Malignant Nervous System Tumors Research Articles

Functional Roles of Long Non-coding RNAs on Stem Cell-related Pathways in Glioblastoma

: Long non-coding RNAs (lncRNAs), characterized by their length exceeding 200 nucleotides and lack of protein-coding capacity, are intricately associated with a wide array of cellular processes, encompassing cell invasion, differentiation, proliferation, migration, apoptosis, and regeneration. Perturbations in lncRNA expression have been observed in numerous diseases and have emerged as pivotal players in the pathogenesis of diverse tumor types. Glioblastoma, a highly malignant primary tumor of the central nervous system (CNS), remains a formidable challenge even with the advent of novel therapeutic interventions, as primary glioblastomas invariably exhibit therapy resistance and aggressive behavior. Glioblastomas can arise from progenitor cells or neuroglial stem cells, revealing profound cellular heterogeneity, notably in the form of glioblastoma stem cells (GSCs) possessing stem-like properties. Glioblastomas comprise neural precursors that harbor essential characteristics of neural stem cells (NSCs). Several signaling pathways have been implicated in the regulation of self-renewal in both cancer cells and stem cells. In addition to their involvement in therapy resistance and survival of glioblastoma, lncRNAs are implicated in the modulation of GSC behaviors through diverse pathways and the intricate regulation of various genes and proteins. This review aims to comprehensively discuss the interplay between lncRNAs, their associated pathways, and GSCs, shedding light on their potential implications in glioblastoma.

Glioblastoma multiforme - disease overview considering sports and neurorehabilitation

The brain is the most important organ, coordinating the work of the entire body. However, even it sometimes makes mistakes. Mutations in its genetic material can lead to the development of one of the most aggressive cancers - glioblastoma multiforme. Glioblastoma multiforme is the most common primary malignant tumor of the central nervous system (CNS). According to the WHO, it is classified as grade 4 in terms of malignancy. The 5-year survival rate is 7.2%. Occurs worldwide with a frequency of less than 10 cases per 100,000 inhabitants. It is more common in men than in women, with an average age at diagnosis of 65 years. The primary confirmed risk factor is exposure to ionizing radiation. Despite advances in medical research, the prognosis for individuals with glioblastoma multiforme remains unfavorable. The median survival time remains around 15 months. This article provides an overview of glioblastoma multiforme, including its etiology, symptoms, diagnosis, and treatment. By elucidating the current state of knowledge on glioblastoma multiforme, this work aims to facilitate early detection, treatment, and raise awareness among both physicians and patients about the disease. [7,14,17]

Survival of pediatric patients with ependymoma in a tertiary cancer center in Rio de Janeiro, Brazil

IntroductionEpendymoma is the third most frequent central malignant nervous system tumor in the pediatric age group. There is scarce data in the literature on survival of these patients, especially in upper and lower middle-income countries. We aimed to describe the clinical and demographic characteristics, treatment, and outcome of pediatric patients with ependymoma admitted to a public cancer hospital.MethodsRetrospective analysis of medical records of patients with ependymoma, admitted to the Pediatric Oncology department (0-20 years) during the period of 2000-2022. Data on patient, disease characteristics, and treatment were analyzed. Overall survival (OS) was calculated using the Kaplan-Meier method.ResultsSeventy-two patients were evaluated; median age at diagnosis was 6.5 years (range: 1-20), 63% were male, 54% of the tumors were in the posterior fossa (PF-EPN), 45% were classified as WHO grade 3, and 68% were operated on in other institutions before referral. Regarding treatment, 72% underwent radiotherapy and 33% of patients underwent chemotherapy. Almost 70% percent of the patients had relapses. The median follow-up time was 5.2 years (Range: 0,1-21,4). The OS in 5 years was 67%. Totally resected tumors had OS in 5 years of 88% (p: 0.028).ConclusionThe results achieved in this series show a survival gap between UMIC and HIC. Relapses occurred mainly in the first ten years and then reached a plateau, with the majority of patients experiencing endocrinological and neurological sequelae.

