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Glioblastoma (GBM) is the most common primary malignant brain tumour and lacks therapeutic options with significant effects. The aberrant activation of STAT3 is a critical factor in glioma progression via activating multiple signalling pathways that promote glioma. Among them, the antiapoptotic gene Bcl-2 could be upregulated by p-STAT3, which is an important reason for the continuous proliferation of glioma. We previously reported that bergaptol, a natural furanocoumarin widely found in citrus products, exerts antineuroinflammatory effects by inhibiting the overactivation of STAT3. Here, we aimed to evaluate whether bergaptol could promote glioma apoptosis by inhibiting the STAT3/Bcl-2 pathway. This study found that bergaptol inhibited the proliferation and migration of GBM cell lines (U87 and A172) and promoted apoptosis in vitro. We also found that bergaptol significantly inhibited the STAT3/Bcl-2 pathway in GBM cells. U87 cells were implanted intracranially into nude mice to establish a glioma model, and glioma-bearing mice were treated with bergaptol (40 mg/kg). Bergaptol treatment significantly inhibited glioma growth and prolonged the glioma-bearing mice's survival time. In addition, bergaptol administration also significantly inhibited the STAT3/Bcl-2 pathway of tumour tissue in vivo. Overall, we found that bergaptol could effectively play an antiglioma role by inhibiting STAT3/Bcl-2 pathway, suggesting the potential efficacy of bergaptol in treating glioma., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background Cerebral blood volume (CBV) maps derived from dynamic susceptibility contrast-enhanced (DSC) MRI are useful but not commonly available in clinical scenarios. Purpose To test image-to-image translation techniques for generating CBV maps from standard MRI sequences of brain tumors using the bookend technique DSC MRI as ground-truth references. Materials and Methods A total of 756 MRI examinations, including quantitative CBV maps produced from bookend DSC MRI, were included in this retrospective study. Two algorithms, the feature-consistency generative adversarial network (GAN) and three-dimensional encoder-decoder network with only mean absolute error loss, were trained to synthesize CBV maps. The performance of the two algorithms was evaluated quantitatively using the structural similarity index (SSIM) and qualitatively by two neuroradiologists using a four-point Likert scale. The clinical value of combining synthetic CBV maps and standard MRI scans of brain tumors was assessed in several clinical scenarios (tumor grading, prognosis prediction, differential diagnosis) using multicenter data sets (four external and one internal). Differences in diagnostic and predictive accuracy were tested using the z test. Results The three-dimensional encoder-decoder network with T1-weighted images, contrast-enhanced T1-weighted images, and apparent diffusion coefficient maps as the input achieved the highest synthetic performance (SSIM, 86.29% ± 4.30). The mean qualitative score of the synthesized CBV maps by neuroradiologists was 2.63. Combining synthetic CBV with standard MRI improved the accuracy of grading gliomas (standard MRI scans area under the receiver operating characteristic curve [AUC], 0.707; standard MRI scans with CBV maps AUC, 0.857; z = 15.17; P < .001), prediction of prognosis in gliomas (standard MRI scans AUC, 0.654; standard MRI scans with CBV maps AUC, 0.793; z = 9.62; P < .001), and differential diagnosis between tumor recurrence and treatment response in gliomas (standard MRI scans AUC, 0.778; standard MRI scans with CBV maps AUC, 0.853; z = 4.86; P < .001) and brain metastases (standard MRI scans AUC, 0.749; standard MRI scans with CBV maps AUC, 0.857; z = 6.13; P < .001). Conclusion GAN image-to-image translation techniques produced accurate synthetic CBV maps from standard MRI scans, which could be used for improving the clinical evaluation of brain tumors. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Branstetter in this issue.

