Upregulated functional gene expression programmes in tumour pericytes mark progression in patients with low-grade glioma.
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ABSTRACT:
SUBMITTER: Oudenaarden C
PROVIDER: S-EPMC8763650 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and purposeThe aim of this longitudinal study is to evaluate large-scale perioperative resting state networks reorganization in patients with diffuse low-grade gliomas following awake surgery.Materials and methodsEighty-two patients with diffuse low-grade gliomas were prospectively enrolled and underwent awake surgical resection. Resting-state functional images were acquired at three time points: preoperative (MRI-1), immediate postoperative (MRI-2) and three months after surgery (MRI-3). We simultaneously performed perfusion-weighted imaging.ResultsComparing functional connectivity between MRI-1 and MRI-2, we observed a statistically significant functional homotopy decrease in cortical and subcortical supratentorial structures (P < 0.05). A functional homotopy increase was observed between MRI-2 and MRI-3 in parietal lobes, cingulum and putamen (P < 0.05). No significant functional connectivity modification was noticed between MRI-1 and MRI-3. Regional cerebral blood flow appeared transiently reduced on MRI-2 (P < 0.05). No correlation between neurological deficit and interhemispheric connectivity results was found.Conclusion/interpretationWe found a supratentorial widely distributed functional homotopy disruption between preoperative and immediate postoperative time points with a complete restitution three months after surgery with simultaneous variation of regional cerebral blood flow.
| S-EPMC5987867 | biostudies-literature
Project description:To examine the effect of Nf1 inactivation in astrocytes on normal microglia in the optic nerve, microglia from Nf1 flox/flox (FF) and Nf1 flox/flox; GFAP-Cre (FFC) were flow sorted. High throughput RNA-seq was employed to compare the expression profiles, and upregulated genes in microglia supportive to Nf1 deficient astrocytes were verified.
2020-07-03 | GSE65865 | GEO
Project description:ObjectiveIn the event of neural injury, the homologous contralateral brain areas may play a compensatory role to avoid or limit the functional loss. However, this dynamic strategy of functional redistribution is not clearly established, especially in the pathophysiological context of diffuse low-grade glioma. Our aim here was to assess the extent to which unilateral tumor infiltration of the insula dynamically modulates the functional connectivity of the contralesional one.MethodsUsing resting-state functional connectivity MRI, a seed-to-ROI approach was employed in 52 insula-centered glioma patients (n = 30 left and 22 right) compared with 19 age-matched healthy controls.ResultsUnsurprisingly, a significant decrease of the inter-insular connectivity was observed in both patient groups. More importantly, the analyses revealed a significant increase of the contralesional insular connectivity towards both cerebral hemispheres, especially in cortical areas forming the visual and the sensorimotor networks. This functional redistribution was not identified when the analyses were performed on three control regions for which the homologous area was not impaired by the tumor. This overall pattern of results indicates that massive infiltration of the insular cortex causes a significant redeployment of the contralesional functional connectivity.ConclusionThis general finding suggests that the undamaged insula plays a role in the functional compensation usually observed in this patient population, and thus provides compelling support for the concept of homotopic functional plasticity in brain-damaged patients.
| S-EPMC7840474 | biostudies-literature
Project description:Purpose of reviewPediatric low-grade gliomas (pLGGs) have been treated with similar therapies for the last 30 years. Recent biological insights have allowed a new generation of targeted therapies to be developed for these diverse tumors. At the same time, technological advances may redefine the late toxicities associated with radiation therapy. Understanding recent developments in pLGG therapy is essential to the management of these common pediatric tumors.Recent findingsIt is now well understood that aberrations of the mitogen-activated protein kinase pathway are key to oncogenesis in low-grade gliomas. This understanding, along with the development of available targeted agents, have heralded a new era of understanding and treatment for these patients. Promising, sustained responses are now being seen in early phase trials among patients with multiply recurrent/progressive disease. Also, newer and highly conformal radiation approaches such as proton beam radiotherapy maintain efficacy of radiation but limit radiation-associated toxicities.SummaryNovel therapies offer the potential for tumor control with greatly reduced toxicities. However, late effects of these therapies are just now being explored. Improved radiation approaches and targeted agents have the potential to redefine traditional therapy for pLGG.