6791 Pituitary Apoplexy as Presentation of Atypical Teratoid/Rhabdoid Tumor

Abstract Disclosure: S.I. Babli: None. H. Alkubedan: None. N.M. Ali: None. R. Alqawahmed: None. M.M. Elhassan: None. Introduction: Pituitary apoplexy occurs in a pituitary adenoma; it migh occur in other less common types of tumors. The atypical teratoid/rhabdoid tumor (ATRT) is a very aggressive malignant tumor of the central nervous system and has a poor prognosis. It is rare to occur in adult and in the sellar region. Clinical Case: 32 years old male presented to ER with 4 days history of fever, headache and vomiting. He was conscious but confused. Vital signs Temperature 39 C, BP 120/80, HR 110 beats/min and Saturation of 95 %, Possibility of meningoencephalitis was raised, patient Brain CT showed Sellar and suprasellar mass with compression over the optic chiasma and invasion to the left cavernous sinus. Patient suddenly developed Generalize tonic-clonic convulsion and hypotension. He received IV midazolam, intubated and was started on noradrenaline and hydrocortisone, he was admitted to ICU as a case of meningoencephalitis and started on Ceftriaxone, Vancomycin and Acyclovir. Cerebrospinal fluid analysis showed RBC 175/cumm, WBC 20/cumm with 20% polymorph and 80% mononuclear cells, Protein 1.38 g/l (0.24-0.49) glucose 7.9 mmol/l with plasma glucose of 10 mmol/l. Repeated Brain CT showed Sellar and suprasellar mass with compression over the optic chiasma and invasion to the left cavernous sinus and with minimal heterogenicity and increased density suggestive of hemorrhagic components. Endocrine history revealed weight gain but no history to suggest acromegaly, Cushing’s syndrome or hypogonadism . Examinations: Patient was intubated and sedated BP 90/60 on Maximum inotropic support. Left oculomotor nerve palsy, Bilateral papilledema, he was having acanthosis nigricans with no signs of acromegaly, CS or hypogonadism. Laboratory finding: WBC17 with neutrophilia, Hgb 14.7 g/dl plt 360 Na 140 mmol/l, creatnin 180 mmol/, FT4 6.2 pmol/l, TSH 0.015, PROLACTINE 22, IGF1 29 ng/ml (41-246) Free testosterone index 2.13 (33-106), LH 0.5, FSH 0.3 .Patient had TTS and histopathology showed: SMARCB1 deficient malignant neoplasm, consistent with sellar atypical teratoid rhabdoid tumor. Post OP, patient had Ventilator associated pneumonia and recurrent attacks of seizures despite multiple antiepileptic medications. Patient was evaluated by medical and radiation oncologists but due to his general condition the treatment was postpone. One month after TSS, he developed intractable seizure new Brain CT showed interventricular haemorrhage with hydrocephalus and marked enlargement of hyperdense pituitary lesion which suggests haemorrhage. External ventricular drain was inserted but patient arrested and died. Conclusions: ATRT of the CNS usually affects young children. In the literature review performed in adults, only nine cases have occurred in the sellar or suprasellar region. Survival is variable in the different cases reported in the literature, with a mean of 26 months. Presentation: 6/2/2024

Identification and validation of a novel robust glioblastoma prognosis model based on bioinformatics

