RESUMO
Medulloblastoma (MB) is the most common malignant childhood brain tumour1,2, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella3-5 have not fully defined the compositional heterogeneity of MBs. Here we undertook single-cell profiling of freshly isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group 3 and metastatic tumours. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group 3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group 3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group 3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs show potential cell populations predisposed to transformation and regulatory circuitries underlying tumour cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.
Assuntos
Neoplasias Encefálicas , Transformação Celular Neoplásica , Feto , Meduloblastoma , Humanos , Neoplasias Encefálicas/patologia , Transformação Celular Neoplásica/patologia , Neoplasias Cerebelares/patologia , Cerebelo/citologia , Cerebelo/patologia , Feto/citologia , Feto/patologia , Meduloblastoma/patologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/patologia , PrognósticoRESUMO
PURPOSE: Lateral ventricle meningiomas (LVM) in children are very rare. The current research is mostly limited to adults, and there are very few related studies on children. The purpose of this study was to analyze the clinicopathological and imaging features of lateral ventricle meningiomas in children. METHODS: A retrospective analysis of five children with pathologically confirmed lateral ventricle meningioma was performed, and we collected clinical data, including clinicopathological data, treatment prognosis data, and imaging features (including tumor location, signal intensity, enhancement degree, intratumoral cyst, calcification, peritumoral edema, and associated hydrocephalus). RESULTS: Among the 5 patients with LVM, 4 were male and 1 was female with an average age of 7.6 years (range 2 to 12 years). All CT scans showed slight hyperintensity or isodensity, and only 1 patient had calcification. Two patients demonstrated cyst changes. Four patients had varying degrees of peritumoral edema. The average tumor volume was 164.1 cm3 (1.4-314.9 cm3). All 5 patients with LVM were iso- or hypointense on T1WI. The T2WI signals had no obvious features. Four patients had a high signal on DWI (80%). The contrast-enhanced signals were mostly homogeneously strong (80%). MRI showed hydrocephalus in 3 patients. All patients underwent gross total resection, and they were followed up regularly after the operation. The average follow-up time was 47.4 months. No recurrence was found in any of the children. All patients were pathologically confirmed to have meningiomas, and WHO grades were all grade I. CONCLUSION: Lateral ventricle meningiomas in children are very rare, and the imaging manifestations of the tumor have certain characteristics, but the clinical diagnosis is still difficult, and the diagnosis still requires pathological analysis.
Assuntos
Coristoma , Cistos , Hidrocefalia , Neoplasias Meníngeas , Meningioma , Adulto , Humanos , Masculino , Criança , Feminino , Pré-Escolar , Meningioma/cirurgia , Neoplasias Meníngeas/cirurgia , Estudos Retrospectivos , Ventrículos Laterais/patologia , Imageamento por Ressonância Magnética/métodos , EdemaRESUMO
Recent efforts have revealed that numerous oncogenic lncRNAs have been found play pivotal role in Glioma progression while there is little know about anti-oncogenic lncRNAs in Glioma. In current study, we found a HMGB1 regulated lncRNA, Linc00320, is significantly decreased in Glioma malignant tissues and its low expression predicts poor prognosis. Moreover, we found that the nucleus localized Linc00320 inhibits Glioma cell proliferation both in vitro and in vivo. In addition, we found that Linc00320 binds to ß-catenin and inhibits the activity of Wnt/ß-catenin signaling by disrupting ß-catenin binds to TCF4 in Glioma cells. Taken together, we firstly demonstrated the tumor suppressive lncRNA, Linc00320, is down-regulated in Glioma tissues and inhibits Glioma cell proliferation by restraining Wnt/ß-catenin signaling through segregating ß-catenin and TCF4 and revealed the novel HMGB1/Linc00320/ß-catenin axis in Glioma progression.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Glioma/genética , Glioma/metabolismo , RNA Longo não Codificante/genética , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo , Genes Supressores de Tumor , Glioma/patologia , Proteína HMGB1/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , RNA Longo não Codificante/metabolismo , Fator de Transcrição 4/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
Objective: It is challenging for neurosurgeons to perform surgeries on patients without detectable structural lesions. Therefore, this retrospective study aimed to explore the outcome of stereo-electroencephalography (SEEG) in suspicious areas guided by magnetoencephalography (MEG)-magnetic resonance imaging (MRI) reconstruction in MRI-negative epilepsy patients. Methods: This study included 47 patients with negative-MRI epilepsy. Seizure outcome at 24 months was assessed using a modified Engel's classification. Accordingly, class I and II were considered favorable outcomes, whereas classes III and IV were unfavorable. Furthermore, patients were classified into a consistent group if the results of MEG and SEEG indicated the same area of the brain. The relationship between surgical outcome and the concordance of MEG and SEEG was analyzed. Results: A complete seizure-free condition was achieved in 22 (47%) patients. Sex, handedness, age and duration of illness were not significantly associated with seizure-free outcome (p = .187 [Pearson chi-squared test]). The number of patients with favorable outcome (Engle I and II) was as high as 68% at the time of follow-up. Furthermore, more seizure-free patients were found in the SEEG and MEG consistent group. Conclusions: SEEG is a valuable tool in the pre-evaluation for resective epilepsy surgery, particularly in negative-MRI epilepsy patients; MEG greatly facilitates localization for SEEG electrode implantation. However, none of these tools are absolutely sensitive and reliable; therefore, collecting as much information as possible is necessary to achieve satisfactory results in epilepsy surgery.