Purpose: Glioma patients have varying degrees of psychiatric symptoms, which severely affect the quality of life of patients and their families. The present study investigated the correlation between preoperative psychiatric symptoms and local cerebral perfusion parameters of in glioma patients., Patients and Methods: The depression, anxiety, and cognitive impairment (CI) scores of 39 patients were assessed separately, and all of the patients underwent a preoperative perfusion computed tomography scan., Results: This study found that: (1) The incidence of preoperative symptoms of depression, anxiety, and CI was 46.15%, 48.72%, and 25.64%, respectively. (2) Cerebral blood volume (CBV) (lesion-sided [LS] occipital lobe white matter [WM] and parietal lobe WM and normal-sided temporal lobe WM), permeability surface (PS) (LS temporal lobe gray matter [GM] and parietal lobe WM) in the depression group were significantly decreased (p < .05). (3) CBV (LS occipital lobe WM), cerebral blood flow (LS parietal lobe GM, centrum ovale and frontal lobe WM and normal-sided frontal lobe WM, temporal lobe WM and parietal lobe WM), and mean transition time (MTT) (normal-sided frontal lobe WM and temporal lobe WM) in the anxiety group were significantly increased (p < .05). (4) CBV (LS temporal lobe GM), MTT (LS anterior limb of internal capsule), and PS (LS thalamus) in the CI group were significantly increased (p < .05)., Conclusion: This study showed that glioma patients had different levels of psychological distress in glioma patients before surgery, which may be related to the changes in brain perfusion caused by the tumor., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Over the past few decades, clinicians and experts applied kinds of therapies for patients with malignant gliomas such as chemotherapy, radiation or surgical extraction. However, they used to ignore the real seriousness of neuropsychiatric symptoms after glioma, including cognitive dysfunction, anxiety, and depression, which severely impeded patients' recovery and prognosis. Interestingly, one of our previous clinical studies have found some behavioral symptoms in glioma patients were associated with systemic inflammation. Notopterol is one of the principal extracts of the traditional Chinese medicinal herb Notopterygium incisum having anti-tumour and anti-inflammatory activity. However, whether notopterol is beneficial to the treatment of glioma has not been reported. In this study, we found that notopterol inhibited growth and increased apoptosis of glioma via inhibiting STAT3 activity. In addition, notopterol treatment improved cognitive impairment and depression-like behavior in GL261 cell-based glioma mice via preventing the loss of dendritic spines and the reduction of synapse related proteins (PSD95 and Synapsin-1) in hippocampal neurons. Notopterol significantly reduced the levels of cytokines (iNOS, TNF-α, IL-6, and IL-β) and the activity of STAT3/NF-kB signalling pathway in peritumoural brain tissues and GL261 conditioned medium (GCM) treated microglial cell line (BV2 cells). These results demonstrated that notopterol not only exerted anti-glioma effects via inhibiting STAT3 activity, but improved neuropsychiatric symptoms via inhibiting tumour associated inflammation through modulation of the STAT3/NF-kB pathway in glioma-bearing mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Glioma has a high incidence in young and middle-aged adults and a poor prognosis. Because of late diagnosis and uncontrollable recurrence of the primary tumor after failure of existing treatments, glioma patients tend to have a poor prognosis. Recent advances in research have revealed that gliomas exhibit unique genetic features. Mitogen-activated protein kinase 9 (MAPK9) is significantly upregulated in mesenchymal glioma spheres and may be a new target for glioma diagnosis. This study aimed to investigate the potential diagnostic significance and predictive value of MAPK9 in glioma., Methods: Paraffin-embedded tumor tissues and paracancerous tissues were collected from 150 glioma patients seen at the General Hospital of Northern Theater Command. Immunohistochemistry and western blot assays were used to detect the expression levels of MAPK9. Prognosis and survival analyses were performed using SPSS 26 software for univariate/multivariate analysis and log-rank analysis. Cellular models were used to assess the effect of MAPK9 overexpression and knockdown in vitro ., Results: MAPK9 expression was higher in glioma tissues than in paraneoplastic tissues. Prognostic and survival analyses revealed that the MAPK9 expression level is an independent prognostic factor in glioma patients. In addition, overexpression of MAPK9 significantly promoted the proliferation and migration of primary glioma cells, possibly via the Wnt/β-catenin-regulated EMT pathway., Conclusions: MAPK9 is an independent prognostic factor in glioma and is involved in tumor progression., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Purpose: Tumor immunotherapy has the advantages of high specificity, minimal damage to the patient's body, and a long-lasting anti-tumor effect. However, due to the existence of immune escape phenomenon, the effect of anti-tumor immunotherapy is still poor. Therefore, a cancer vaccine that reverses tumor-associated immunosuppression is a very promising approach for research and treatment., Methods: Vaccines were prepared using autologous and allogeneic tumor cells and their lysates to syngeneic tumor cell lysates as immunogens. The glioma cell proliferation, apoptosis and the secretion level of MCP-2, IFN-γ were detected to evaluate the efficacy of this treatment against glioma in vitro. In addition, a rat glioma model was established to investigate the anti-tumor effect in vivo, and evaluated its efficacy by observing the changes of CD4 + T cells, CD8 + T cells, NK cells, and the level of IL-2 and IL-10 in peripheral blood before and after treatment., Results: The C6 + 9L glioma cell lysate vaccine (C6 + 9L-CL) not only inhibited the proliferation of glioma cells and promoted their apoptosis in vitro, but also significantly inhibited the tumor growth in vivo and improved the survival time of rats. In addition, the C6 + 9L-CL vaccine enhanced the anti-tumor immune response by promoting the secretion of T cell chemokines