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Magnetic Resonance Imaging Clinics of... Feb 2024Accurate diagnosis and treatment evaluation of patients with gliomas is imperative to make clinical decisions. Multiparametric MR perfusion imaging reveals physiologic... (Review)
Review
Accurate diagnosis and treatment evaluation of patients with gliomas is imperative to make clinical decisions. Multiparametric MR perfusion imaging reveals physiologic features of gliomas that can help classify them according to their histologic and molecular features as well as distinguish them from other neoplastic and nonneoplastic entities. It is also helpful in distinguishing tumor recurrence or progression from radiation necrosis, pseudoprogression, and pseudoresponse, which is difficult with conventional MR imaging. This review provides an update on MR perfusion imaging for the diagnosis and treatment monitoring of patients with gliomas following standard-of-care chemoradiation therapy and other treatment regimens such as immunotherapy.
Topics: Humans; Magnetic Resonance Imaging; Brain Neoplasms; Contrast Media; Glioma; Perfusion Imaging
PubMed: 38007284
DOI: 10.1016/j.mric.2023.07.003 -
Cellular & Molecular Biology Letters Dec 2023Glioma is the most pervasive intracranial tumor in the central nervous system (CNS), with glioblastoma (GBM) being the most malignant type having a highly heterogeneous... (Review)
Review
Glioma is the most pervasive intracranial tumor in the central nervous system (CNS), with glioblastoma (GBM) being the most malignant type having a highly heterogeneous cancer cell population. There is a significantly high mortality rate in GBM patients. Molecular biomarkers related to GBM malignancy may have prognostic values in predicting survival outcomes and therapeutic responses, especially in patients with high-grade gliomas. In particular, N6-methyladenine (m6A) mRNA modification is the most abundant form of post-transcriptional RNA modification in mammals and is involved in regulating mRNA translation and degradation. Cumulative findings indicate that m6A methylation plays a crucial part in neurogenesis and glioma pathogenesis. In this review, we summarize recent advances regarding the functional significance of m6A modification and its regulatory factors in glioma occurrence and progression. Significant advancement of m6A methylation-associated regulators as potential therapeutic targets is also discussed.
Topics: Animals; Humans; Glioma; Central Nervous System; Brain Neoplasms; Adenosine; Methylation; Mammals
PubMed: 38072944
DOI: 10.1186/s11658-023-00514-0 -
Cancer Letters Feb 2024Despite therapeutic advances, overall survival in glioblastoma is dismal. To optimize progress, a more detailed understanding of glioma's molecular, cellular, and... (Review)
Review
Despite therapeutic advances, overall survival in glioblastoma is dismal. To optimize progress, a more detailed understanding of glioma's molecular, cellular, and intercellular pathophysiology is needed. Recent investigation has revealed a vital role for exosomes in inter-cellular signaling, tumor cell support, and regulation of the tumor microenvironment. Exosomes carry miRNAs, lncRNAs, mRNAs, proteins, immune regulatory molecules, nucleic acids, and lipids; however, the composition of exosome cargo is variable depending on the cell of origin. Specific exosomal miRNA contents such as miR-21, miR-301a, miR-151a, miR-148a, and miR-5096 are altered in high-grade glioma. Unique proteomic, genomic, and miRNA signatures of tumor exosomes have been associated with disease pathobiology, temozolomide resistance, immunosuppression, and tumor proliferation. Exosomes hold promise for tissue diagnostic glioma diagnosis and monitoring response to therapy. This review summarizes the current understanding of exosomes, their crucial role in glioma pathology, and future directions for their use in diagnosis and treatment. METHODS: The MEDLINE/PubMed database was reviewed for papers written in English and publication dates of 1981-2023, using the search string "Exosome", "Extracellular vesicles", "Glioma", "Exosomes in glioma".
Topics: Humans; Exosomes; Proteomics; Glioma; MicroRNAs; Glioblastoma; Cell Line, Tumor; Tumor Microenvironment
PubMed: 38092145
DOI: 10.1016/j.canlet.2023.216592 -
Cellular and Molecular Life Sciences :... Aug 2023We previously reported that TRPM7 regulates glioma cells' stemness through STAT3. In addition, we demonstrated that FOSL1 is a response gene for TRPM7, and the FOSL1...
INTRODUCTION
We previously reported that TRPM7 regulates glioma cells' stemness through STAT3. In addition, we demonstrated that FOSL1 is a response gene for TRPM7, and the FOSL1 gene serves as an oncogene to promote glioma proliferation and invasion.
