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Neurosurgical Focus Nov 2023Racial and socioeconomic disparities in neuro-oncological care for patients with brain tumors remain underexplored. This study aimed to analyze county-level disparities...
OBJECTIVE
Racial and socioeconomic disparities in neuro-oncological care for patients with brain tumors remain underexplored. This study aimed to analyze county-level disparities in glioblastoma (GBM) care in the United States, focusing on access to surgery and the use of adjuvant temozolomide chemotherapy and radiation therapy.
METHODS
Using repeated cross-sectional data from the Surveillance, Epidemiology, and End Results 17 database; the Area Health Resources File; and the American Community Survey, from 2010 to 2019, the authors performed multivariate regression analyses to understand the associations between county-level racial and socioeconomic characteristics, as well as the rates of surgery performed, delays in surgery, and use of adjuvant chemotherapy and radiation therapy for newly diagnosed GBM.
RESULTS
In total, 29,609 GBM patients from 602 different US counties over a decade were included in this study. Counties with lower rates of surgery for GBM were associated with a higher percentage of Black residents (coefficient [CE] -0.001, 95% CI -0.002 to 0; p < 0.05) and being located in the Midwest (CE -0.132, 95% CI -0.195 to -0.069; p < 0.001) or West (CE -0.127, 95% CI -0.189 to -0.065; p < 0.001) relative to the Northeast. Counties with delayed surgical treatment were more likely to lack neurosurgeons (adjusted OR [aOR] 2.52, 95% CI 1.77-3.60; p < 0.001), have a higher percentage of Black residents (aOR 1.011, 95% CI 1.00-1.02; p < 0.05), and be located in the Midwest (aOR 3.042, 95% CI 1.12-8.24; p < 0.05) or West (aOR 3.175, 95% CI 1.12-8.97 p < 0.05). Counties with high rates of adjuvant radiation therapy were less likely to have higher percentages of Black residents (aOR 0.987, 95% CI 0.980-0.995; p < 0.01) and uninsured individuals (aOR 0.962, 95% CI 0.937-0.987; p < 0.01).
CONCLUSIONS
Counties without neurosurgeons and those with a higher percentage of Black patients have delays in surgical care and demonstrate lower overall rates of surgery and adjuvant therapy for GBM. This study underscores the need for targeted interventions and policies that address structural barriers in healthcare access, improve equitable distribution of the neurosurgery workforce, and ensure timely and comprehensive GBM care to all populations.
Topics: Humans; United States; Glioblastoma; Cross-Sectional Studies; Socioeconomic Factors; Brain Neoplasms; Health Resources
PubMed: 37913538
DOI: 10.3171/2023.8.FOCUS23454 -
International Journal of Molecular... Dec 2023Glioma cells exhibit genetic and metabolic alterations that affect the deregulation of several cellular signal transduction pathways, including those related to glucose... (Review)
Review
Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma.
Glioma cells exhibit genetic and metabolic alterations that affect the deregulation of several cellular signal transduction pathways, including those related to glucose metabolism. Moreover, oncogenic signaling pathways induce the expression of metabolic genes, increasing the metabolic enzyme activities and thus the critical biosynthetic pathways to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates that are essential to accomplish the biosynthetic needs of glioma cells. In this review, we aim to explore how dysregulated metabolic enzymes and their metabolites from primary metabolism pathways in glioblastoma (GBM) such as glycolysis and glutaminolysis modulate anabolic and catabolic metabolic pathways as well as pro-oncogenic signaling and contribute to the formation, survival, growth, and malignancy of glioma cells. Also, we discuss promising therapeutic strategies by targeting the key players in metabolic regulation. Therefore, the knowledge of metabolic reprogramming is necessary to fully understand the biology of malignant gliomas to improve patient survival significantly.
Topics: Humans; Glioblastoma; Glutamine; Metabolic Reprogramming; Glycolysis; Glioma; Signal Transduction; Apoptosis; Cell Proliferation
PubMed: 38139462
DOI: 10.3390/ijms242417633 -
Journal of Nanobiotechnology Jul 2023Although RNA interference (RNAi) therapy has emerged as a potential tool in cancer therapeutics, the application of RNAi to glioblastoma (GBM) remains a hurdle. Herein,...
