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The Analyst Jun 2024Live chicken egg embryos offer new opportunities for evaluation and continuous monitoring of tumour growth for studies compared to traditional rodent models. Here, we...
Live chicken egg embryos offer new opportunities for evaluation and continuous monitoring of tumour growth for studies compared to traditional rodent models. Here, we report the first use of surface enhanced Raman scattering (SERS) mapping and surface enhanced spatially offset Raman scattering (SESORS) for the detection and localisation of targeted gold nanoparticles in live chicken egg embryos bearing a glioblastoma tumour.
Topics: Animals; Spectrum Analysis, Raman; Gold; Chick Embryo; Metal Nanoparticles; Glioblastoma; Humans; Surface Properties; Disease Models, Animal; Cell Line, Tumor
PubMed: 38842276
DOI: 10.1039/d4an00617h -
Health Science Reports Jun 2024Brain tumors are common, requiring physicians to have a precise understanding of them for accurate diagnosis and treatment. Considering that various histological tumor...
BACKGROUND AND AIM
Brain tumors are common, requiring physicians to have a precise understanding of them for accurate diagnosis and treatment. Considering that various histological tumor types present different cellularity, we conducted this research to examine the role of apparent diffusion coefficient (ADC) values in the differential diagnosis and pathologic grading of brain tumor types.
METHODS
In this cross-sectional study, we gathered pathology reports of histological samples of adult brain tumors. The tissue sample of brain tumors were examined histologically by a pathologist. The magnetic resonance imaging data of these patients were interpreted by a neuroradiologist. The measured ADC values and ADC ratios were calculated. Standard mean ADC values were expressed as 10 mm/s. The findings were compared according to the histological diagnosis of each tumor.
RESULTS
Sixty-eight patients were included in the study: 34 (50%) were male, and 34 (50%) were female. The average age of the patients was 51.69 + 16.40 years. In the examination of tumor type, 16 (23.5%) were astrocytoma, 9 (13.2%) were oligodendroglioma, 20 (29.4%) were glioblastoma, 4 (5.9%) were medulloblastoma, and 19 (27.9%) were metastatic tumors. the average value of ADC was statistically significantly different according to the pathological type of tumor ( < 0.001). The two-by-two comparison of average ADC among tumor types revealed significant differences, except for oligodendroglioma and glioblastoma (-value = 0.87) and glioblastoma and medulloblastoma (-value = 0.347). The average value of ADC and ADC ratio was statistically significantly different according to the pathological grade of the tumor ( < 0.001). In the two-by-two comparison of average ADC between all pathological grades of the tumor showed a significance difference except for Grade I and Grade II (-value = 0.355). The mean value of ADC and ADC ratio for glioblastoma and metastatic tumors showed no significant difference.
CONCLUSION
The assessment of brain tumor grade through ADC examination will help to estimate prognosis and devising suitable therapeutic strategies.
PubMed: 38841116
DOI: 10.1002/hsr2.2110 -
SA Journal of Radiology 2024Leptomeningeal dissemination is a rare manifestation of pilocytic astrocytoma. It may occur with higher-grade tumours like medulloblastoma, ependymoma and high-grade...
UNLABELLED
Leptomeningeal dissemination is a rare manifestation of pilocytic astrocytoma. It may occur with higher-grade tumours like medulloblastoma, ependymoma and high-grade glioma, but is extremely rare with low-grade glioma. There has been a growing number of reported cases documenting leptomeningeal dissemination of pilocytic astrocytoma in the medical literature.
CONTRIBUTION
Description of a World Health Organization (WHO) Grade I suprasellar pilocytic astrocytoma with leptomeningeal dissemination in the brain and spinal cord which showed progression of the leptomeningeal nodules without tumour upgrading on long-term follow-up.
PubMed: 38840827
DOI: 10.4102/sajr.v28i1.2876 -
Redox Biology Jul 2024Temozolomide (TMZ) is a widely utilized chemotherapy treatment for patients with glioblastoma (GBM), although drug resistance constitutes a major therapeutic hurdle....
