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Context The phosphorylation of signal transducer and activator of transcription protein 3 (STAT3) is up-regulated in glioblastoma (GBM) cells and is regulated by protein tyrosine phosphatase receptor type M (PTPRM). Fibronectin-1 (FN1) is also reported to be up-regulated in GBM. Objective We explored the role of FN1-induced PTPRM methylation in GBM. Materials and methods The lentivirus particles of oe-PTPRM, sh-PTPRM, oe-FN1, sh-FN1, or their negative controls (NSCs) were transfected into GBM cells with or without stattic (0.5 μM, 24 h) or 5-aza (1 μM, 0, 2, 4 h) treatments. Methylation-specific PCR was performed to detect PTPRM methylation levels. Results PTPRM was down-regulated (0.373 ± 0.124- and 0.455 ± 0.109-fold), FN1 and p-STAT3 were up-regulated (p

Negative magnetoresistances (NMRs) have been widely observed in two-dimensional electron gases (2DEGs). However, their origins are under debate. Here, we report on NMRs in the 2DEG in AlGaN/GaN heterostructures, aiming to uncover their origins by utilizing electric field gating. We systematically measured the magnetoresistances in magnetic fields up to 12 T and at temperatures between 3 and 260 K and observed NMRs over a wide range of temperatures from 3 to 170 K, which become more pronounced with decreasing temperature. We conducted electric field gating experiments to correlate the occurrence of NMRs with the relationship between electron mobility and density. The latter is governed by defect scattering sources in the sample and can be theoretically modeled. Comparison of the measured electron mobility and electron density relationship with theory reveals that interface roughness scattering plays a crucial role in obtaining large NMRs. Our work demonstrates that electric field gating provides a means not only to tune the values of NMRs but also to uncover their mechanisms.

Treatments of glioblastoma (GBM) have not been very effective, largely due to the inefficiency of drugs in penetrating the blood brain barrier (BBB). In this study, we investigated the potential of exosome‐coated doxorubicin (DOX)‐loaded nanoparticles (ENPDOX) in BBB penetration, inducing immunogenic cell death (ICD) and promoting survival of GBM‐bearing mice. DOX‐loaded nanoparticles (NPDOX) were coated with exosomes prepared from mouse brain endothelial bEnd.3 cells. ENPDOX cellular uptake was examined. Penetration of ENPDOX through the BBB was tested in an in vitro transwell system and a GBM mouse model. The effects of ENPDOX in inducing apoptosis and ICD were assessed. Finally, the efficacy of ENPDOX in the treatment of GBM‐bearing mice was assessed. ENPDOX was taken up by bEnd.3 cells and could penetrate the BBB both in vitro and in vivo. In vitro, ENDDOX induced apoptosis and ICD of glioma GL261 cells. Systemic administration of ENPDOX resulted in maturation of dendritic cells, activation of cytotoxic cells, altered production of cytokines, suppressed proliferation and increased apoptosis of GBM cells in vivo and prolonged survival of GBM‐bearing mice. Our findings indicate that ENPDOX may be a potent therapeutic strategy for GBM which warrants further investigation in clinical application.

Glioma stem cell (GSC)-derived extracellular vesicles (EVs) can mediate the communication between GSCs and microglia. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression in GSCs, EVs, and supernatant was detected by real-time PCR. The direct targeting between MALAT1 and miR-129-5p, miR-129-5p, and HMGB1 were tested with luciferase reporter analysis. The expression and secretion of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α were determined in lipopolysaccharide-stimulated microglia or miR-129-5p inhibitor transferred to microglia exposed to GSC EVs or EVs derived from siMALAT1 pre-transferred GSCs. MALAT1 was enriched in GSC EVs compared with GSCs, and up-regulated MALAT1 was also observed in microglia upon GSC EVs incubation. The relative expression and secretion of IL-6, IL-8, and TNF-α in lipopolysaccharide-stimulated microglia were up-regulated in the GSC supernatant group, which could be reversed by dimethyl amiloride (DMA) (EV secretion inhibitor) co-administration or si-MALAT1 pre-transfection of GSCs. Luciferase reporter assay testified the direct binding of MALAT1 and miR-129-5p, miR-129-5p, and HMGB1, and si-MALAT1 could up-regulate miR-129-5p expression and down-regulate HMGB1 expression in microglia cells. The concentration of IL-6, IL-8, and TNF-α in lipopolysaccharide-stimulated microglia exposed to EVs from siMALAT1 transfected GSCs could be up-regulated by miR-129-5p inhibition. EVs lncRNA MALAT1 released from GSCs could modulate the inflammatory response of microglia after lipopolysaccharide stimulation through regulating the miR-129-5p/HMGB1 axis.