Although RNA interference (RNAi) therapy has emerged as a potential tool in cancer therapeutics, the application of RNAi to glioblastoma (GBM) remains a hurdle. Herein, to improve the therapeutic effect of RNAi on GBM, a cancer cell membrane (CCM)-disguised hypoxia-triggered RNAi nanomedicine was developed for short interfering RNA (siRNA) delivery to sensitize cells to chemotherapy and radiotherapy. Our synthesized CCM-disguised RNAi nanomedicine showed prolonged blood circulation, high BBB transcytosis and specific accumulation in GBM sites via homotypic recognition. Disruption and effective anti-GBM agents were triggered in the hypoxic region, leading to efficient tumor suppression by using phosphoglycerate kinase 1 (PGK1) silencing to enhance paclitaxel-induced chemotherapy and sensitize hypoxic GBM cells to ionizing radiation. In summary, a biomimetic intelligent RNAi nanomedicine has been developed for siRNA delivery to synergistically mediate a combined chemo/radiotherapy that presents immune-free and hypoxia-triggered properties with high survival rates for orthotopic GBM treatment.
Topics: Humans; Glioblastoma; RNA Interference; Brain Neoplasms; Nanomedicine; Biomimetics; RNA, Small Interfering; Hypoxia; Cell Line, Tumor
PubMed: 37408007
DOI: 10.1186/s12951-023-01960-w -
Seminars in Cancer Biology Jun 2024Glioblastoma (GBM) is the most aggressive tumor among the gliomas and intracranial tumors and to date prognosis for GBM patients remains poor, with a median survival... (Review)
Review
Glioblastoma (GBM) is the most aggressive tumor among the gliomas and intracranial tumors and to date prognosis for GBM patients remains poor, with a median survival typically measured in months to a few years depending on various factors. Although standardized therapies are routinely employed, it is clear that these strategies are unable to cope with heterogeneity and invasiveness of GBM. Furthermore, diagnosis and monitoring of responses to therapies are directly dependent on tissue biopsies or magnetic resonance imaging (MRI) techniques. From this point of view, liquid biopsies are arising as key sources of a variety of biomarkers with the advantage of being easily accessible and monitorable. In this context, extracellular vesicles (EVs), physiologically shed into body fluids by virtually all cells, are gaining increasing interest both as natural carriers of biomarkers and as specific signatures even for GBM. What makes these vesicles particularly attractive is they are also emerging as therapeutical vehicles to treat GBM given their native ability to cross the blood-brain barrier (BBB). Here, we reviewed recent advances on the use of EVs as biomarker for liquid biopsy and nanocarriers for targeted delivery of anticancer drugs in glioblastoma.
Topics: Humans; Glioblastoma; Extracellular Vesicles; Biomarkers, Tumor; Brain Neoplasms; Animals; Liquid Biopsy; Blood-Brain Barrier; Antineoplastic Agents
PubMed: 38754752
DOI: 10.1016/j.semcancer.2024.04.003 -
Journal of Cellular and Molecular... Aug 2023Suppressor of cytokine signalling (SOCS) 1/2/3/4 are involved in the occurrence and progression of multiple malignancies; however, their prognostic and developmental...
Suppressor of cytokine signalling (SOCS) 1/2/3/4 are involved in the occurrence and progression of multiple malignancies; however, their prognostic and developmental value in patients with glioblastoma (GBM) remains unclear. The present study used TCGA, ONCOMINE, SangerBox3.0, UALCAN, TIMER2.0, GENEMANIA, TISDB, The Human Protein Atlas (HPA) and other databases to analyse the expression profile, clinical value and prognosis of SOCS1/2/3/4 in GBM, and to explore the potential development mechanism of action of SOCS1/2/3/4 in GBM. The majority of analyses showed that SOCS1/2/3/4 transcription and translation levels in GBM tissues were significantly higher than those in normal tissues. qRT-PCR, western blotting (WB) and immunohistochemical staining were used to verify that SOCS3 was expressed at higher mRNA and protein levels in GBM than in normal tissues or cells. High SOCS1/2/3/4 mRNA expression was associated with poor prognosis in patients with GBM, especially SOCS3. SOCS1/2/3/4 were highly contraindicated, which had few mutations, and were not associated with clinical prognosis. Furthermore, SOCS1/2/3/4 were associated with the infiltration of specific immune cell types. In addition, SOCS3 may affect the prognosis of patients with GBM through JAK/STAT signalling pathway. Analysis of the GBM-specific protein interaction (PPI) network showed that SOCS1/2/3/4 were involved in multiple potential carcinogenic mechanisms of GBM. In addition, colony formation, Transwell, wound healing and western blotting assays revealed that inhibition of SOCS3 decreased the proliferation, migration and invasion of GBM cells. In conclusion, the present study elucidated the expression profile and prognostic value of SOCS1/2/3/4 in GBM, which may provide potential prognostic biomarkers and therapeutic targets for GBM, especially SOCS3.