Temozolomide (TMZ) is a widely utilized chemotherapy treatment for patients with glioblastoma (GBM), although drug resistance constitutes a major therapeutic hurdle. Emerging evidence suggests that ferroptosis-mediated therapy could offer an appropriate alternative treatment option against cancer cells that are resistant to certain drugs. However, recurrent gliomas display robust ferroptosis resistance, although the precise mechanism of resistance remains elusive. In the present work, we report that proline rich protein 11 (PRR11) depletion significantly sensitizes GBM cells to TMZ by inducing ferroptosis. Mechanistically, PRR11 directly binds to and stabilizes dihydroorotate dehydrogenase (DHODH), which leads to glioma ferroptosis-resistant in a DHODH-dependent manner in vivo and in vitro. Furthermore, PRR11 inhibits HERC4 and DHODH binding, by suppressing the recruitment of E3 ubiquitin ligase HERC4 and polyubiquitination degradation of DHODH at the K306 site, which maintains DHODH protein stability. Importantly, downregulated PRR11 increases lipid peroxidation and alters DHODH-mediated mitochondrial morphology, thereby promoting ferroptosis and increasing TMZ chemotherapy sensitivity. In conclusion, our results reveal a mechanism via which PRR11 drives ferroptosis resistance and identifies ferroptosis induction and TMZ as an attractive combined therapeutic strategy for GBM.
Topics: Humans; Ferroptosis; Glioblastoma; Temozolomide; Drug Resistance, Neoplasm; Cell Line, Tumor; Mice; Dihydroorotate Dehydrogenase; Animals; Gene Expression Regulation, Neoplastic; Brain Neoplasms
PubMed: 38838551
DOI: 10.1016/j.redox.2024.103220 -
Cancer Research Communications Jun 2024Glioblastoma (GBM) is the deadliest adult brain cancer. Under the current standard of care, almost all patients succumb to the disease and novel treatments are urgently...
UNLABELLED
Glioblastoma (GBM) is the deadliest adult brain cancer. Under the current standard of care, almost all patients succumb to the disease and novel treatments are urgently needed. Recognizing that GBMs are addicted to cholesterol, past clinical trials have repurposed statins against GBM but failed. The purpose of this study was to test whether treatments that upregulate the cholesterol biosynthesis pathway in GBM would generate a metabolic vulnerability that can be exploited using statins and to determine the underlying mechanisms.Effects of radiotherapy and temozolomide or dopamine receptor antagonists on the mevalonate pathway in GBM were assessed in vitro and in vivo. The impact of statins on self-renewal of glioma stem cells and median survival was studied. Branches of the mevalonate pathway were probed to identify relevant effector proteins.Cells surviving combination treatments that converge in activating the immediate early response, universally upregulated the mevalonate pathway and increased stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 was inhibited by statins, which led to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.We conclude that a combination of dopamine receptor antagonists and statins could potentially improve radiotherapy outcome and warrants further investigation.
SIGNIFICANCE
Combination therapies that activate the mevalonate pathway in GBM cells after sublethal treatment enhance self-renewal and migratory capacity through Rac-1 activation, which creates a metabolic vulnerability that can be further potentially exploited using statins.
Topics: Glioblastoma; Mevalonic Acid; Humans; Animals; rac1 GTP-Binding Protein; Mice; Brain Neoplasms; Cell Line, Tumor; Temozolomide; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Neoplasm Recurrence, Local; Xenograft Model Antitumor Assays; Neoplastic Stem Cells; Signal Transduction; Dopamine Antagonists
PubMed: 38837899
DOI: 10.1158/2767-9764.CRC-24-0049 -
Cureus May 2024Awake craniotomy is a surgical procedure that has been gaining significance over the past decades. Neuronavigation is an intraoperative technology that locates tumors...
Awake craniotomy is a surgical procedure that has been gaining significance over the past decades. Neuronavigation is an intraoperative technology that locates tumors and monitors the brain cortex during awake craniotomy. The presence of cerebral low-grade gliomas in the frontal lobe creates a risk of affecting vital centers of the brain cortex during surgery. We present a clinical case of a 42-year-old male patient who entered the neurosurgery clinic with a clinical manifestation of headache for two months. MRI showed evidence of the recurrence of a left frontal glioma. Differential diagnoses of frontal gliomas include metastases, abscesses, and cysts. The pathophysiologic background of the disease is the mutation of neuroglial cells, which leads to an abnormal and uncontrollable proliferation. Under sleep-awake anesthesia, operative treatment was performed through left frontal awake craniotomy under neuronavigation. As a result, a total excision was achieved. Motor functions of the right limbs and speech have been preserved. The patient was mobilized on the day after the intervention. Surgery-related complications were not observed. The patient had relief from the symptoms and was discharged on the fifth day. Awake craniotomy combined with neuronavigation was the most efficient and the least harmful method for the excision of the tumor. For low-grade gliomas localized in the frontal area of the encephalon, awake craniotomy is the only secure option for surgery.
PubMed: 38836145
DOI: 10.7759/cureus.59667 -
ESMO Open Jun 2024The World Health Organization (WHO) 2021 classification of central nervous system (CNS) tumors classified astrocytoma isocitrate dehydrogenase-mutant (A IDHm) with...