BackgroundGlioblastoma (GBM) is a very common primary malignant tumor of the central nervous system (CNS). Aging, macrophage, autophagy, and methylation related genes are hypothesized to be crucial to its pathogenesis. In this study, we aimed to explore the role of these genes in the prognosis of GBM. MethodsThe RNA sequence (RNA-seq) and clinical information were downloaded from The Cancer Genome Atlas database (TCGA) and the Chinese Glioma Genome Atlas database (CGGA). We performed univariate and least absolute shrinkage and selection operator (LASSO) multivariate Cox regression analysis to identify risk signatures related to overall survival (OS). We further developed a nomogram to predict individual outcomes. In addition, the immune microenvironment was analyzed by CIBERSORT. Results256 differentially expressed genes (DEGs) were obtained based on aging, macrophage, autophagy, and methylation related genes between GBM samples and normal tissues in TCGA-GBM cohort. We identified five optimal risk signatures with prognostic values in TCGA-GBM cohort and established a prognostic risk score model. The validity of the model was verified in the CGGA cohort and Huanhu cohort. Finally, we constructed a nomogram for clinical application by combining age, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and risk score. Activated NK cells and resting mast cells were highly expressed and memory B cells, plasma cells, resting NK cells, M1 macrophages, and neutrophils exhibited low expression in the high-risk score group. GBM patients with a low-risk score had a higher Tumor Immune Dysfunction and Exclusion (TIDE) score. The risk score of hot tumors was higher than that of the cold tumors. Additionally, 29 genes involved in glucose and lipid metabolism were highly expressed with a high-risk score. 31 metabolism-related pathways were significantly different between high-risk and low-risk groups. ConclusionsWe constructed and validated a novel prognostic model for GBM. Aging, macrophage, autophagy, and methylation related genes may serve as prognostic and therapeutic biomarkers. The model developed may assist in guiding treatment for GBM patients. Our research had great significance in accurately predicting the prognosis of GBM and may offer reference for immunotherapy decision for GBM patients.

Short-chain fatty acids reverses gut microbiota dysbiosis-promoted progression of glioblastoma by up-regulating M1 polarization in the tumor microenvironment

Glioblastoma (GBM), known as the most malignant and common primary brain tumor of the central nervous system, has finite therapeutic options and a poor prognosis. Studies have shown that host intestinal microorganisms play a role in the immune regulation of parenteral tumors in a number of different ways, either directly or indirectly. However, the potential impact of gut microbiota on tumor microenvironment, particularly glioma immunological milieu, has not been clarified exactly. In this study, by using an orthotopic GBM model, we found gut microbiota dysbiosis caused by antibiotic cocktail treatment boosted the tumor process in vivo. An obvious change that followed gut microbiota dysbiosis was the enhanced percentage of M2-like macrophages in the TME, in parallel with a decrease in the levels of gut microbial metabolite, short-chain fatty acids (SCFAs) in the blood and tumor tissues. Oral supplementation with SCFAs can increase the proportion of M1-like macrophages in the TME, which improves the outcomes of glioma. In terms of mechanism, SCFAs-activated glycolysis in the tumor-associated macrophages may be responsible for the elevated M1 polarization in the TME. This study will enable us to better comprehend the “gut-brain” axis and be meaningful for the development of TAM-targeting immunotherapeutic strategies for GBM patients.

Multidisciplinary monitoring in pediatric patients with medulloblastoma by primary care physician

Diagnostic and treatment facilities in pediatric oncology have reached a very technological advances in a short period of time, contributing to increased relapse-free and overall survival rates. Obviously, the key factors are the improvement of diagnostic and screening programs, anticancer and concomitant therapy, including personification of clinical guidelines for monitoring and correction of early and late complications in time. Issues regarding the quality of life of patients, including social, psychological rehabilitation and aspects of reproductive potential, are becoming highly actual. The critical importance is that an informed multidisciplinary team of specialists at all stages of anticancer treatment should be involved. This article presents the main algorithms and the most significant issues for pediatricians in the diagnosis and supervision of patients with an oncological diagnosis, using the example of medulloblastoma, as the most common malignant tumor of the central nervous system in children. The proposed recommendations are based on a retrospective analysis of pediatric patients with relapsed and refractory forms of medulloblastoma (n = 270) who received antitumor therapy in the period from 07/01/1993 to 07/01/2023, as well as international clinical data.

Research Progress on the Mechanism of Histone Deacetylases in Ferroptosis of Glioma.