| S-EPMC6664811 | biostudies-literature
Project description:Diffuse low-grade gliomas (DLGGs) growing on the insular lobe induce contralesional hemispheric insular lobe compensation of damaged functioning by increasing cortical volumes. However, it remains unclear how functional networks are altered in patients with insular lobe DLGGs during functional compensation. Thirty-five patients with insular DLGGs were classified into the left (insL, n = 16) and right groups (insR, n = 19), and 33 healthy subjects were included in the control group. Resting state functional magnetic resonance imaging was used to generate functional connectivity (FC), and network topological properties were evaluated using graph theoretical analysis based on FC matrices. Network-based statistics were applied to compare differences in the FC matrices. A false discovery rate was applied to correct the topological properties. There was no difference in the FC of edges between the control and insL groups; however, the nodal shortest path length of the right insular lobe was significantly increased in the insL group compared to the control group. Additionally, FC was increased in the functional edges originating from the left insular lobe in the insR group compared to the control group. Moreover, there were no differences in topological properties between the insR and control groups. The contralesional insular lobe is crucial for network alterations. The detailed patterns of network alterations were different depending on the affected hemisphere. The observed network alterations might be associated with functional network reorganization and functional compensation.
| S-EPMC7804949 | biostudies-literature
Project description:Low-grade gliomas (LGGs) are associated with neurological disability. The present study used microRNA (miRNA) expression profiles to identify risk miRNAs for potential prognosis of cerebral LGGs. miRNA expression profiles and clinical data from 408 patients with cerebral LGGs were obtained from the Cancer Genome Atlas database. Risk miRNAs were identified by plotting Kaplan?Meier curves and Cox proportional hazard regression analysis with the survival and KMsurv packages in R. A regulatory network of miRNA?targets was constructed, followed by gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis using the Database for Annotation, Visualization and Integrated Discovery. A protein?protein interaction (PPI) network of miRNA targets was built using Search Tool for the Retrieval of Interacting Genes software, and sub?pathway identification was performed using the iSubpathwayMiner package in R. In total, 39 miRNAs had significant effect on survival curves. Following the Cox analysis and construction of miRNA?targets regulatory network, hsa?miRNA (miR)?326 was identified to regulate 397 target genes. Additionally, targets of miR?326 were primarily enriched in the GO terms of cell proliferation, epithelial growth factor receptor and nerve growth factor signaling pathways. Additionally, son of sevenless homolog 1 (SOS1), neuroblastoma RAS viral oncogene homolog (NRAS), vitamin D receptor (VDR) and mothers against decapentaplegic family member 3 (SMAD3) were most enriched in the PPI network. Targets of miR?326 were primarily enriched in sub?pathways including sphingolipid metabolism and arachidonic acid metabolism, in which sphingomyelin synthase 1 (SGMS1) and hematopoietic prostaglandin D synthase (HPGDS) were screened out. Hsa?miR?326 was identified as a risk miRNA for prognosis and may improve the outcome prediction of patients with cerebral LGG. This miRNA may regulate cancer cell proliferation by targeting SOS1, NRAS, VDR, SMAD3, SGMS1 and HPGDS.
| S-EPMC5562009 | biostudies-literature
Project description:BackgroundLarge-scale genome-wide association studies (GWAS) have implicated thousands of germline genetic variants in modulating individuals' risk to various diseases, including cancer. At least 25 risk loci have been identified for low-grade gliomas (LGGs), but their molecular functions remain largely unknown.MethodsWe hypothesized that GWAS loci contain causal single nucleotide polymorphisms (SNPs) that reside in accessible open chromatin regions and modulate the expression of target genes by perturbing the binding affinity of transcription factors (TFs). We performed an integrative analysis of genomic and epigenomic data from The Cancer Genome Atlas and other public repositories to identify candidate causal SNPs within linkage disequilibrium blocks of LGG GWAS loci. We assessed their potential regulatory role via in silico TF binding sequence perturbations, convolutional neural network trained on TF binding data, and simulated annealing-based interpretation methods.ResultsWe built an interactive website (http://education.knoweng.org/alg3/) summarizing the functional footprinting of 280 variants in 25 LGG GWAS regions, providing rich information for further computational and experimental scrutiny. We identified as case studies PHLDB1 and SLC25A26 as candidate target genes of rs12803321 and rs11706832, respectively, and predicted the GWAS variant rs648044 to be the causal SNP modulating ZBTB16, a known tumor suppressor in multiple cancers. We showed that rs648044 likely perturbed the binding affinity of the TF MAFF, as supported by RNA interference and in vitro MAFF binding experiments.ConclusionsThe identified candidate (causal SNP, target gene, TF) triplets and the accompanying resource will help accelerate our understanding of the molecular mechanisms underlying genetic risk factors for gliomas.