BACKGROUND
The World Health Organization (WHO) 2021 classification of central nervous system (CNS) tumors classified astrocytoma isocitrate dehydrogenase-mutant (A IDHm) with either microvascular proliferation and/or necrosis or homozygous deletion of CDKN2A/B as CNS grade 4 (CNS WHO G4), introducing a distinct entity and posing new challenges to physicians for appropriate management and prognostication.
PATIENTS AND METHODS
We retrospectively collected information about patients diagnosed with A IDHm CNS WHO G4 at three reference neuro-oncological Italian centers and correlated them with survival.
RESULTS
A total of 133 patients were included. Patients were young (median age 41 years) and most received post-operative treatment including chemo-radiation (n = 101) and/or temozolomide maintenance (n = 112). With a median follow-up of 51 months, the median overall survival (mOS) was 31.2 months, with a 5-year survival probability of 26%. In the univariate analysis, complete resection (mOS: 40.2 versus 26.3 months, P = 0.03), methyl-guaninemethyltransferase (MGMT) promoter methylation (mOS: 40.7 versus 18 months, P = 0.0136), and absence of telomerase reverse transcriptase (TERT) promoter mutation (mOS: 40.7 versus 18 months, P = 0.0003) correlated with better prognosis. In the multivariate models, lack of TERT promoter mutation [hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.07-0.82, P = 0.024] and MGMT methylation (HR 0.40, 95% CI 0.20-0.81, P = 0.01) remained associated with improved survival.
CONCLUSIONS
This is the largest experience in Western countries exploring the prognostic signature of patients with A IDHm CNS G4. Our results show that MGMT promoter methylation and TERT promoter mutation may impact clinical outcomes. This may support physicians in prognostication, clinical management, and design of future studies of this distinct diagnostic entity.
Topics: Humans; Retrospective Studies; Isocitrate Dehydrogenase; Astrocytoma; Male; Female; Adult; Prognosis; Middle Aged; Mutation; Young Adult; Brain Neoplasms; DNA Repair Enzymes; DNA Modification Methylases; Aged; Telomerase; Adolescent; Neoplasm Grading; DNA Methylation; Tumor Suppressor Proteins
PubMed: 38833969
DOI: 10.1016/j.esmoop.2024.103485 -
Communications Biology Jun 2024We present a quantitative sandwich immunoassay for CD63 Extracellular Vesicles (EVs) and a constituent surface cargo, EGFR and its activity state, that provides a...
We present a quantitative sandwich immunoassay for CD63 Extracellular Vesicles (EVs) and a constituent surface cargo, EGFR and its activity state, that provides a sensitive, selective, fluorophore-free and rapid alternative to current EV-based diagnostic methods. Our sensing design utilizes a charge-gating strategy, with a hydrophilic anion exchange membrane functionalized with capture antibodies and a charged silica nanoparticle reporter functionalized with detection antibodies. With sensitivity and robustness enhancement by the ion-depletion action of the membrane, this hydrophilic design with charged reporters minimizes interference from dispersed proteins, thus enabling direct plasma analysis without the need for EV isolation or sensor blocking. With a LOD of 30 EVs/μL and a high relative sensitivity of 0.01% for targeted proteomic subfractions, our assay enables accurate quantification of the EV marker, CD63, with colocalized EGFR by an operator/sample insensitive universal normalized calibration. We analysed untreated clinical samples of Glioblastoma to demonstrate this new platform. Notably, we target both total and "active" EGFR on EVs; with a monoclonal antibody mAb806 that recognizes a normally hidden epitope on overexpressed or mutant variant III EGFR. Analysis of samples yielded an area-under-the-curve (AUC) value of 0.99 and a low p-value of 0.000033, surpassing the performance of existing assays and markers.
Topics: Humans; Glioblastoma; Tetraspanin 30; ErbB Receptors; Extracellular Vesicles; Immunoassay; Biomarkers, Tumor; Brain Neoplasms
PubMed: 38830977
DOI: 10.1038/s42003-024-06385-1 -
Oncology Research 2024The dysregulation of Isocitrate dehydrogenase (IDH) and the subsequent production of 2-Hydroxyglutrate (2HG) may alter the expression of epigenetic proteins in Grade 4...
The interplay mechanism between IDH mutation, MGMT-promoter methylation, and PRMT5 activity in the progression of grade 4 astrocytoma: unraveling the complex triad theory.