MCP-2, IFN-γ and IL-2, and by stimulating the proliferation of T cells and NK cells in peripheral blood and glioma tissues., Conclusion: Our findings demonstrate the inhibitory effect of molecular mimic vaccines on glioma and provided a theoretical basis for molecular mimic hybrid vaccines as a potential therapeutic approach., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: PRKCH is a member of the PKC family with the potential to regulate cell proliferation and differentiation. Glioma is the most common primary tumor of the central nervous system, with a high recurrence rate and poor prognosis. Recent studies have demonstrated that PRKCH can promote the proliferation of glioma cells. The purpose of this study was to investigate the promoting effect and possible mechanism of PRKCH on glioma development., Methods: Tumor tissue and paracancerous tissue were collected from 160 glioma patients treated at the General Hospital of Northern Theater Command. The expression level of PRKCH was detected by immunohistochemistry and immunoblotting. Univariate/multivariate analysis and log-rank analysis, as well as prognosis and survival analysis, were performed using SPSS26 software. The PRKCH overexpression model was constructed in vitro to study the effect of PRKCH expression on the characteristics of glioma stem cells., Results: The expression of PRKCH in glioma tissues was higher than that in adjacent tissues. PRKCH expression level is an independent prognostic factor in glioma patients, promoting poor prognosis and shorter survival in glioma patients. Furthermore, overexpression of PRKCH in glioma stem cells significantly increased stem cell properties and enhanced cell viability. Downregulation of PRKCH significantly inhibited the progression of glioma stem cells., Conclusion: PRKCH promotes the development of gliomas and may be a therapeutic target for gliomas., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: To fully understand the clinical features and prognosis of Glioblastoma (GBM), we extracted the data from the Surveillance, Epidemiology, and End Results (SEER) database and performed a series of analyses., Methods: We retrospectively analyzed the data of 1674 patients with GBM obtained from the SEER database from 1983 to 2015. Kaplan-Meier analysis was performed to calculate the survival rate, and the log-rank test was used to analyze the survival outcomes., Results: Older patients with GBM had a worse survival period (P < .05). Laterality had no effect on the prognosis (P > .05). Patients with high-grade gliomas may have a shorter lifespan (P < .05). In terms of overall survival (OS) and disease specificity, all 3 classical treatments failed to improve the life expectancy (P > .05). In adult patients with GBM, we found that age, tumor grade, surgery, radiotherapy, and chemotherapy were independent risk factors for all-cause mortality. In the univariate disease-specific analysis, age, tumor grade, surgery, radiotherapy, and chemotherapy were independent risk factors. However, in multivariate disease-specific analysis, the results showed that only tumor grade and surgery were independent risk factors for GBM., Conclusions: Older patients diagnosed with GBM have worse survival, and patients with glioma of higher grades have a shorter lifespan. Age, grade, surgery, radiation therapy, and chemotherapy were independent prognostic factors for patients with GBM., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Mutations in the human protein patched homolog (PTCH) gene have been demonstrated to be associated with cancer development in several types of malignancy. However, the underlying mechanism of PTCH-associated cancer development remains poorly understood, to the best of our knowledge. In the present study, the expression of PTCH2 in glioma tumor tissues from The Cancer Genome Atlas (TCGA) database and clinical patients with glioma were measured. Reduced expression levels of PTCH2 were observed in patients with glioma with poor prognose. In vitro, overexpression of PTCH2 significantly suppressed the proliferation and invasion of the glioma cell lines, LN229 and U87-MG. Mechanistically, PTCH2 upregulated the expression of tumor suppressor PTEN, thereby leading to the suppression of pro-survival AKT signals in glioma. Reduced expression of PTEN and enhanced expression of AKT promoted glioma development in vitro and in vivo. Blockade of PTCH2/AKT signals efficiently strengthened the anticancer effects of chemotherapy and prolonged the survival time in tumor-bearing mice, which provided a novel insight into potential treatment strategies for glioma in the clinic., Competing Interests: Declaration of competing interest The authors declare that there are no competing interests associated with the manuscript., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The current study aimed to investigate the effects associated with SNAI2 on the proliferation of glioma stem cells (GSCs) to elucidate its underlying molecular mechanism in the development of glioma. The expression of Snail family transcriptional repressor 2 (SNAI2) in glioma tissues was initially predicted via bioinformatics analysis and subsequently confirmed by reverse transcription quantitative polymerase chain reaction (RT-qPCR), which revealed that SNAI2 was highly expressed in glioma tissues as well as GSCs, with an inverse correlation with overall glioma patient survival detected. Loss- and gain- of-function assays were performed to determine the roles of SNAI2 and pleckstrin homology domain and leucine rich repeat protein phosphatase 2 (PHLPP2) on GSC viability, proliferation and apoptosis. Data were obtained indicating that SNAI2 promoted the proliferation of GSCs, while overexpressed PHLPP2 brought about a contrasting trend. As detected by chromatin immunoprecipitation, RT-qPCR and agarose gel electrophoresis, SNAI2 bound to the promoter region of PHLPP2 and repressed the transcription of PHLPP2 while SNAI2 was found to inhibit PHLPP2 resulting in activation of the Akt pathway. Finally, the roles of SNAI2 and PHLPP2 were verified in glioma growth in nude mice xenografted with tumor. Taken together, the key findings of the present study suggest that SNAI2 may promote the proliferation of GSCs through activation of the Akt pathway by downregulating PHLPP2., (© 2022. The Author(s).)