Glioma is the most prevalent primary malignant tumor of the central nervous system. While traditional treatment modalities such as surgical resection, radiotherapy, and chemotherapy have made significant advancements in glioma treatment, the prognosis for glioma patients remains often unsatisfactory. Ferroptosis, a novel form of programmed cell death, plays a crucial role in glioma and is considered to be the most functionally rich programmed cell death process. Histone deacetylases have emerged as a key focus in regulating ferroptosis in glioma. By inhibiting the activity of histone deacetylases, histone deacetylase inhibitors elevate acetylation levels of both histones and non-histone proteins, thereby influencing various cellular processes. Numerous studies have demonstrated that histone deacetylases are implicated in the development of glioma and hold promise for its treatment. This article provides an overview of research progress on the mechanism by which histone deacetylases contribute to ferroptosis in glioma.

Cordycepin inhibits glioma growth by downregulating PD-L1 expression via the NOD-like receptor/NFKB1/STAT1 axis

Glioma is a serious primary malignant tumor of the human central nervous system with a poor prognosis and a high recurrence rate; however, inhibition of immune checkpoints can greatly improve the survival rate of patients. The purpose of this study was to investigate the regulation of PD-L1 by cordycepin and the mechanism of its anti-tumor action. The results of previous studies indicate that cordycepin has good anti-proliferative and anti-migratory activities and can induce apoptosis in U251 and T98G cells in vitro. Here, transcriptome sequencing showed that cordycepin may exert anti-tumor effects through the NOD-like receptor signaling pathway. Further intervention with BMS-1, a small molecule inhibitor of PD-L1, was used to explore whether inhibition of PD-L1 affected the regulation of the NOD-like receptor signaling pathway by cordycepin. Mechanistically, on the one hand, cordycepin regulated the expression of NFKB1 and STAT1 through the NOD-like receptor signaling pathway, thereby inhibiting the expression of PD-L1. In addition, inhibition of PD-L1 enhanced the regulation by cordycepin of the NOD-like receptor signaling pathway. On the other hand, cordycepin directly upregulated expression of STAT1 and downregulated that of PD-L1. In vivo studies further showed that cordycepin could downregulate expression of PD-L1 and NFKB1 and upregulate that of STAT1 in glioma xenograft tumor tissues, consistent with the results of in vitro studies. The results suggest that cordycepin may down-regulate the expression of PD-L1 through NOD-like receptor signaling pathway and NFKB signaling pathway, thereby inhibiting the immune escape of glioma, and can be developed as a PD-L1 inhibitor. Our results therefore provide a theoretical foundation for the use of cordycepin in treatment of glioma and enrich our understanding of its pharmacological mechanism.

WZ-3146 acts as a novel small molecule inhibitor of KIF4A to inhibit glioma progression by inducing apoptosis

BackgroundGlioma is considered the most common primary malignant tumor of the central nervous system. Although traditional treatments have not achieved satisfactory outcomes, recently, targeted therapies for glioma have shown promising efficacy. However, due to the single-target nature of targeted therapy, traditional targeted therapies are ineffective; thus, novel therapeutic targets are urgently needed.MethodsThe gene expression data for glioma patients were derived from the GEO (GSE4290, GSE50161), TCGA and CGGA databases. Next, the upregulated genes obtained from the above databases were cross-analyzed, finally, 10 overlapping genes (BIRC5, FOXM1, EZH2, CDK1, KIF11, KIF4A, NDC80, PBK, RRM2, and TOP2A) were ultimately screened and only KIF4A expression has the strongest correlation with clinical characteristics in glioma patients. Futher, the TCGA and CGGA database were utilized to explore the correlation of KIF4A expression with glioma prognosis. Then, qRT-PCR and Western blot was used to detect the KIF4A mRNA and protein expression level in glioma cells, respectively. And WZ-3146, the small molecule inhibitor targeting KIF4A, were screened by Cmap analysis. Subsequently, the effect of KIF4A knockdown or WZ-3146 treatment on glioma was measured by the MTT, EdU, Colony formation assay and Transwell assay. Ultimately, GSEA enrichment analysis was performed to find that the apoptotic pathway could be regulated by KIF4A in glioma, in addition, the effect of WZ-3146 on glioma apoptosis was detected by flow cytometry and Western blot.ResultsIn the present study, we confirmed that KIF4A is abnormally overexpressed in glioma. In addition, KIF4A overexpression is a key indicator of glioma prognosis; moreover, suppressing KIF4A expression can inhibit glioma progression. We also discovered that WZ-3146, a small molecule inhibitor of KIF4A, can induce apoptosis in glioma cells and exhibit antiglioma effects.ConclusionIn conclusion, these observations demonstrated that targeting KIF4A can inhibit glioma progression. With further research, WZ-3146, a small molecule inhibitor of KIF4A, could be combined with other molecular targeted drugs to cooperatively inhibit glioma progression.