Assuntos
Eletrocorticografia/métodos , Epilepsia/diagnóstico , Epilepsia/cirurgia , Magnetoencefalografia/métodos , Procedimentos Neurocirúrgicos/métodos , Avaliação de Resultados em Cuidados de Saúde , Adolescente , Adulto , Criança , Eletrocorticografia/normas , Epilepsia/fisiopatologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: The occurrence and predictors of symptomatic subdural hygroma (SSH) subsequent to the fenestration of pediatric intracranial arachnoid cysts (IACs) are unclear. In this study, the authors aimed to investigate the likelihood of an SSH following IAC fenestration and the impact on operative efficacy with the ultimate goal of constructing a nomogram. METHODS: The medical records of 1782 consecutive patients who underwent surgical treatment at the Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were reviewed. Among these patients, a training cohort (n = 1214) underwent surgery during an earlier period and was used for the development of a nomogram. The remaining patients formed the validation cohort (n = 568) and were used to confirm the performance of the developed model. The development of the nomogram involved the use of potential predictors, while internal validation was conducted using a bootstrap-resampling approach. RESULTS: SSH was detected in 13.2% (160 of 1214) of patients in the training cohort and in 11.1% (63 of 568) of patients in the validation cohort. Through multivariate analysis, several factors including Galassi type, IAC distance to the basal cisterns, temporal bulge, midline shift, IAC shape in the coronal view, area of the stoma, and artery location near the stoma were identified as independent predictors of SSH. These 7 predictors were used to construct a nomogram, which exhibited a concordance statistic (C-statistic) of 0.826 and demonstrated good calibration. Following internal validation, the nomogram maintained good calibration and discrimination with a C-statistic of 0.799 (95% CI 0.665-0.841). Patients who had nomogram scores < 30 or ≥ 30 were considered to be at low and high risk of SSH occurrence, respectively. CONCLUSIONS: The predictive model and derived nomogram achieved satisfactory preoperative prediction of SSH. Using this nomogram, the risk for an individual patient can be estimated, and the appropriate surgery can be performed in high-risk patients.
Assuntos
Cistos Aracnóideos , Derrame Subdural , Humanos , Criança , Cistos Aracnóideos/diagnóstico por imagem , Cistos Aracnóideos/cirurgia , Nomogramas , China , HospitaisRESUMO
Medulloblastoma (MB) is a prevalent malignant brain tumor among children, which can be classified into four primary molecular subgroups. Group 3 MB (G3-MB) is known to be highly aggressive and associated with a poor prognosis, necessitating the development of novel and effective therapeutic interventions. Ferroptosis, a regulated form of cell death induced by lipid peroxidation, has been identified as a natural tumor suppression mechanism in various cancers. Nevertheless, the potential role of ferroptosis in the treatment of G3-MB remains unexplored. In this study, we demonstrate that RNF126 acts as an anti-ferroptotic gene by interacting with ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) and ubiquitinating FSP1 at the 4KR-2 sites. Additionally, the deletion of RNF126 reduces the subcellular localization of FSP1 in the plasma membrane, resulting in an increase in the CoQ/CoQH2 ratio in G3-MB. The RNF126-FSP1-CoQ10 pathway plays a pivotal role in suppressing phospholipid peroxidation and ferroptosis both in vivo and in vitro. Clinically, RNF126 exhibited elevated expression in G3-MB and its overexpression was significantly associated with reduced patient survival. Our findings indicate that RNF126 regulates G3-MB sensitivity to ferroptosis by ubiquitinating FSP1, which provides new evidence for the potential G3-MB therapy.