In this article, we have compared and analyzed the clinical effects of temozolomide single agent and combined doxorubicin in the treatment of glioma. To evaluate this, a total of 70 patients diagnosed with glioma in our hospital from July 2019 to July 2020 were randomly divided into two groups, the observation group and the control group, with 35 patients in each group. The control group received temozolomide capsules orally. The observation group was treated with temozolomide single agent and doxorubicin. After treatment, the clinical efficacy, adverse reactions, and KPS score of the two groups were observed. After treatment, the total response rate of the control group was 31.43%, and the total response rate of the observation group was 62.86%. The difference between the two groups was statistically significant ( P < 0.05). Before treatment, there was no significant difference in KPS scores between the two groups ( P > 0.05). After treatment, the KPS scores of both groups were improved, and the KPS scores of the observation group and the control group were significantly better, with statistical significance ( P < 0.05). In the observation group, 17 cases had adverse reactions, including 10 cases of nausea and vomiting, 2 cases of leucopenia, and 5 cases of thrombocytopenia, with a total incidence of 48.57%. In the control group, there were 31 cases of adverse reactions, including 22 cases of nausea and vomiting, 6 cases of leucopenia, and 4 cases of thrombocytopenia, with a total incidence of 91.43%. The difference between the two groups was statistically significant ( P < 0.05). The efficacy of temozolomide single agent and combined doxorubicin in the treatment of glioma was significant. Moreover, it can significantly improve clinical efficacy, reduce the incidence of adverse reactions, and improve the health status of patients, which is worthy of further clinical application., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Yibo Liu and Ligang Chen.)

Objective: To explore the relationship between preoperative psychological personality traits of glioma patients and preoperative psychological distress of their primary caregivers., Methods: A retrospective analysis was conducted on 85 glioma patients (tumor group) who were admitted to our hospital from February 2016 to December 2018 and 85 primary caregivers. Forty-one healthy volunteers were used as controls., Results: The scores of 9 scales of the Minnesota Multiphasic Personality Inventory (MMPI) increased significantly in the tumor group compared to the healthy controls (P < 0.05), including L (lie): [(56.0 ± 11.5 vs. 50.0 ± 10.0)], F (fake): [(53.0 ± 10.6 vs. 41.7 ± 8.8)], Hs (hypochondriasis): [(55.6 ± 11.2 vs. 44.2 ± 8.3)], D (depressive personality): [(49.2 ± 9.6 vs. 42.2 ± 10.3)], Mf (masculinity-femininity): [(49.9 ± 9.4 vs. 42.8 ± 14.0)], Pt (psychasthenia): [(51.5 ± 10.0 vs. 40.9 ± 11.5)], Sc (schizophrenia): [(51.2 ± 10.6 vs. 40.2 ± 10.6)], Ma (hypomania): [(51.8 ± 9.1 vs. 47.7 ± 9.4)] and Si (social introversion): [(46.6 ± 8.7 vs. 36.7 ± 13.0)]. However, the K (defensive responses) scale score in the tumor group decreased significantly (52.1 ± 13.9 vs. 58.8 ± 12.1, P = 0.009). The F (fake): [(r s =0.253, P=0.019 / r s =0.215, P=0.048)], Hs (hypochondriasis): [(r s =0.310, P=0.004 / r s =0.345, P=0.001)], Pt (psychasthenia): [(r s =0.299, P=0.006 / r s =0.258, P=0.017)], and Sc (schizophrenia): [(r s =0.325,P=0.002/r s =0.322, P=0.003)] of preoperative glioma patients were positively correlated with their preoperative psychological distress (depression/anxiety); the D (depressive personality): [(r s =0.229, P=0.035)] of preoperative glioma patients was positively correlated with the preoperative depression symptoms of their primary caregivers, and the Hy (hysteria): [(r s =0.233, P=0.002)] and Pd (psychopathic deviate): [(r s =0.215, P=0.006)] of preoperative glioma patients were positively correlated with the preoperative anxiety symptoms of their primary caregivers., Conclusions: The preoperative psychological personality traits of glioma patients were positively correlated with preoperative symptoms of depression and anxiety in primary caregivers., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Long non-coding RNAs (lncRNAs) have been manifested to manipulate diverse biological processes, including tumor-induced immune tolerance. Thus, we aimed in this study to identify the expression pattern of lncRNA homeobox A cluster antisense RNA 2 (HOXA-AS2) in glioma and decipher its role in immune tolerance and glioma progression. We found aberrant upregulation of lncRNA HOXA-AS2, lysine demethylase 2A (KDM2A), and jagged 1 (JAG1) and a downregulation of microRNA-302a (miR-302a) in glioma specimens. Next, RNA immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter gene assay demonstrated that lncRNA HOXA-AS2 upregulated KDM2A expression by preventing miR-302a from binding to its 3'untranslated region. The functional experiments suggested that lncRNA HOXA-AS2 could promote regulatory T (T reg ) cell proliferation and immune tolerance, which might be achieved through inhibition of miR-302a and activation of KDM2A/JAG1 axis. These findings were validated in a tumor xenograft mouse model. To conclude, lncRNA HOXA-AS2 facilitates KDM2A/JAG1 expression to promote T reg cell proliferation and immune tolerance in glioma by binding to miR-302a. These findings may aid in the development of novel antitumor targets., (© 2022. The Author(s).)