METHODS
In the present study, we determined the effects of FOSL1 on glioma stem cell (GSC) markers CD133 and ALDH1 by flow cytometry, and the maintenance of stem cell activity by extreme limiting dilution assays (ELDA). To further gain insight into the mechanism by which TRPM7 activates transcription of the FOSL1 gene to contribute to glioma stemness, we constructed a FOSL1 promoter and its GAS mutants followed by luciferase reporter assays and ChIP-qPCR in a glioma cell line and glioma patient-derived xenoline. We further examined GSC markers ALDH1 and TRPM7 as well as FOSL1 by immunohistochemistry staining (IHC) in brain tissue microarray (TMA) of glioma patients.
RESULTS
We revealed that FOSL1 knockdown reduces the expression of GSC markers CD133 and ALDH1, and FOSL1 is required to maintain stem cell activity in glioma cells. The experiments also showed that mutations of - 328 to - 336 and - 378 to - 386 GAS elements markedly reduced FOSL1 promoter activity. Constitutively active STAT3 increased while dominant-negative STAT3 decreased FOSL1 promoter activity. Furthermore, overexpression of TRPM7 enhanced while silencing of TRPM7 reduced FOSL1 promoter activity. ChIP-qPCR assays revealed that STAT3, present in nuclear lysates of glioma cells stimulated by constitutively activated STAT3, can bind to two GAS elements, respectively. We demonstrated that deacetylation of FOSL1 at the Lys-116 residue located within its DNA binding domain led to an increase in FOSL1 transcriptional activity. We found that the expression of TRPM7, ALDH1, and FOSL1 protein is associated with grades of malignant glioma, and TRPM7 protein expression correlates to the expression of ALDH1 and FOSL1 in glioma patients.
CONCLUSIONS
These combined results demonstrated that TRPM7 induced FOSL1 transcriptional activation, which is mediated by the action of STAT3, a mechanism shown to be important in glioma stemness. These results indicated that FOSL1, similar to GSC markers ALDH1 and TRPM7, is a diagnostic marker and potential drug target for glioma patients.
Topics: Humans; TRPM Cation Channels; Oncogenes; Biological Assay; Brain; Glioma; Protein Serine-Threonine Kinases; STAT3 Transcription Factor
PubMed: 37642779
DOI: 10.1007/s00018-023-04921-6 -
The Journal of Gene Medicine Oct 2023The glioma is the most malignant human brain tumor. Early glioma detection and treatment are still difficult. New biomarkers are desperately required to aid in the...
BACKGROUND
The glioma is the most malignant human brain tumor. Early glioma detection and treatment are still difficult. New biomarkers are desperately required to aid in the evaluation of diagnosis and prognosis.
METHODS
The single cell sequencing dataset scRNA-6148 for glioblastoma was obtained from the Chinese Glioma Genome Atlas database. Data were gathered for the transcriptome sequencing project. Genes involved in liquid-liquid phase separation (LLPS) were taken out of the DrLLPS database. To find the modules connected to LLPS, the weighted co-expression network was analyzed. Differential expression analysis was used to identify the differentially expressed genes (DEGs) in gliomas. Pseudo-time series analysis, gene set enrichment analysis (GSEA) and immune cell infiltration analysis were used to investigate the role of important genes in the immunological microenvironment. We examined the function of key glioma genes using polymerase chain reaction (PCR) testing, CCK-8 assays, clone generation assays, transwell assays and wound healing assays.
RESULTS
FABP5 was identified as a key gene in glioblastoma by multiomics research. Pseudo-time series analysis showed that FABP5 was highly linked with the differentiation of many different types of cells. GSEA revealed that FABP5 was strongly linked to several hallmark pathways in glioblastoma. We looked at immune cell infiltration and discovered a significant link between FABP5, macrophages and T cell follicular helpers. The PCR experiment results demonstrated that FABP5 expression was elevated in glioma samples. Cell experiments showed that FABP5 knockdown dramatically decreased the viability, proliferation, invasion and migration of the LN229 and U87 glioma cell lines.
CONCLUSIONS
Our study provides a new biomarker, FABP5, for glioma diagnosis and treatment.
Topics: Humans; Brain Neoplasms; Fatty Acid-Binding Proteins; Glioblastoma; Glioma; Prognosis; Tumor Microenvironment
PubMed: 37114595
DOI: 10.1002/jgm.3517 -
BMC Cancer Aug 2023Glioblastoma (GBM) is the most malignant glioma, with poor survival rates and prognosis. Several studies have reported the abnormal expression of circular RNAs...
BACKGROUND
Glioblastoma (GBM) is the most malignant glioma, with poor survival rates and prognosis. Several studies have reported the abnormal expression of circular RNAs (circRNAs) and their functions in the malignant biological behavior of GBM. However, such research is still in the preliminary stages, and further study is needed to confirm the therapeutic potential of circRNAs in GBM.