BACKGROUND
The dysregulation of Isocitrate dehydrogenase (IDH) and the subsequent production of 2-Hydroxyglutrate (2HG) may alter the expression of epigenetic proteins in Grade 4 astrocytoma. The interplay mechanism between IDH, O-6-methylguanine-DNA methyltransferase (-promoter methylation, and protein methyltransferase proteins-5 ( activity, with tumor progression has never been described.
METHODS
A retrospective cohort of 34 patients with G4 astrocytoma is classified into IDH-mutant and IDH-wildtype tumors. Both groups were tested for -promoter methylation and through methylation-specific and gene expression PCR analysis. Inter-cohort statistical significance was evaluated.
RESULTS
Both IDH-mutant WHO grade 4 astrocytomas (n = 22, 64.7%) and IDH-wildtype glioblastomas (n = 12, 35.3%) had upregulated gene expression except in one case. Out of the 22 IDH-mutant tumors, 10 (45.5%) tumors showed -promoter methylation and 12 (54.5%) tumors had unmethylated . All IDH-wildtype tumors had unmethylated . There was a statistically significant relationship between -promoter methylation and IDH in G4 astrocytoma (-value = 0.006). Statistically significant differences in progression-free survival (PFS) were also observed among all G4 astrocytomas that expressed and received either temozolomide (TMZ) or TMZ plus other chemotherapies, regardless of their IDH or -methylation status (-value=0.0014). Specifically, IDH-mutant tumors that had upregulated activity and -promoter methylation, who received only TMZ, have exhibited longer PFS.
CONCLUSIONS
The relationship between , -promoter, and IDH is not tri-directional. However, accumulation of D2-hydroxyglutarate (2-HG), which partially activates 2-OG-dependent deoxygenase, may not affect their activities. In IDH-wildtype glioblastomas, the 2HG-2OG pathway is typically inactive, leading to upregulation. TMZ alone, compared to TMZ-plus, can increase PFS in upregulated tumors. Thus, using a inhibitor in G4 astrocytomas may help in tumor regression.
Topics: Humans; Protein-Arginine N-Methyltransferases; Tumor Suppressor Proteins; Promoter Regions, Genetic; DNA Repair Enzymes; DNA Modification Methylases; DNA Methylation; Isocitrate Dehydrogenase; Male; Female; Astrocytoma; Disease Progression; Middle Aged; Mutation; Adult; Retrospective Studies; Brain Neoplasms; Neoplasm Grading; Aged; Temozolomide; Gene Expression Regulation, Neoplastic
PubMed: 38827324
DOI: 10.32604/or.2024.051112 -
Neoplasia (New York, N.Y.) Aug 2024Successful treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain neoplasm, mandates the need to develop new therapeutic strategies. In this...
Successful treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain neoplasm, mandates the need to develop new therapeutic strategies. In this study, we investigated the potential of PBI-05204 in targeting GBM stem cells (GSCs) and the underlying mechanisms. Treatment with PBI-05204 significantly reduced both the number and size of tumor spheres derived from patient-derived GSCs (GBM9, GSC28 and TS543), and suppressed the tumorigenesis of GBM9 xenografts. Moreover, PBI-05204 treatment led to a significant decrease in the expression of CD44 and NANOG, crucial markers of progenitor stem cells, in GBM9 and GSC28 GSCs. This treatment also down-regulated GRP78 expression in both GSC types. Knocking down GRP78 expression through GRP78 siRNA transfection in GBM9 and GSC28 GSCs also resulted in reduced spheroid size and CD44 expression. Combining PBI-05204 with GRP78 siRNA further decreased spheroid numbers compared to GRP78 siRNA treatment alone. PBI-05204 treatment led to increased expression of pRIP1K and pRIP3K, along with enhanced binding of RIPK1/RIPK3 in GBM9 and GSC28 cells, resembling the effects observed in GRP78-silenced GSCs, suggesting that PBI-05204 induced necroptosis in these cells. Furthermore, oleandrin, a principle active cardiac glycoside component of PBI-05204, showed the ability to inhibit the self-renewal capacity in GSCs. These findings highlight the potential of PBI-05204 as a promising candidate for the development of novel therapies that target GBM stem cells.
Topics: Endoplasmic Reticulum Chaperone BiP; Humans; Glioblastoma; Neoplastic Stem Cells; Animals; Mice; Heat-Shock Proteins; Cell Line, Tumor; Xenograft Model Antitumor Assays; Plant Extracts; Necroptosis; Brain Neoplasms; Cell Proliferation; Apoptosis; Disease Models, Animal; Hyaluronan Receptors
PubMed: 38823209
DOI: 10.1016/j.neo.2024.101008