Background: The aim of this study was to investigate the relationship between tumor biology and values of cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), time to peak (TTP), permeability surface (PS) of tumor in patients with glioma., Methods: Forty-six patients with glioma were involved in the study. Histopathologic and molecular pathology diagnoses were obtained by tumor resection, and all patients accepted perfusion computed tomography (PCT) before operation. Regions of interests were placed manually at tumor and contralateral normal-appearing thalamus. The parameters of tumor were divided by those of contralateral normal-appearing thalamus to normalize at tumor (relative [r] CBV, rCBF, rMTT, rTTP, rPS). The relationships of the parameters, world health organization (WHO) grade, molecular pathological findings were analysed., Results: The rCBV, rMTT and rPS of patients are positively related to the pathological classification (P < 0.05). The values of rCBV and rPS in IDH mutated patients were lower than those IDH wild-type. The values of rCBF in patients with MGMT methylation were lower than those MGMT unmethylation (P < 0.05). The MVD of TERT wild-type group was lower than TERT mutated group (P < 0.05). The values of rCBV were significant difference in the four molecular groups divided by the combined IDH/TERT classification (P < 0.05). The progression free survival (PFS) and overall survival (OS) were significant difference in the four molecular groups divided by the combined IDH/TERT classification (P < 0.05)., Conclusions: Our study introduces and supports the changes of glioma flow perfusion may be closely related to its biological characteristics., (© 2021. The Author(s).)

Glioma is regarded as an aggressive lethal primary brain tumor. Jumonji domain containing 1C (JMJD1C) is a H3K9 demethylase which participates in the progression of various tumors, but its specific function and underlying mechanism in glioma development remain undefined, which is the purpose of our work. We initially assessed JMJD1C expression in glioma tissues and cells using the assays of RT-qPCR and immunohistochemistry. Meanwhile, the H3K9 level at the microRNA (miR)-302a promoter region was measured by chromatin immunoprecipitation assay, while luciferase-based reporter assay was performed for validation of the binding affinity between miR-302a and methyltransferase-like 3 (METTL3). The effect of METTL3 on suppressor of cytokine signaling 2 (SOCS2) was subsequently analyzed by MeRIP-RT-qPCR. Finally, a xenograft tumor model was established in nude mice, followed by measurement of tumor-associated macrophages using flow cytometry. JMJD1C was poorly expressed in glioma tissues. Furthermore, JMJD1C increased miR-302a expression through promoting H3K9me1 demethylation at the miR-302a promoter region. miR-302a was identified to target METTL3, which could inhibit SOCS2 expression via m6A modification. JMJD1C promoted M1 macrophage polarization and suppressed the growth of glioma xenografts through the miR-302a/METTL3/SOCS2 axis both in vivo and in vitro. In conclusion, JMJD1C could enhance M1 macrophage polarization to inhibit the onset of glioma, bringing a new insight into the contribution of JMJD1C to the pathobiology of glioma, with possible implications for targeted therapeutic method., (© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Matrix stiffness is a key physical characteristic of the tumor microenvironment and correlates tightly with tumor progression. Here, we explored the association between matrix stiffness and glioma development. Using atomic force microscopy, we observed higher matrix stiffness in highly malignant glioma tissues than in low-grade/innocent tissues. In vitro and in vivo analyses revealed that culturing glioma cells on stiff polyacrylamide hydrogels enhanced their proliferation, tumorigenesis and CD133 expression. Greater matrix stiffness could obviously up-regulated the expression of BCL9L, thereby promoting the activation of Wnt/β-catenin signaling and ultimately increasing the stemness of glioma cells. Inhibiting Wnt/β-catenin signaling using gigantol consistently improved the anticancer effects of chemotherapy and radiotherapy in mice with subcutaneous glioma tumors. These findings demonstrate that a stiffer matrix increases the stemness of glioma cells by activating BCL9L/Wnt/β-catenin signaling. Moreover, we have provided a potential strategy for clinical glioma treatment by demonstrating that gigantol can improve the effectiveness of traditional chemotherapy/radiotherapy by suppressing Wnt/β-catenin signaling.