Deep learning models for predicting the survival of patients with medulloblastoma based on a surveillance, epidemiology, and end results analysis

Medulloblastoma is a malignant neuroepithelial tumor of the central nervous system. Accurate prediction of prognosis is essential for therapeutic decisions in medulloblastoma patients. We analyzed data from 2,322 medulloblastoma patients using the SEER database and randomly divided the dataset into training and testing datasets in a 7:3 ratio. We chose three models to build, one based on neural networks (DeepSurv), one based on ensemble learning that Random Survival Forest (RSF), and a typical Cox Proportional-hazards (CoxPH) model. The DeepSurv model outperformed the RSF and classic CoxPH models with C-indexes of 0.751 and 0.763 for the training and test datasets. Additionally, the DeepSurv model showed better accuracy in predicting 1-, 3-, and 5-year survival rates (AUC: 0.767–0.793). Therefore, our prediction model based on deep learning algorithms can more accurately predict the survival rate and survival period of medulloblastoma compared to other models.

Unveiling the therapeutic potential of IHMT-337 in glioma treatment: targeting the EZH2-SLC12A5 axis

Glioma is the most common malignant tumor of the central nervous system, with EZH2 playing a crucial regulatory role. This study further explores the abnormal expression of EZH2 and its mechanisms in regulating glioma progression. Additionally, it was found that IHMT-337 can potentially be a therapeutic agent for glioma. The prognosis, expression, and localization of EZH2 were determined using bioinformatics, IHC staining, Western blot (WB) analysis, and immunofluorescence (IF) localization. The effects of EZH2 on cell function were assessed using CCK-8 assays, Transwell assays, and wound healing assays. Public databases and RT-qPCR were utilized to identify downstream targets. The mechanisms regulating these downstream targets were elucidated using MS-PCR and WB analysis. The efficacy of IHMT-337 was demonstrated through IC50 measurements, WB analysis, and RT-qPCR. The effects of IHMT-337 on glioma cells in vitro were evaluated using Transwell assays, EdU incorporation assays, and flow cytometry. The potential of IHMT-337 as a treatment for glioma was assessed using a blood–brain barrier (BBB) model and an orthotopic glioma model. Our research confirms significantly elevated EZH2 expression in gliomas, correlating with patient prognosis. EZH2 facilitates glioma proliferation, migration, and invasion alongside promoting SLC12A5 DNA methylation. By regulating SLC12A5 expression, EZH2 activates the WNK1-OSR1-NKCC1 pathway, enhancing its interaction with ERM to promote glioma migration. IHMT-337 targets EZH2 in vitro to inhibit WNK1 activation, thereby suppressing glioma cell migration. Additionally, it inhibits cell proliferation and arrests the cell cycle. IHMT-337 has the potential to cross the BBB and has successfully inhibited glioma progression in vivo. This study expands our understanding of the EZH2-SLC12A5 axis in gliomas, laying a new foundation for the clinical translation of IHMT-337 and offering new insights for precision glioma therapy.