Background:Glioblastoma multiforme (GBM) is the most aggressive and deadly primary brain cancer that arises from astrocytes and classified as grade IV. Recently, exosomes have been reported as an essential mediator in diverse cancer carcinogenesis and metastasis. However, their role in GBM is still unclear. In this study, we aimed to investigate whether blood exosomes can be potential clinical diagnostic markers for GBM.Methods:We used a xenograft orthotopic mouse model to detect the differentially expressed genes in the brain and blood exosomes of original/recurrent GBM.Results:We found that recurrent GBM had stronger growth capacity and lethality than original GBM in the mouse model. A gene microarray of original tumors and blood exosomes from GBM orthotopic xenografts results showed that DNM3, p65 and CD117 expressions increased, whereas PTEN and p53 expressions decreased in both original tumors and blood exosomes. In the recurrent GBM tumor model, DNM3 and p65 showed increased expressions, whereas ST14 and p53 showed decreased expressions in tumor and blood exosomes of the recurrent GBM mouse model.Conclusion:In summary, we found that DNM3, p65 and p53 had a similar trend in brain and blood exosomes both for original and recurrent GBM, and could serve as potential clinical diagnostic markers for GBM.

MicroRNA is an important regulator of glioblastoma. This study aims at validating microRNA-221 (miR-221) as a biomarker for glioblastoma, and understanding how miR-221 regulates glioblastoma progression. Using clinical samples, miR-221 expression was analyzed by quantitative reverse-transcriptase PCR (qPCR). SHG-44 cells were treated with anti-miR-221 or U87MG-derived exosomes followed by monitoring changes in cell viability, migration and temozolomide (TMZ) resistance. Bioinformatics approach was used to identify targets of miR-221. The interaction between miR-221 and its target, DNM3 gene, was studied with dual-luciferase reporter assay, Spearman's correlation analysis, and western blotting. To verify that RELA regulates miR-221 expression, RELA-expressing vector or shRNA was introduced into SHG-44 cells and its effect on miR-221 expression was monitored. Both tissue-level and exosomal miR-221 expression increased with glioma grades. In SHG-44 cells, downregulating miR-221 expression inhibited cell proliferation, migration, and TMZ resistance, whereas incubation with U87MG-derived exosomes exerted tumor-promoting effects. DNM3 gene is a target of miR-221. RELA induced miR-221 expression. In glioma, elevated miR-221 expression is a biomarker for glioma. DNM3 is a target of miR-221 and RELA regulates miR-221 expression. The RELA/miR-221 axis is a target for glioma diagnosis and therapy.

To investigate the changes of protein kinase C (PKC) activity and its role in the development of presyrinx state in rabbits.Presyrinx state was established in 56 rabbits by intra-cisternal injection of kaolin. At 1, 3, 7, 14, and 21 days after the injection, the water content in the upper cervical spinal cord was measured, its pathological changes observed microscopically and the PKC activity determined with substrate phosphorolysis kinase assay.Spinal cord edema occurred in rabbits one day after kaolin injection, with water content of (68.35-/+0.70)%, which increased to (72.70-/+0.88)% on day 3, reaching the peak level of (72.92-/+0.86)% on day 7, followed by gradual decline after 3 weeks [(70.03-/+0.77)%]. The membrane PKC activity increased from 5.67-/+0.26 pmol.mg(-1).min(-1) on day 1 after the injection to reach the peak level on day 7 (13.27-/+3.15 pmol.mg(-1).min(-1)), which was maintained till day 14 with subsequent decrease to 8.85-/+1.56 pmol.mg(-1).min(-1) on day 21. The cytoplasmic PKC activity showed changes of a reverse pattern.In rabbits with experimental presyrinx state, PKC translocation and activation is involved in ischemic spinal edema.

In a double-well system, we investigate theoretically the population distribution of a particle perturbed by a weak sinusoidal signal with a Gaussian white noise accompanied. Our numerical simulation shows that the probability of the particle staying in the right potential well, PR, exhibits an extreme value at specific noise intensity D depending on the frequency of the sinusoidal signal, which is a key feature of stochastic resonance. This is confirmed by calculating the power spectrum of the output signal, in which the extreme value of the amplitude locates at the same noise intensity. These results provide us with a new way to quantify the stochastic resonance by measuring the population distribution of the particle.

We investigate the distribution of the switching current of a current-biased Josephson junction (CBJJ) and its dependence on the microwave frequency using two theoretical methods, one of which is the quantum trajectory method and the other is the master equation method. Both the methods show that the distribution of the switching current of CBJJ will exhibit double peaks in a certain range of microwave frequency if proper microwave power is given, and the gap between the two peaks will increase with the microwave frequency. The obtained results can be used to identify the energy difference of the ground and first excited states in a Josephson junction for any bias current.