Cancer development is a complex set of proliferative progression, which arises in most cases via multistep pathways associated with various factors, including the tumor microenvironment and extracellular matrix. However, the underlying mechanisms of cancer development remain unclear and this study aimed to explore the role of extracellular matrix in glioma progression. Methods: The expression of type I collagen and fibronectin in tumor tissues from glioma patients was examined by immunofluorescence staining. The correlations between collagen/fibronectin and glioma progression were then analyzed. A 3D collagen/fibronectin cultured system was established for tumor cells culture in vitro . Quantitative, real-time PCR and western blot were used to detect PI3K/ATK and CDC42 signals associated proteins expression in glioma. We used in vitro Cell Counting Kit-8, colony formation, and tumorigenesis assays to investigate the function of PI3K/AKT and CDC42 signals associated proteins. A xenograft glioma mice model was also used to study the anticancer effects of integrin inhibitor in vivo . Results: Our study demonstrated that type I collagen and fibronectin collaborate to regulate glioma cell stemness and tumor growth. In a 3D collagen/fibronectin culture model, glioma cells acquired tumorigenic potential and revealed strengthened proliferative characteristics. More significantly, collagen/fibronectin could facilitate the activation of PI3K/AKT/SOX2 and CDC42/YAP-1/NUPR1/Nestin signaling pathways via integrin αvβ3, eliciting sustained tumor growth and cancer relapse. Combination of the integrin signaling pathway inhibitor and the chemotherapeutic agent efficiently suppressed glioma cell proliferation and tumorigenic ability. Conclusion: We demonstrated that type I collagen and fibronectin could collaborate to promote glioma progression through PI3K/AKT/SOX2 and CDC42/YAP-1/NUPR1/Nestin signaling pathways. Blockade of the upstream molecular integrin αvβ3 revealed improved outcome in glioma therapy, which provide new insights for eradicating tumors and reducing glioma cancer relapse., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: Behavioral symptoms, including depression, anxiety, and cognitive impairment, are common clinical symptoms of patients with glioma. However, the mechanisms underlying the behavioral symptoms of glioma patients remain unclear. In this study, we explore the correlation between markers of systemic inflammation and preoperational behavioral symptoms in glioma patients., Patients and Methods: Patients (n = 71) who had recently undertaken imaging (i.e., CT, MRI) for suspected glioma had a face-to-face interview, completed self-report scales, and provided blood samples. Furthermore, we tested blood samples by a protein chip to select differential inflammatory cytokines and further confirm such differences using liquid-phase chip technology., Results: The prevalence of depression, anxiety, and cognitive impairment in glioma patients prior to surgery in this study was 53.5%, 70.4%, and 32.4%, respectively. The increased levels of IFN-γ were positively correlated with clinical symptoms of depression in the glioma patients. Moreover, increased IL-2 levels were negatively associated with anxiety symptoms (p = .00) and positively correlated with cognitive impairment in glioma patients., Conclusion: This study suggests that systemic inflammation is associated with behavioral symptoms in glioma patients. This provides further evidence of the contribution of inflammatory markers to psychological symptoms in the context of physical conditions and lays the foundation for the development of further treatments of the behavioral symptoms in glioma patients., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Glioma is the most common and fatal brain tumour and has a poor prognosis. Ribosomal S6 protein kinase 4 (RSK4) has been found to be involved in multiple tumour types; however, the role of RSK4 in gliomas and its clinical relevance remain unclear. In the present study, RSK4 expression was found to be significantly increased in glioma tissues compared with matched adjunct non-noncancerous tissues. Moreover, the expression of RSK4 was significantly higher in high-grade (III and IV) glioma tissues than in low-grade (I and II) glioma tissues. The data showed that the expression of RSK4 was significantly correlated with WHO grade, three-year survival rate and five-year survival rate. Kaplan-Meier analyses showed that patients with high RSK4 expression had poor overall survival. In addition, multivariate Cox regression analysis showed that RSK4 might be an independent prognostic factor in glioma patients. Collectively, these results suggest that RSK4 may be a new prognostic factor in glioma patients, and RSK4 is expected to be a potential biomarker and a potential target for glioma therapy., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Over the past decade, increasing researches have demonstrated the implication of microRNAs (miRNAs or miRs) in tumorigenicity of glioma stem cells (GSCs). The regulatory functions of miRNAs in GSCs have emerged as potential therapeutic candidates for glioma treatment. Herein, we aim to investigate the role of miR-30a in the proliferation and self-renewal of GSCs and the possible mechanism in relation to ecto-5'-nucleotidase (NT5E)-dependent Akt signaling pathway. RT-qPCR and Western blot analysis were performed to determine the expression of miR-30a and NT5E in glioma tissues and cell lines. GSCs were isolated from glioma cells and identified using flow cytometry. The relationship between miR-30a and NT5E was determined by dual-luciferase reporter gene assay. Gain- and loss-of-function experiments were performed to examine the effects of miR-30a and NT5E on sphere formation, colony formation, and proliferation of GSCs in vitro, as well as orthotopic tumor growth of GSCs in nude mice. Additionally, the Akt signaling pathway was blocked with an Akt inhibitor, LY294002, to investigate its involvement in the regulatory effect of miR30a. miR-30a was poorly expressed in glioma tissues and cell lines as well as GSCs. NT5E, highly expressed in GSCs, was identified as a target of miR-30a. In addition, miR-30a upregulation or NT5E silencing could reduce GSC sphere formation, clone formation, proliferation, and orthotopic tumor growth in nude mice. Moreover, miR-30a inhibited the activation of the Akt signaling pathway by targeting NT5E, and ultimately suppressing the self-renewal and orthotopic tumor growth of GSCs. Our results demonstrate that miR-30a targets NT5E to inhibit the Akt signaling pathway, by which could suppress the self-renewal and orthotopic tumor growth of GSCs. Those findings may provide theoretical basis of miR-30a as a therapeutic target to suppress the glioma progression., (© 2020 Federation of American Societies for Experimental Biology.)