Topics: Humans; Glioblastoma; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling 3 Protein; Prognosis; Suppressor of Cytokine Signaling Proteins; RNA, Messenger; Biomarkers
PubMed: 37315184
DOI: 10.1111/jcmm.17807 -
Cell Reports Sep 2023Metabolic rewiring is essential for cancer onset and progression. We previously showed that one-carbon metabolism-dependent formate production often exceeds the anabolic...
Metabolic rewiring is essential for cancer onset and progression. We previously showed that one-carbon metabolism-dependent formate production often exceeds the anabolic demand of cancer cells, resulting in formate overflow. Furthermore, we showed that increased extracellular formate concentrations promote the in vitro invasiveness of glioblastoma cells. Here, we substantiate these initial observations with ex vivo and in vivo experiments. We also show that exposure to exogeneous formate can prime cancer cells toward a pro-invasive phenotype leading to increased metastasis formation in vivo. Our results suggest that the increased local formate concentration within the tumor microenvironment can be one factor to promote metastases. Additionally, we describe a mechanistic interplay between formate-dependent increased invasiveness and adaptations of lipid metabolism and matrix metalloproteinase activity. Our findings consolidate the role of formate as pro-invasive metabolite and warrant further research to better understand the interplay between formate and lipid metabolism.
Topics: Humans; Lipid Metabolism; Glioblastoma; Formates; Neoplasm Invasiveness; Tumor Microenvironment
PubMed: 37651228
DOI: 10.1016/j.celrep.2023.113034 -
Drug Delivery Dec 2023Sonodynamic therapy (SDT) has aroused great interest for its potential in the treatment of glioblastoma (GBM). SDT relies on tumor-selective accumulation of a...
Sonodynamic therapy (SDT) has aroused great interest for its potential in the treatment of glioblastoma (GBM). SDT relies on tumor-selective accumulation of a sonosensitizer that is activated by ultrasound irradiation (UI) to generate cytotoxic actions. The efficacy of GBM-SDT depends on sufficient sonosensitizer buildup in the tumor, which is, however, seriously hampered by the anatomical and biochemical barriers of the GBM. To overcome this difficulty, we herein propose a delivery strategy of 'platelets with ultrasound-triggered release property', which takes advantage of 1) the platelets' ability to carry cargo and release cargo upon activation, and 2) the ROS-generating property of SDT. To provide proof of concept for the strategy, we first stably loaded platelets with IOPD-Ce6, a nano-formed sonosensitizer consisting of iron oxide nanoparticles coated with polyglycerol and doxorubicin and loaded with chlorine e6. UI of the IOPD-Ce6-loaded platelets (IOPD-Ce6@Plt) elicited ROS generation in the IOPD-Ce6@Plt, which were immediately activated to release IOPD-Ce6 into GBM cells in co-culture which, when subjected to a second time of UI, exhibited pronounced ROS production, DNA injury, viability loss, and cell death in the GBM cells. In the in vivo experiments, mice bearing intracranial GBM grafts exhibited substantial tumor distribution of IOPD-Ce6 following intravenous injection of IOPD-Ce6@Plt and subsequent UI at the tumor site. The GBM grafts then exhibited pronounced cell injury and death after another round of UI of the tumors. Finally, the growth of intra-cranial GBM grafts was significantly slowed when an SDT protocol consisting of an intravenous IOPD-Ce6@Plt injection followed by multiple times of tumor UI had been applied twice to the mice. Our results are strong evidence for the idea that platelets are sound and amenable carriers to deliver sonosensitizers in the GBM in an ultrasound-triggered manner and thus to produce highly targeted and effective SDT of GBM.
Topics: Animals; Mice; Glioblastoma; Drug Liberation; Reactive Oxygen Species; Cell Line, Tumor; Ultrasonography
PubMed: 37264811
DOI: 10.1080/10717544.2023.2219429 -
Advanced Science (Weinheim,... Feb 2024Glioblastoma (GBM) is a lethal cancer characterized by hypervascularity and necrosis associated with hypoxia. Here, it is found that hypoxia preferentially induces the...