Assuntos
Ferroptose , Proteínas Mitocondriais , Ubiquitina-Proteína Ligases , Ubiquitinação , Ferroptose/genética , Humanos , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Animais , Camundongos , Linhagem Celular Tumoral , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Regulação Neoplásica da Expressão GênicaRESUMO
Background: The significant progress of immune therapy in non-central nervous system tumors has sparked interest in employing the same strategy for adult brain tumors. However, the advancement of immunotherapy in pediatric central nervous system (CNS) tumors is not yet on par. Currently, there is a lack of comprehensive comparative studies investigating the immune ecosystem in pediatric and adult CNS tumors at a high-resolution single-cell level. Methods: In this study, we comprehensively analyzed over 0.3 million cells from 171 samples, encompassing adult gliomas (IDH wild type and IDH mutation) as well as four major types of pediatric brain tumors (medulloblastoma (MB), ependymoma (EPN), H3K27M-mutation (DIPG), and pediatric IDH-mutation glioma (P-IDH-M)). Our approach involved integrating publicly available and newly generated single-cell datasets. We compared the immune landscapes in different brain tumors, as well as the detailed functional phenotypes of T-cell and myeloid subpopulations. Through single-cell analysis, we identified gene sets associated with major cell types in the tumor microenvironment (gene features from single-cell data, scFes) and compared them with existing gene sets such as GSEA and xCell. The CBTTC and external GEO cohort was used to analyze and validate the immune-stromal-tumor patterns in pediatric brain tumors which might potentially respond to the immunotherapy. Results: From the perspective of single-cell analysis, it was observed that major pediatric brain tumors (MB, EPN, P-IDH-M, DIPG) exhibited lower immune contents compared with adult gliomas. Additionally, these pediatric brain tumors displayed diverse immunophenotypes, particularly in regard to myeloid cells. Notably, the presence of HLA-enriched myeloid cells in MB was found to be independently associated with prognosis. Moreover, the scFes, when compared with commonly used gene features, demonstrated superior performance in independent single-cell datasets across various tumor types. Furthermore, our study revealed the existence of heterogeneous immune ecosystems at the bulk-RNA sequencing level among different brain tumor types. In addition, we identified several immune-stromal-tumor patterns that could potentially exhibit significant responses to conventional immune checkpoint inhibitors. Conclusion: The single-cell technique provides a rational path to deeply understand the unique immune ecosystem of pediatric brain tumors. In spite of the traditional attitudes of "cold" tumor towards pediatric brain tumor, the immune-stroma-tumor patterns identified in this study suggest the feasibility of immune checkpoint inhibitors and pave the way for the upcoming tide of immunotherapy in pediatric brain tumors.
Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Neoplasias Cerebelares , Glioma , Meduloblastoma , Humanos , Criança , Adulto , Ecossistema , Inibidores de Checkpoint Imunológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patologia , Glioma/genética , Glioma/terapia , Análise de Sequência de RNA , RNA , Microambiente Tumoral/genéticaRESUMO
Minichromosome maintenance proteins are DNA-dependent ATPases that bind to replication origins and allow a single round of DNA replication. One member of this family, MCM3, is reportedly active in most cancers. To systematically elucidate the mechanisms affected by aberrant MCM3 expression and evaluate its clinical significance, we analyzed multi-omics data from the GEO database and validated them in cell lines and tumor samples. First, we showed the upregulation of MCM3 in medulloblastoma (MB) at bulk and single-cell RNA sequence levels and revealed the potential role of MCM3 via DNA replication. Then we found the dysregulation of MCM3 might result from abnormal methylation of MCM3. Moreover, we discovered that MCM3 might affect varied biological processes such as apoptosis, autophagy, and ferroptosis and that MCM3 was correlated with immune components such as fibroblast and neutrophils, which were associated with overall survival in different medulloblastoma subtypes. Furthermore, we found that MCM3 expression was correlated with the IC50 values of cisplatin and etoposide. The nomogram of MCM3-related genes showed the reliable and better prediction of 1- and 5-year survival compared to current histological and molecular classifications. Overall, the results of our study demonstrated that MCM3 might serve as a potential biomarker with clinical significance and better guidance than current histological and molecular classifications for clinical decision-making.