METHODS
RNA-seq was performed using four tumor tissues from patients with GBM and their adjacent non-tumor brain tissues to screen differentially expressed circRNAs. Fluorescence in situ hybridization assay was used to examine the location of circ_0021350 in glioma cells. In addition, a series of biological function assays were employed to verify the oncogenic role of circ_0021350 in GBM. Quantitative reverse transcription PCR was used to examine circular, micro- (miRNA), and messenger RNA (mRNA) levels. Furthermore, dual-luciferase reporter, RNA pull-down, and RNA binding protein immunoprecipitation assays were applied to verify the interaction between circ_0021350 and its downstream effectors.
RESULTS
Circ_0021350 was significantly elevated in GBM tissues and glioma cells. Overexpression of circ_0021350 promoted glioma cell proliferation and metastatic ability; silencing of circ_0021350 had the opposite effect. Mechanistic analysis revealed that circ_0021350 sponged miR-1207-3p to regulate PIK3R3, whose overexpression reversed the reduction in the malignant biological behavior of glioma cells caused by silencing circ_0021350.
CONCLUSION
Our findings suggest that circ_0021350 is an oncogenic circRNA in GBM, and the circ_0021350/miR-1207-3p/PIK3R3 axis may serve as a potential therapeutic target in GBM treatment.
Topics: Humans; Glioblastoma; In Situ Hybridization, Fluorescence; RNA, Circular; Oncogenes; Glioma; MicroRNAs; Phosphatidylinositol 3-Kinases
PubMed: 37644421
DOI: 10.1186/s12885-023-11263-w -
The Journal of Clinical Investigation Jan 2024Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to... (Review)
Review
Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to understand and therapeutically target the STING pathway in cancer have ensued. Relative to other cancer types, the glioma immune microenvironment harbors few infiltrating T cells, but abundant tumor-associated myeloid cells, possibly explaining disappointing responses to immune checkpoint blockade therapies in cohorts of patients with glioblastoma. Notably, unlike most extracranial tumors, STING expression is absent in the malignant compartment of gliomas, likely due to methylation of the STING promoter. Nonetheless, several preclinical studies suggest that inducing cGAS/STING signaling in the glioma immune microenvironment could be therapeutically beneficial, and cGAS/STING signaling has been shown to mediate inflammatory and antitumor effects of other modalities either in use or being developed for glioblastoma therapy, including radiation, tumor-treating fields, and oncolytic virotherapy. In this Review, we discuss cGAS/STING signaling in gliomas, its implications for glioma immunobiology, compartment-specific roles for STING signaling in influencing immune surveillance, and efforts to target STING signaling - either directly or indirectly - for antiglioma therapy.
Topics: Humans; Glioblastoma; Nucleotidyltransferases; Signal Transduction; Glioma; DNA; Tumor Microenvironment
PubMed: 38226619
DOI: 10.1172/JCI163452 -
ACS Nano Jul 2023Glioblastoma (GBM) is one of the most challenging malignant brain tumors to treat. Herein, we describe a nanoenzyme hemostatic matrix strategy with the tumor cavity...
Glioblastoma (GBM) is one of the most challenging malignant brain tumors to treat. Herein, we describe a nanoenzyme hemostatic matrix strategy with the tumor cavity application that simultaneously serves as photothermal agent and induces immunogenic cell death after GBM surgical resection to enhance the antitumor immunity and delay tumor recurrence. The hemostatic matrix system (Surgiflo@PCN) contains Surgiflo, a multispace structure that can be used to penetrate different shapes of tumor cavities to prevent postoperative tumor cavity hemorrhage. As well, porous palladium-copper nanoclusters (PCNs) have adjustable enzyme-like activities (oxidase, peroxidase, and catalase) responsible for formation of reactive oxygen species (ROS) under near-infrared (808 nm) laser irradiation. When the Surgiflo@PCN entered the resected tumor cavity, the first action was the direct killing of glioma cells via ROS and photothermal therapy (PTT). The second action was the induction of immunogenic cell death by PCN-enhanced oxidative stress and PTT, which reversed the immunosuppressive tumor microenvironment and enhanced the antitumor immune response. This eradicated residual glioma cells and prevented recurrence. The collective findings demonstrate that Surgiflo@PCN kills glioma cells directly through ROS and PTT and enhances antiglioma immunity and kills glioma cells indirectly. The "one-stone, two-birds" strategy could become an effective photothermal immunotherapy in GBM patients.
Topics: Humans; Reactive Oxygen Species; Glioma; Glioblastoma; Immunomodulation; Hemostatics; Cell Line, Tumor; Tumor Microenvironment; Neoplasms
PubMed: 37399132
DOI: 10.1021/acsnano.3c03696 -
Scientific Reports Oct 2023Glioma is the most common primary malignant tumor in the central nervous system. Disulfidptosis is a recently identified programmed cell death in tumor cells...