Glioblastoma (GBM) is a lethal cancer characterized by hypervascularity and necrosis associated with hypoxia. Here, it is found that hypoxia preferentially induces the actin-binding protein, Transgelin (TAGLN), in GBM stem cells (GSCs). Mechanistically, TAGLN regulates HIF1α transcription and stabilizes HDAC2 to deacetylate p53 and maintain GSC self-renewal. To translate these findings into preclinical therapeutic paradigm, it is found that sodium valproate (VPA) is a specific inhibitor of TAGLN/HDAC2 function, with augmented efficacy when combined with natural borneol (NB) in vivo. Thus, TAGLN promotes cancer stem cell survival in hypoxia and informs a novel therapeutic paradigm.
Topics: Humans; Glioblastoma; Tumor Suppressor Protein p53; Acetylation; Brain Neoplasms; Microfilament Proteins; Hypoxia; Neoplastic Stem Cells; Muscle Proteins
PubMed: 38087889
DOI: 10.1002/advs.202305620 -
Clinical and Translational Medicine Feb 2024Paediatric and adult astrocytomas are notably different, where clinical treatments used for adults are not as effective on children with the same form of cancer and... (Review)
Review
Paediatric and adult astrocytomas are notably different, where clinical treatments used for adults are not as effective on children with the same form of cancer and these treatments lead to adverse long-term health concerns. Integrative omics-based studies have shown the pathology and fundamental molecular characteristics differ significantly and cannot be extrapolated from the more widely studied adult disease. Recent clinical advances in our understanding of paediatric astrocytomas, with the aid of next-generation sequencing and epigenome-wide profiling, have led to the identification of key canonical mutations that vary based on the tumour location and age of onset. These driver mutations, in particular the identification of the recurrent histone H3 mutations in high-grade tumours, have confirmed the important role epigenetic dysregulations play in cancer progression. This review summarises the current updates of the classification, epidemiology, pathogenesis and clinical management of paediatric astrocytoma based on their grades and the ongoing clinical trials. It also provides novel insights on genetic and epigenetic alterations as diagnostic biomarkers, highlighting the potential of targeting these pathways as therapeutics for this devastating childhood cancer.
Topics: Adult; Humans; Child; Brain Neoplasms; Astrocytoma; Histones; Epigenesis, Genetic; Epigenomics
PubMed: 38299304
DOI: 10.1002/ctm2.1560 -
Cancer Letters Sep 2023Oncolytic viruses (OVs) have emerged as a clinical therapeutic modality potentially effective for cancers that evade conventional therapies, including central nervous...
Oncolytic viruses (OVs) have emerged as a clinical therapeutic modality potentially effective for cancers that evade conventional therapies, including central nervous system malignancies. Rationally designed combinatorial strategies can augment the efficacy of OVs by boosting tumor-selective cytotoxicity and modulating the tumor microenvironment (TME). Photodynamic therapy (PDT) of cancer not only mediates direct neoplastic cell death but also primes the TME to sensitize the tumor to secondary therapies, allowing for the combination of two potentially synergistic therapies with broader targets. Here, we created G47Δ-KR, clinical oncolytic herpes simplex virus G47Δ that expresses photosensitizer protein KillerRed (KR). Optical properties and cytotoxic effects of G47Δ-KR infection followed by amber LED illumination (peak wavelength: 585-595 nm) were examined in human glioblastoma (GBM) and malignant meningioma (MM) models in vitro. G47Δ-KR infection of tumor cells mediated KR expression that was activated by LED and produced reactive oxygen species, leading to cell death that was more robust than G47Δ-KR without light. In vivo, we tested photodynamic-oncolytic virus (PD-OV) therapy employing intratumoral injection of G47Δ-KR followed by laser light tumor irradiation (wavelength: 585 nm) in GBM and MM xenografts. PD-OV therapy was feasible in these models and resulted in potent anti-tumor effects that were superior to G47Δ-KR alone (without laser light) or laser light alone. RNA sequencing analysis of post-treatment tumor samples revealed PD-OV therapy-induced increases in TME infiltration of variable immune cell types. This study thus demonstrated the proof-of-concept that G47Δ-KR enables PD-OV therapy for neuro-oncological malignancies and warrants further research to advance potential clinical translation.
Topics: Humans; Oncolytic Virotherapy; Central Nervous System Neoplasms; Meningioma; Oncolytic Viruses; Glioblastoma; Meningeal Neoplasms; Tumor Microenvironment
PubMed: 37619813
DOI: 10.1016/j.canlet.2023.216363