Purpose: This study investigated the underlying mechanism of LIM and SH3 protein 1 (LASP1)-induced malignant glioma growth and invasion., Materials and Methods: We compared the expression of LASP1 in malignant glioma tumor tissues and low-grade glioma tissues by immunohistochemistry. We also compared LASP1 overexpression and LASP1 knockout glioma cell proliferation and invasion in vitro and in vivo. We detected activation of the PI3K/AKT signaling pathway and epithelial-mesenchymal transition (EMT) process in tumor cells by western blotting or immunofluorescence. Glioma-bearing mice were used to investigate the anticancer effects of PI3K/AKT inhibitors in combination with temozolomide., Results: We observed the enhanced expression of LASP1 in malignant glioma tumor tissues compared to low-grade glioma tissues, and LASP1 overexpression in glioma cells revealed an elevated capability of proliferation and invasion in vitro and in vivo. LASP1 overexpression also facilitated PI3K/AKT signaling and the EMT process through the downstream transcription factor Snail, which resulted in the intensive invasion of cancer cells. We combined PI3K/AKT inhibitors and temozolomide to block the LASP1/PI3K/AKT/Snail signaling pathway, which dramatically enhanced tumor suppression and provides an innovative approach for clinical glioma treatment., Conclusion: LASP1 is upregulated in malignant glioma and facilitates glioma cell proliferation and invasion by activation the PI3K/AKT/Snail signaling pathway. Blockade of the PI3K/AKT signal efficiently enhanced the anticancer effects of chemotherapeutic agents, which provides an innovative target in glioma treatment., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Glioblastoma multiforme (GBM), a highly malignant brain tumor, accounts for half of all gliomas. Despite surgery, radiation and chemotherapy, the median survival is between 12 and 15 months. The poor prognosis is due to tumor recurrence attributed to chemoresistant glioma cancer stem cells (GSCs). Here we examined the effects of a novel compound NEO212, which is composed of two covalently conjugated anti-cancer compounds - temozolomide (TMZ) and perillyl alcohol (POH), on GSCs expressing either the proneural or mesenchymal gene signatures. These GSCs were obtained from patient-derived tumor tissue. Our findings demonstrate that NEO212 is 10 fold more cytotoxic to GSCs than TMZ (standard-of-care). Furthermore, NEO212 is effective against both proneural and clinically aggressive mesenchymal GSC subtypes. The mechanism of NEO212 mediated-cytotoxicity is through double-strand DNA breaks and apoptosis. In vivo studies show that NEO212 significantly delays tumor growth of both proneural and mesenchymal tumor stem cell populations. Patient-derived GSCs and tumors derived from these cells are highly reflective of the heterogeneity in human GBM. The efficacy of NEO212 against both GSC subtypes indicates that NEO212 has great clinical potential to effectively target GBM., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Gliomas are the most prevalent form of primary malignant brain tumor, which currently have no effective treatments. Evidence from human studies has indicated that oral microbiota is closely related to cancers; however, whether oral microbiota plays a role in glioma malignancy remains unclear. The present study aimed to investigate the association between oral microbiota and grade of glioma and examine the relationship between malignancy-related oral microbial features and the isocitrate dehydrogenase 1 (IDH1) mutation in glioma. High-grade glioma (HGG; n =23) patients, low-grade glioma (LGG; n =12) patients, and healthy control (HCs; n =24) participants were recruited for this case-control study. Saliva samples were collected and analyzed for 16S ribosomal RNA (rRNA) sequencing. We found that the shift in oral microbiota β-diversity was associated with high-grade glioma (p =0.01). The phylum Patescibacteria was inversely associated with glioma grade (LGG and HC: p =0.035; HGG and HC: p <0.01). The genera Capnocytophaga (LGG and HC: p =0.043; HGG and HC: p <0.01) and Leptotrichia (LGG and HC: p =0.044; HGG and HC: p <0.01) were inversely associated with glioma grades. The genera Bergeyella and Capnocytophaga were significantly more positively correlated with the IDH1 mutation in gliomas when compared with the IDH1-wild-type group. We further identified five oral microbial features (Capnocytophaga Porphyromonas , Haemophilus , Leptotrichia , and TM7x) that accurately discriminated HGG from LGG (area under the curve [AUC]: 0.63, 95% confidence interval [CI]: 0.44–0.83) and HCs (AUC: 0.79, 95% CI: 0.68–0.92). The functional prediction analysis of oral bacterial communities showed that genes involved in cell adhesion molecules (p <0.001), extracellular matrix molecule-receptor interaction (p <0.001), focal adhesion (p <0.001), and regulation of actin cytoskeleton (p <0.001) were associated with glioma grades, and some microbial gene functions involving lipid metabolism and the adenosine 5'-monophosphate-activated protein kinase signaling pathway were significantly more enriched in IDH1 mutant gliomas than compared with the IDH1-wild-type gliomas. In conclusion, our work revealed oral microbiota features and gene functions that were associated with glioma malignancy and the IDH1 mutation in glioma. [ABSTRACT FROM AUTHOR]