Involvement of RAGE in radiation-induced acquisition of malignant phenotypes in human glioblastoma cells

Glioblastoma (GBM), a highly aggressive malignant tumor of the central nervous system, is mainly treated with radiotherapy. However, since irradiation may lead to the acquisition of migration ability by cancer cells, thereby promoting tumor metastasis and invasion, it is important to understand the mechanism of cell migration enhancement in order to prevent recurrence of GBM. The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor activated by high mobility group box 1 (HMGB1). In this study, we found that RAGE plays a role in the enhancement of cell migration by γ-irradiation in human GBM A172 cells. γ-Irradiation induced actin remodeling, a marker of motility acquisition, and enhancement of cell migration in A172 cells. Both phenotypes were suppressed by specific inhibitors of RAGE (FPS-ZM1 and TTP488) or by knockdown of RAGE. The HMGB1 inhibitor ethyl pyruvate similarly suppressed γ-irradiation-induced enhancement of cell migration. In addition, γ-irradiation-induced phosphorylation of STAT3 was suppressed by RAGE inhibitors, and a STAT3 inhibitor suppressed γ-irradiation-induced enhancement of cell migration, indicating that STAT3 is involved in the migration enhancement downstream of RAGE. Our results suggest that HMGB1-RAGE-STAT3 signaling is involved in radiation-induced enhancement of GBM cell migration, and may contribute to GBM recurrence by promoting metastasis and invasion.

Efficacy and safety of dinutuximab in the management of high-risk neuroblastoma: A systematic review and meta-analysis.

e22000 Background: Neuroblastoma (NB) is a malignant tumor of the sympathetic nervous system that usually occurs in children below 5 years of age. High-risk neuroblastoma (HR-NB) has a poor prognosis despite a number of treatment strategies. Dinutuximab, an anti-GD2 monoclonal antibody, has been recently added to the standard of care due to its improved prognosis. We aimed to systematically assess the outcomes of HR-NB patients treated with dinutuximab and compare them with those on other treatment regimens. Methods: A comprehensive search strategy was used to search PubMed and the Cochrane Library for articles investigating the effect of dinutuximab on the outcomes of patients with HR-NB. Eligibility criteria included: 1) Diagnosis of HR-NB based on INRG and INSS staging and MYCN status 2) Dinutuximab as the primary agent used in the intervention group 3) Mean/median follow-up time greater than 6 months. Three investigators independently reviewed and extracted relevant articles. Any disagreements were addressed through consultation with other authors. The risk of bias assessment of the selected articles was conducted using the Cochrane Risk of Bias Tool for randomized controlled trials (RCTs) and the Newcastle-Ottawa scale for observational studies. Review Manager software was used to obtain and display the meta-analysis estimates in forest plots. Random effects models were used to calculate the mean difference and overall estimated effects for continuous variables. The primary outcomes were all-cause mortality and 5-year event-free survival (5-year-EFS). Results: Five studies, including two RCTs, two secondary analyses of clinical trials, and one retrospective cohort study, comprising 1,393 participants, were included in the analysis. 686 of the patients received dinutuximab, while the remaining 707 patients were assigned to other therapies as controls. Dinutuximab was associated with lower all-cause mortality as compared to control [pooled RR, 0.41; 95% CI, 0.22-0.75, P = 0.004, I2 = 31%]. 5-year-EFS was also greater for patients treated with dinutuximab [MD: 0.12; 95% CI, 0.09-0.16; P < 0.001, I2= 98%]. Conclusions: Our findings suggest that dinutuximab is linked to a significant reduction in overall mortality and a noteworthy improvement in the 5-Year-EFS for patients with HR-NB, when compared to other treatment options.

Prognostic stratification of glioblastoma patients by unsupervised clustering of morphology patterns on whole slide images furthering our disease understanding.