RESUMO
[This corrects the article DOI: 10.3389/fmolb.2022.815260.].
RESUMO
Background: Children are more susceptible to the higher rate of massive blood transfusion because of the less allowable blood loss and lower intraoperative tolerance to blood loss during the resection of brain tumors. The surgical concept of en bloc resection, which is widely used in other tumors, may contribute to the improvement of brain tumor resection. However, there is still a lack of comprehensive research on its application in pediatric brain tumors. Objective: The aim of this study is to investigate the outcomes of the en bloc concept and the factors associated with the application of the en bloc concept in pediatric brain tumors. Methods: According to the surgical concept involved, the patients were divided into three subgroups: complete en bloc concept, partial en bloc concept, and piecemeal concept. The matching comparison (complete and partial en bloc concept groups vs. piecemeal concept group) was conducted to investigate the effect of the en bloc concept on the outcomes. Then, the patient data from January 2018, when the en bloc concept was routinely integrated into the brain tumor surgery in our medical center, were reviewed and analyzed to find out the predictors associated with the application of en bloc concept. Results: In the en bloc group, the perioperative parameters, such as hospital stay (p = 0.001), pediatric intensive care unit (PICU) stay (p = 0.003), total blood loss (p = 0.015), transfusion rate (p = 0.005), and complication rate (p = 0.039), were all significantly improved. The multinomial logistic regression analysis showed that tumor volume, bottom vessel, and imaging features, such as encasing nerve or pass-by vessel, finger-like attachment, ratio of "limited line", and ratio of "clear line", were independent predictors for the application of the en bloc concept in our medical center. Conclusion: This study supports the application of complete and partial en bloc concept in the pediatric brain tumor surgery based on the preoperative evaluation of imaging features, and compared with the piecemeal concept, the en bloc concept can improve the short outcomes without significant increases in the neurological complications. Large-series and additional supportive pieces of evidence are still warranted.
RESUMO
Background: Tumor purity is defined as the proportion of cancer cells in the tumor tissue, and its effects on molecular genetics, the immune microenvironment, and the prognosis of children's central nervous system (CNS) tumors are under-researched. Methods: We applied random forest machine learning, the InfiniumPurify algorithm, and the ESTIMATE algorithm to estimate the tumor purity of every child's CNS tumor sample in several published pediatric CNS tumor sample datasets from Gene Expression Omnibus (GEO), aiming to perform an integrated analysis on the tumor purity of children's CNS tumors. Results: Only the purity of CNS tumors in children based on the random forest (RF) machine learning method was normally distributed. In addition, the children's CNS tumor purity was associated with primary clinical pathological and molecular indicators. Enrichment analysis of biological pathways related to the purity of medulloblastoma (MB) revealed some classical signaling pathways associated with MB biology and development-related pathways. According to the correlation analysis between MB purity and the immune microenvironment, three immune-related genes, namely, CD8A, CXCR2, and TNFRSF14, were negatively related to MB purity. In contrast, no significant correlation was detected between immunotherapy-associated markers, such as PD-1, PD-L1, and CTLA4; most infiltrating immune cells; and MB purity. In the tumor purity-related survival analysis of MB, ependymoma (EPN), and children's high-grade glioma, we discovered a minor effect of tumor purity on the survival of the aforementioned pediatric patients with CNS tumors. Conclusion: Our purity pediatric pan-CNS tumor analysis provides a deeper understanding and helps with the clinical management of pediatric CNS tumors.