Glioma is the most common primary malignant tumor in the central nervous system. Disulfidptosis is a recently identified programmed cell death in tumor cells overexpressing SLC7A11 under glucose starvation. Clinical prognostic significance of disulfidptosis has been reported in several tumors, and in this study, we explored the correlation of disulfidptosis with clinical prognosis, immune cell infiltration, and immunotherapy response in glioma. A total of 1592 glioma patients were included in this study, including 691 glioma patients from The Cancer Genomic Atlas (TCGA), 300 patients with from the Chinese Glioma Genomic Atlas (CGGA) array, 325 patients from CGGA sequencing, and 276 patients from Gene Expression Omnibus (GEO) GSE16011. R software (V4.2.2) and several R packages were applied to develop the risk score model and correlation calculation and visualization. Three disulfidptosis-related genes, LRPPRC, RPN1, and GYS1, were screened out and applied to establish the risk score model. Low-risk patients exhibit favorable prognosis, and the disulfidptosis-related signature significantly correlated with clinicopathological properties, molecular subtypes, and immunosuppressive microenvironment of glioma patients. We developed a disulfidptosis-related risk model to predict the prognosis and immune features in glioma patients, and this risk model may be applied as an independent prognostic factor for glioma.
Topics: Humans; Glioma; Central Nervous System; Chromosome Mapping; Prognosis; Apoptosis; Tumor Microenvironment
PubMed: 37864127
DOI: 10.1038/s41598-023-45295-w -
The Lancet. Child & Adolescent Health Jul 2023Outcomes of recurrent paediatric high-grade glioma are poor, with a median overall survival of less than 6 months. Viral immunotherapy, such as the polio-rhinovirus...
BACKGROUND
Outcomes of recurrent paediatric high-grade glioma are poor, with a median overall survival of less than 6 months. Viral immunotherapy, such as the polio-rhinovirus chimera lerapolturev, is a novel approach for treatment of recurrent paediatric high-grade glioma and has shown promise in adults with recurrent glioblastoma. The poliovirus receptor CD155 is ubiquitously expressed in malignant paediatric brain tumours and is a treatment target in paediatric high-grade glioma. We aimed to assess the safety of lerapolturev when administered as a single dose intracerebrally by convection enhanced delivery in children and young people with recurrent WHO grade 3 or grade 4 glioma, and to assess overall survival in these patients.
METHODS
This phase 1b trial was done at the Duke University Medical Center (Durham, NC, USA). Patients aged 4-21 years with recurrent high-grade malignant glioma (anaplastic astrocytoma, glioblastoma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma, or anaplastic pleomorphic xanthoastrocytoma) or anaplastic ependymoma, atypical teratoid rhabdoid tumour, or medulloblastoma with infusible disease were eligible for this study. A catheter was tunnelled beneath the scalp for a distance of at least 5 cm to aid in prevention of infection. The next day, lerapolturev at a dose of 5 × 10 median tissue culture infectious dose in 3 mL infusate loaded in a syringe was administered via a pump at a rate of 0·5 mL per h as a one-time dose. The infusion time was approximately 6·5 h to compensate for volume of the tubing. The primary endpoint was the proportion of patients with unacceptable toxic effects during the 14-day period after lerapolturev treatment. The study is registered with ClinicalTrials.gov, NCT03043391.
FINDINGS
Between Dec 5, 2017, and May 12, 2021, 12 patients (11 unique patients) were enrolled in the trial. Eight patients were treated with lerapolturev. The median patient age was 16·5 years (IQR 11·0-18·0), five (63%) of eight patients were male and three (38%) were female, and six (75%) of eight patients were White and two (25%) were Black or African American. The median number of previous chemotherapeutic regimens was 3·50 (IQR 1·25-5·00). Six of eight patients had 26 treatment-related adverse events attributable to lerapolturev. There were no irreversible (ie, persisted longer than 2 weeks) treatment-related grade 4 adverse events or deaths. Treatment-related grade 3 adverse events included headaches in two patients and seizure in one patient. Four patients received low-dose bevacizumab on-study for treatment-related peritumoural inflammation or oedema, diagnosed by both clinical symptoms plus fluid-attenuated inversion recovery MRI. The median overall survival was 4·1 months (95% CI 1·2-10·1). One patient remains alive after 22 months.
INTERPRETATION
Convection enhanced delivery of lerapolturev is safe enough in the treatment of recurrent paediatric high-grade glioma to proceed to the next phase of trial.
FUNDING
Solving Kids Cancer, B+ Foundation, Musella Foundation, and National Institutes of Health.
Topics: Adult; Humans; Child; Male; Female; Adolescent; Glioblastoma; Rhinovirus; Neoplasm Recurrence, Local; Glioma; Brain Neoplasms; Immunotherapy; Astrocytoma; Poliomyelitis; Cerebellar Neoplasms
PubMed: 37004712
DOI: 10.1016/S2352-4642(23)00031-7