Glioblastoma (GBM) is a highly aggressive malignant tumor of the central nervous system that displays varying molecular and morphological profiles, leading to challenging prognostic assessments. Stratifying GBM patients according to overall survival (OS) from H&E-stained whole slide images (WSI) using advanced computational methods is challenging, but with direct clinical implications. This work is focusing on GBM (IDH-wildtype, CNS WHO Gr.4) cases, identified from the TCGA-GBM and TCGA-LGG collections after considering the 2021 WHO classification criteria. The proposed approach starts with patch extraction in each WSI, followed by comprehensive patch-level curation to discard artifactual content, i.e., glass reflections, pen markings, dust on the slide, and tissue tearing. Each patch is then computationally described as a feature vector defined by a pre-trained VGG16 convolutional neural network. Principal component analysis provides a feature representation of reduced dimensionality, further facilitating identification of distinct groups of morphology patterns, via unsupervised k-means clustering. The optimal number of clusters, according to cluster reproducibility and separability, is automatically determined based on the rand index and silhouette coefficient, respectively. Our proposed approach achieved prognostic stratification accuracy of 83.33% on a multi-institutional independent unseen hold-out test set with sensitivity and specificity of 83.33%. We hypothesize that the quantification of these clusters of morphology patterns, reflect the tumor's spatial heterogeneity and yield prognostic relevant information to distinguish between short and long survivors using a decision tree classifier. The interpretability analysis of the obtained results can contribute to furthering and quantifying our understanding of GBM and potentially improving our diagnostic and prognostic predictions.

Neutrophils in glioma microenvironment: from immune function to immunotherapy.

Glioma is a malignant tumor of the central nervous system (CNS). Currently, effective treatment options for gliomas are still lacking. Neutrophils, as an important member of the tumor microenvironment (TME), are widely distributed in circulation. Recently, the discovery of cranial-meningeal channels and intracranial lymphatic vessels has provided new insights into the origins of neutrophils in the CNS. Neutrophils in the brain may originate more from the skull and adjacent vertebral bone marrow. They cross the blood-brain barrier (BBB) under the action of chemokines and enter the brain parenchyma, subsequently migrating to the glioma TME and undergoing phenotypic changes upon contact with tumor cells. Under glycolytic metabolism model, neutrophils show complex and dual functions in different stages of cancer progression, including participation in the malignant progression, immune suppression, and anti-tumor effects of gliomas. Additionally, neutrophils in the TME interact with other immune cells, playing a crucial role in cancer immunotherapy. Targeting neutrophils may be a novel generation of immunotherapy and improve the efficacy of cancer treatments. This article reviews the molecular mechanisms of neutrophils infiltrating the central nervous system from the external environment, detailing the origin, functions, classifications, and targeted therapies of neutrophils in the context of glioma.

Novel cancer-fighting role of ticagrelor inhibits GTSE1-induced EMT by regulating PI3K/Akt/NF-κB signaling pathway in malignant glioma

BackgroundGlioma is the most common malignant brain tumor of the central nervous system. Despite of the improvement of therapeutic strategy, the prognosis of malignant glioma patients underwent by STUPP strategy is still unexpected. Previous studies have suggested that ticagrelor exerted chemotherapeutic effects by inhibition of epithelial-mesenchymal transition (EMT) in various diseases including tumors. However, whether ticagrelor can exhibit the antitumor efficiency in glioma by affecting the EMT process is still unclear. In this study, we investigated the cancer-fighting role of ticagrelor and demonstrated its chemotherapeutic mechanism in glioma. Materials and methodsThe MTT assay was performed to detect the cytotoxicity of ticagrelor in glioma cells. We evaluated the expression of Ki67 in glioma cells by immunofluorescence assay after ticagrelor treatment. We conducted wound healing assay and transwell assay to determine the effects of ticagrelor on the migration and invasion of glioma cells. RNA-seq analysis was conducted to examine potential target genes and alternative signaling pathways for ticagrelor treatment. The expression levels of key EMT -related proteins were examined by Western blot experiment. ResultsTicagrelor inhibited the proliferation, migration and invasion of glioma cells with a favorable toxicity profile in vitro. Ticagrelor downregulated the expression of GTSE1 in glioma cells. RNA-seq analysis explored that GTSE1 acted as the potential target gene for ticagrelor treatment. Upregulation of GTSE1 antagonized the inhibitory effect of ticagrelor on the invasion of glioma and EMT progression by regulation of PI3K/Akt/NF-κB signaling pathway. And ticagrelor also exhibited the similar chemotherapeutic effect of glioma in vivo. ConclusionsTicagrelor as a potential chemotherapeutic option induced the inhibition of the GTSE1-induced EMT progression by regulation of PI3K/AKT/NF-κB signaling pathway.