| S-EPMC8041333 | biostudies-literature
Project description:Background:Diffuse low-grade gliomas (DLGGs) are rare and incurable tumors. Whereas maximal safe, functional-based surgical resection is the first-line treatment, the timing and choice of further treatments (chemotherapy, radiation therapy, or combined treatments) remain controversial. Methods:An online survey on the management of DLGG patients was sent to 28 expert centers from the European Low-Grade Glioma Network (ELGGN) in May 2015. It contained 40 specific questions addressing the modalities of use of chemotherapy in these patients. Results:The survey demonstrated a significant heterogeneity in practice regarding the initial management of DLGG patients and the use of chemotherapy. Interestingly, radiation therapy combined with the procarbazine, CCNU (lomustine), and vincristine regimen has not imposed itself as the gold-standard treatment after surgery, despite the results of the Radiation Therapy Oncology Group 9802 study. Temozolomide is largely used as first-line treatment after surgical resection for high-risk DLGG patients, or at progression. Conclusions:The heterogeneity in the management of patients with DLGG demonstrates that many questions regarding the postoperative strategy and the use of chemotherapy remain unanswered. Our survey reveals a high recruitment potential within the ELGGN for retrospective or prospective studies to generate new data regarding these issues.
| S-EPMC6660823 | biostudies-literature
Project description:This study aimed to assess the incidence and management of pseudoprogression after radiation therapy (RT) in patients with pediatric low-grade glioma (LGG). This retrospective review included patients aged 21 years or younger with intracranial LGG treated with curative-intent RT. Pseudoprogression was defined as an increase in tumor size by ≥10% in at least two dimensions between two and three consecutive MR imaging studies. Overall survival (OS) and event-free survival (EFS) were measured from the first day of RT. EFS was defined as survival without true progression or secondary high-grade glioma. Sixty-two of 221 patients developed pseudoprogression, with a 10-year cumulative incidence of 29.0% (95% CI 23.0-35.2). Median time to pseudoprogression was 6.1 months after RT. Symptomatic pseudoprogression was managed with subtotal resection, shunt/Ommaya reservoir placement, or corticosteroids in 11 (18%), 7 (11%), and 2 patients (3%), respectively. The remaining tumors were observed (68%). Patients with pilocytic astrocytoma (PA) had 5.4-fold greater odds of developing pseudoprogression relative to tumors of other histology (odds ratio 95% CI 2.5-11.4, P < 0.0001). Among patients with PA (n = 127), the 10-year cumulative incidence of pseudoprogression was 42.9%. In this group, pseudoprogression was associated with improved 10-year EFS (84.5% vs. 58.5%, P = 0.008) and OS (98.0% vs. 91.2%, P = 0.03). Pseudoprogression after irradiation was common, especially in patients with pilocytic astrocytoma, and was associated with improved survival. Knowledge of the incidence and temporal course of pseudoprogression may help avoid unnecessary salvage therapy.
| S-EPMC8717050 | biostudies-literature
Project description:Gliomas demonstrate epigenetic dysregulation exemplified by the Glioma CpG Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. 5-Hydroxymethylcytosine (5hmC) is implicated in glioma pathogenesis; however, its role in IDH1 mutant gliomas is incompletely understood. To characterize 5hmC in IDH1 mutant gliomas further, we examine 5hmC in a cohort of IDH1 mutant and wild-type high-grade gliomas (HGG) using a quantitative locus-specific approach. Regions demonstrating high 5hmC abundance and differentially hydroxymethylated regions (DHMR) enrich for enhancers implicated in glioma pathogenesis. Among these regions, IDH1 mutant tumors possess greater 5hmC compared to wild type. 5hmC contributes to overall methylation status of G-CIMP genes. 5hmC targeting gene body regions correlates significantly with increased gene expression. In particular, a strong correlation between increased 5hmC and increased gene expression is identified for genes highly expressed in the IDH1 mutant cohort. Overall, locus-specific gain of 5hmC targeting regulatory regions and associated with overexpressed genes suggests a significant role for 5hmC in IDH1 mutant HGG.
| S-EPMC5978937 | biostudies-literature