volume (rCBV) in the true progression group (1.094, 95%CI: 1.135-1.636) was significantly higher than that of the pseudoprogression group (0.541 ± 0.154) (p < 0.001). Among the 18 patients who had serial DSC-MRI, the rCBV of the progression group (0.480, 95%CI: 0.173-0.810) differed significantly from pseudoprogression (-0.083, 95%CI: -1.138-0.620) group (p=0.015). With an rCBV threshold of 0.743, the sensitivity and specificity for discriminating true progression from pseudoprogression were 76.5% and 92.9%, respectively. The Cho/Cr and Cho/NAA ratios of the true progression group (2.520, 95%CI: 2.331-2.773; 2.414 ± 0.665, respectively) were higher than those of the pseudoprogression group (1.719 ± 0.664; 1.499 ± 0.500, respectively) ((p=0.001), (p < 0.001), respectively). The areas under ROC curve (AUCs) of enhancement pattern, MRS, and DSC-MRI for the differentiation were 0.782, 0.881, and 0.912, respectively. Interestingly, when combined enhancement pattern, MRS, and DSC-MRI variables, the AUC was 0.965 and achieved sensitivity 90.2% and specificity 100.0%. Our results suggest that DSC-MRI can significantly improve the diagnostic performance for identifying glioma progression. DSC-MRI combined with conventional MRI may promptly distinguish true gliomas progression from pseudoprogression when the suspected gadolinium-enhancing lesion was found, without the need for a long-term follow-up.

circRNA circARNT2 Suppressed the Sensitivity of Hepatocellular Carcinoma Cells to Cisplatin by Targeting the miR-155-5p/PDK1 Axis.

Circular RNA (circRNA) is a novel subclass of noncoding-RNA molecules that participate in development and progression of a variety of human diseases via sponging microRNAs (miRNAs). Until now, the contributions of circRNAs in chemoresistance of hepatocellular carcinoma (HCC) remain largely unknown. In the present study, we aimed to investigate the role of circRNA in cisplatin resistance of HCC. We investigated the expression of circRNAs in 5 paired cisplatin-sensitive and cisplatin-resistant HCC tissues by microarray analysis. The qRT-PCR analysis was to investigate the expression pattern of circARNT2 in HCC patient tissues and cell lines. Then, the effects of circARNT2 on cisplatin resistance, cell proliferation, and apoptosis were assessed in HCC in vitro and in vivo. circARNT2 was significantly upregulated in HCC tissues and cell lines. Overexpression of circARNT2 in HCC was significantly correlated with aggressive characteristics and served as an independent risk factor for overall survival in patients with HCC. In vitro experiments showed that knockdown of circARNT2 inhibited cell proliferation and enhances the cisplatin sensitivity of HCC cells. Furthermore, circARNT2 facilitates HCC progression in vivo. We demonstrated that circARNT2 acts as a sponge for miR-155-5p and verified that PDK1 is a novel target of miR-155-5p. In summary, our study demonstrated that circARNT2 modulates cisplatin resistance through miR-155-5p/PDK1 pathway. Our findings indicated that circARNT2 may serve as a promising therapeutic target for overcoming cisplatin resistance for HCC.