Immune Checkpoint Inhibitors and Glioblastoma: A Review on Current State and Future Directions.

Glioblastoma (GBM) is the most prevalent malignant tumor of the central nervous system. The prognosis of GBM is grim, with a median overall survival of 14.6 months and only 6.9% of patients surviving 5 years after the initial diagnosis. Despite poor outcomes, standard therapy of surgical resection, radiotherapy, chemotherapy, and tumor-treating fields has remained largely unchanged. The introduction of immune checkpoint inhibitors (ICI) has been a paradigm shift in oncology, with efficacy across a broad spectrum of cancer types. Nonetheless, investigations of ICIs in both newly diagnosed and recurrent GBM have thus far been disappointing. This lack of clinical benefit has been largely attributed to the highly immunosuppressive nature of GBM. However, immunotherapy still holds promise for the treatment of GBM, with combinatorial strategies offering hope for potentially overcoming these current limitations. In this review, we discuss the outcomes of clinical trials employing ICIs in patients with GBM. Afterward, we review ICI combination strategies and how these combinations may overcome the immunosuppressive microenvironment of GBM in the context of preclinical/clinical evidence and ongoing clinical trials.

Efficient Delivery of Lomitapide using Hybrid Membrane-Coated Tetrahedral DNA Nanostructures for Glioblastoma Therapy.

Glioblastoma (GBM) is the most aggressive and prevalent primary malignant tumor of the central nervous system. Traditional chemotherapy has poor therapeutic effects and significant side effects due to drug resistance, the natural blood-brain barrier (BBB), and nonspecific distribution, leading to a lack of clinically effective therapeutic drugs. Here, 1430 small molecule compounds are screened based on a high-throughput drug screening platform and a novel anti-GBM drug, lomitapide (LMP) is obtained. Furthermore, a bionic nanodrug delivery system (RFA NPs) actively targeting GBM is constructed, which mainly consists of tetrahedral DNA nanocages (tFNA NPs) loaded with LMP as the core and a folate-modified erythrocyte-cancer cell-macrophage hybrid membrane (FRUR) as the shell. FRUR camouflage conferred unique features on tFNA NPs, including excellent biocompatibility, improved pharmacokinetic profile, efficient BBB permeability, and tumor targeting ability. The results show that the LMP RFA NPs exhibited superior and specific anti-GBM activities, reduced off-target drug delivery, prolonged lifespan, and has negligible side effects in tumor-bearing mice. This study combines high-throughput drug screening with biomimetic nanodrug delivery system technology to provide a theoretical and practical basis for drug development and the optimization of clinical treatment strategies for GBM treatment.

Mesenchymal-Stem-Cell-Based Therapy against Gliomas.

Glioblastoma is the most aggressive, malignant, and lethal brain tumor of the central nervous system. Its poor prognosis lies in its inefficient response to currently available treatments that consist of surgical resection, radiotherapy, and chemotherapy. Recently, the use of mesenchymal stem cells (MSCs) as a possible kind of cell therapy against glioblastoma is gaining great interest due to their immunomodulatory properties, tumor tropism, and differentiation into other cell types. However, MSCs seem to present both antitumor and pro-tumor properties depending on the tissue from which they come. In this work, the possibility of using MSCs to deliver therapeutic genes, oncolytic viruses, and miRNA is presented, as well as strategies that can improve their therapeutic efficacy against glioblastoma, such as CAR-T cells, nanoparticles, and exosomes.