RESUMO
Glioblastoma is a rare yet lethal type of tumor that poses a crucible for the medical profession, owing to its rapid proliferation and invasion resulting in poor prognosis. Circular RNAs (circRNAs), a subclass of regulatory RNAs, are implicated in the regulation of cancerous progression. This study aims to investigate the roles and underlying mechanism of circPIK3C2A in regulating proliferation and invasion of glioblastoma. qRT-PCR assays showed that the expression level of circPIK3C2A was aberrantly higher in glioblastoma cell lines, in comparison with that in normal glia cells. The ectopic expression of circPIK3C2A promoted the proliferation, invasion and clonal formation of glioblastoma cells, while circPIK3C2A loss-of-function exerted exactly the opposite biological effects on the cells. The construction of subcutaneous xenograft tumor model in nude mice indicated that circPIK3C2A loss-of-function effectively diminished tumor load in vivo and prolonged the survival time of tumor-bearing animals. Luciferase reporter assay confirmed the interaction among circPIK3C2A/miR-877-5p and FOXM1. CircPIK3C2A function as competitive endogenous RNA via sponging miR-877-5p through certain binding sites, thereby modulating the expression of FOXM1. Our results collectively indicate that circPIK3C2A functions as ceRNA by mediating miR-877-5p/FOXM1 axis, providing a novel perspective of applying CircPIK3C2A in the clinical intervention of glioblastoma in the future.
RESUMO
PURPOSE: In medulloblastoma (MB), group 3 (G3) patients with MYC amplification tend to exhibit worse prognosis, thus creating a need for novel effective therapies. As the driver and crucial dependency for MYC-amplified G3-MB, MYC has been proven to be a prospective therapeutic target. Here, we aimed to identify novel effective therapeutic strategies against MYC-amplified G3-MB via targeting MYC translation. MATERIALS AND METHODS: Major components of translation initiation complex eIF4F were subjected to MB tumor dataset analysis, and EIF4A1 was identified to be a potential therapeutic target of MYC-amplified G3-MB. Validation was performed through genetic or pharmacological approaches with multiple patient-derived tumor models of MYC-amplified G3-MB in vitro and in vivo. Underlying mechanisms were further explored by Western blot, quantitative real-time PCR and mass spectrometry (MS) analyses. RESULTS: MB tumor datasets analyses showed that EIF4A1 was significantly up-regulated in G3-MB patients relative to normal cerebella, positively correlated with MYC in G3-MB at transcriptional level and a crucial cancer dependency in MYC-amplified G3-MB cells. Targeting EIF4A1 with a CRISPR/Cas9 approach or small-molecule inhibitor silvestrol effectively attenuated growth in multiple preclinical models of MYC-amplified G3-MB via blocking proliferation and inducing apoptosis. Mechanistically, EIF4A1 inhibition effectively impeded MYC expression at translational level, and its potency was positively associated with MYC level. Whole-proteome MS analysis of silvestrol-treated cells further unveiled other biological functions and pathways influenced by EIF4A1 inhibition. CONCLUSION: Our investigation shows that interrupting MYC translation by EIF4A1 inhibition could be a potential effective therapeutic approach when treating patients with MYC-amplified G3-MB.
RESUMO
Despite various lines of evidence implicating impaired decision-making ability in individuals with obsessive-compulsive disorder (OCD), neuropsychological investigation has generated inconsistent findings. Although the cortico-striato-thalamo-cortical (CSTC) circuitry has been suggested, the involvement of the cortex has not yet been fully demonstrated. Moreover, it is unknown whether surgical intervention on the CSTC circuitry results in a predicted improvement of decision-making ability of OCD. Here we present a study of decision making based on the Iowa Gambling Task (IGT) to investigate decision making in a large sample of individuals with treatment-resistant OCD with and without anterior capsulotomy (AC). Task performance was evaluated in healthy subjects, individuals with OCD that had not undergone surgery, and postsurgical OCD patients with AC. The latter group was further divided into a short-term postsurgical group and a long-term postsurgical group. We found that the OCD patients without surgery performed significantly worse than the healthy controls on the IGT. There were no significant differences in decision-making between the presurgical OCD patients and those at the short-term postsurgical follow-up. Decision-making ability of the long-term postsurgical OCD patients was improved to the level comparable to that of healthy controls. All clinical symptoms (OCD, depression, and anxiety) assessed by psychiatric rating scales were significantly alleviated post-surgically, but exhibited no correlation with their IGT task performance. Our findings provide strong evidence that OCD is linked to impairments in decision-making ability; that impaired CSTC circuitry function is directly involved in the manifestation of OCD; and that AC related improvements in cognitive functions are caused by long-term plasticity in the brain circuitry.