Purpose: Tumors derived from the neuroepithelium are collectively termed gliomas and are the most common malignant primary brain tumor. Epilepsy is a common clinical symptom in patients with glioma, which can impair neurocognitive function and quality of life. Currently, the pathogenesis of glioma-related epilepsy is not fully described. Therefore, it is necessary to further understand the mechanism of seizures in patients with glioma. In this study, a comprehensive meta-analysis was conducted to investigate the relationship between five commonly used tumor molecular markers and the incidence of perioperative epilepsy in patients with glioma. Methods: PubMed, EMBASE, and Cochrane Library databases were searched for related research studies. Odds ratio and the corresponding 95% confidence interval were used as the main indicators to evaluate the correlation between tumor molecular markers and the incidence of perioperative epilepsy in patients with glioma. Results: A total of 12 studies were included in this meta-analysis. The results showed that isocitrate dehydrogenase 1 (IDH1) mutation was significantly correlated with the incidence of perioperative epilepsy. A subgroup analysis showed that IDH1 was significantly correlated with the incidence of preoperative epilepsy, but not with intraoperative and postoperative epilepsy. There was no correlation between O6-methylguanine-DNA methyltransferase methylation and 1p/19q deletion and the incidence of perioperative epilepsy. Tumor protein p53 and epidermal growth factor receptor could not be analyzed because of the limited availability of relevant literature. There was no significant heterogeneity or publication bias observed among the included studies. Conclusion: The present meta-analysis confirms the relationship between tumor molecular markers and the incidence of perioperative epilepsy in patients with glioma. The present results provide more comprehensive evidence for the study of the pathogenesis of glioma-related epilepsy. Our research may offer a new method for the treatment of perioperative seizures in patients with glioma. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to explore the potential role of B7-H3 in malignant glioma progression and identify an innovative approach in clinical glioma therapy. Methods: The protein expression of B7-H3 in high- and low-grade tumor tissues from glioma patients was assessed by immunohistochemistry. The proliferative and invasive ability of B7-H3-overexpressing or knockout glioma cells was analyzed in vitro and in vivo by CCK-8 assay and an orthotopic mouse glioma model, respectively. Activation of the JAK2/STAT3/Slug signaling pathway and epithelial–mesenchymal transition (EMT) was examined by Western blotting and immunofluorescence. The anticancer effects of napabucasin (NAP) and temozolomide (TMZ) were analyzed in an orthotopic mouse glioma model. Results: The expression of B7-H3 was higher in high-grade than in low-grade tumor tissues from glioma patients. In line with this, overexpression of B7-H3 enhanced glioma cell proliferation, induced sustained glioma growth, and promoted glioma cell invasion in vitro and in vivo. Moreover, these effects were mediated through the activation of the JAK2/STAT3/Slug signaling pathway in B7-H3 overexpression glioma cells. We also found that B7-H3 induced EMT processes through downregulation of E-cadherin and upregulation of MMP-2/-9 expression, resulting in enhanced invasion of glioma cells. Finally, we show that the combination of NAP and TMZ significantly suppressed glioma growth and glioma cell invasion, both in vitro and in vivo. Conclusion: B7-H3 overexpression facilitated sustained glioma growth and promoted glioma cell invasion through a JAK2/STAT3/Slug-dependent signaling pathway. Application of the STAT3 inhibitor NAP significantly suppressed glioma growth and invasion, and has potential as a therapeutic strategy for the treatment of glioma. [ABSTRACT FROM AUTHOR]

There is compelling evidence that brain tumors, particularly glioblastoma multiforme (GBM), harbor a small population of cancer stem cells (CSCs). These CSCs have the ability to undergo self-renewal, initiate tumors in vivo, and are resistant to chemotherapy and radiation therapy. The present study determined the spatial distribution of CSCs within the donated brains of two deceased patients affected by glioblastoma multiforme. The following six grossly visible functional regions were identified: Necrotic tumor, viable solid tumor, infiltrating tumor edge, peritumoral normal brain, normal brain close to the tumor and normal brain distant from the tumor. Each region was snap-frozen, sectioned and immunostained for the CSC biomarkers prominin-1 (CD133) and sex-determining region Y-box 2 (SOX2). The percentages of CD133+ and SOX2+ cells within each region were determined. Different percentages of CD133+ and SOX2+ cells were identified in different regions. Significantly higher percentages of CD133+ and SOX2+ cells were indicated at the infiltrating tumor edge when compared with other areas. In summary, the spatial distributions of CSCs in these two brains with glioblastoma multiforme were similar, with the highest concentration being at the infiltrating tumor edge. This suggests that the edge of the tumor is the moving front for tumor progression and invasion, and should be targeted for therapeutic intervention. [ABSTRACT FROM AUTHOR]

The incidence rate of gliomas is the highest among primary brain tumors. Although the understanding of the molecular pathology of glioma has improved during the previous two decades, effective therapies are not yet available to treat these tumors. Previous studies have indicated that long non-coding RNAs (lncRNAs) have a close association with glioma, suggesting that lncRNAs may be potential targets for the development of novel treatments for glioma. The present review summarized the latest studies on the dysregulation of lncRNAs in glioma, and discussed their potential use in the diagnosis, prognosis and therapies of glioma. The emergence of lncRNAs has revealed an additional facet to glioma oncogenesis. An improved understanding of their functions is important to advance lncRNA-based diagnosis, prognosis and therapeutic interventions of glioma. [ABSTRACT FROM AUTHOR]