UBE2D1 promotes glioblastoma proliferation by modulating p21 ubiquitination.

Glioblastoma (GBM) cells exhibit aberrant proliferative abilities and resistance to conventional therapies. However, the mechanisms underlying these malignant phenotypes are poorly understood. In this study, we identified ubiquitin-conjugating enzyme E2D1 (UBE2D1) as a crucial stimulator of GBM development. It is highly expressed in GBM and closely associated with poor prognosis in patients with GBM. UBE2D1 knockdown inhibits GBM cell growth and leads to G1 cell cycle arrest. Mechanistically, UBCH5A binds to p21 at the protein level and induces the ubiquitination and degradation of p21. This negative regulation is mediated by STUB1. Our findings are the first to identify UBE2D1 as a key driver of GBM growth and provide a potential target for improving prognosis and therapy.

Novel insights into the classification of Shamblin III carotid body tumors from a neurosurgical perspective.

BACKGROUND AND PURPOSE: The classic Shamblin system fails to provide valuable guidance in many Shamblin's III carotid body tumors (III-CBTs) due to the variable forms of carotid arteries and the complex anatomic relationships in parapharyngeal space. We proposed a modified classification to separately divide III-CBTs into different subgroups on the basis of arterial relevant features and anatomical relevant features. MATERIALS AND METHODS: From 2020 to 2023, a total of 129 III-CBTs at a single institution were retrospectively analyzed. All cases were independently classified as arterial-relevant and anatomical-relevant subgroups. The pre-, peri- and postoperative data were summarized and compared accordingly. RESULTS: Among the 129 cases, 69 cases were identified as "Classical type", 23 cases as "Medial type", 27 cases as "Lateral type" and 10 cases as "Enveloped type" according to arterial morphologies. Besides, 76 cases were identified as "Common type", 15 cases as "Pharynx- invasion type", 18 cases as "Skull base-invasion type" and 20 cases as "Mixed type" according to anatomical relationships. "Enveloped type" of tumors in arterial-relevant classification and "Mixed type" of tumors in anatomical-relevant classification are the most challenging cases for surgeons with the lowest resection rate, highest incidence of carotid arteries injury and postoperative stroke. CONCLUSION: The modified classifications provide comprehensive understanding of different III-CBTs which are applicable for individualized treatment in clinical practice.

Accurate diagnosis and treatment of sacral meningeal cysts without spinal nerve root fibres: identifying leakage orificium using high-resolution spherical arbitrary-dimensional reconstructing magnetic resonance imaging.

Objective: This study aimed to develop an arbitrary-dimensional nerve root reconstruction magnetic resonance imaging (ANRR-MRI) technique for identifying the leakage orificium of sacral meningeal cysts (SMCs) without spinal nerve root fibres (SNRFs). Methods: This prospective study enrolled 40 consecutive patients with SMCs without SNRFs between March 2021 and March 2022. Magnetic resonance neural reconstruction sequences were performed for preoperative evaluation. The cyst and the cyst-dura intersection planes were initially identified based on the original thin-slice axial T2-weighted images. Sagittal and coronal images were then reconstructed by setting each intersecting plane as the centre. Then, three-dimensional reconstruction was performed, focusing on the suspected leakage point of the cyst. Based on the identified leakage location and size of the SMC, individual surgical plans were formulated. Results: This cohort included 30 females and 10 males, with an average age of 42.6 ± 12.2 years (range, 17-66 years). The leakage orificium was located at the rostral pole of the cyst in 23 patients, at the body region of the cyst in 12 patients, and at the caudal pole in 5 patients. The maximum diameter of the cysts ranged from 2 cm to 11 cm (average, 5.2 ± 1.9 cm). The leakage orificium was clearly identified in all patients and was ligated microscopically through a 4 cm minimally invasive incision. Postoperative imaging showed that the cysts had disappeared. Conclusion: ANRR-MRI is an accurate and efficient approach for identifying leakage orificium, facilitating the precise diagnosis and surgical treatment of SMCs without SNRFs.

HNRNPA2B1 and HNRNPR stabilize ASCL1 in an m6A-dependent manner to promote neuroblastoma progression.

HNRNPA2B1 and HNRNPR stabilize ASCL1 mRNA in neuroblastoma, but whether their regulatory effects depend on m6A modification and whether their function involves ASCL1 remain unknown. This study investigated the m6A-dependent binding of HNRNPA2B1 and HNRNPR to ASCL1 and subsequent regulation, as well as the expression, clinical significance, and function of HNRNPA2B1 and HNRNPR in neuroblastoma. We revealed that METTL14 mediated ASCL1 m6A modification to stabilize ASCL1. HNRNPA2B1 and HNRNPR significantly enriched ASCL1 mRNA by binding to the 5' and 3' untranslated regions, respectively, and METTL14 knockdown reduced this enrichment. Mutations in m6A sites in the untranslated regions of ASCL1 mRNA considerably decreased probe capacity to engage HNRNPA2B1 and HNRNPR. HNRNPR interacts with IGF2BP1, and knocking down either impaired binding to ASCL1 mRNA. HNRNPA2B1 and HNRNPR knockdown suppressed neuroblastoma cell growth and invasion, while ASCL1 overexpression restored these effects. The high HNRNPA2B1 and HNRNPR expression in neuroblastoma correlated with ASCL1 expression. Thus, HNRNPA2B1 and HNRNPR bind and stabilize ASCL1 mRNA in an m6A-dependent manner to promote neuroblastoma progression. This study not only discovered a new mechanism underlying the high ASCL1 expression in neuroblastoma but also identified the HNRNPA2B1/HNRNPR/ASCL1 axis as a promising target for inhibiting neuroblastoma progression.

Feasibility and safety of one-stage sacral laminoplasty with autologous sacral laminar reimplantation fixed by absorbable fixation clamps in direct microsurgical treatment of symptomatic sacral extradural spinal meningeal cysts.

Introduction: Sacral laminoplasty with titanium mesh and titanium screws can reduce symptomatic sacral extradural spinal meningeal cysts (SESMCs) recurrence and operation complications. However, due to a defect or thinning of the sacrum, the screws cannot be securely anchored and there are also problems with permanent metal implantation for titanium mesh and screws. We propose that sacral laminoplasty with absorbable clamps can provide rigid fixation even for a thinned or defected sacrum without leaving permanent metal implants. Methods: In the direct microsurgical treatment of symptomatic SESMCs, we performed one-stage sacral laminoplasty with autologous sacral lamina reimplantation fixed by absorbable fixation clamps. Retrospectively, we analyzed intraoperative handling, planarity of the sacral lamina, and stability of the fixation based on clinical and radiological data. Results: Between November 2021 to October 2022, we performed sacral laminoplasty with the absorbable craniofix system in 28 consecutive patients with SESMCs. The size of the sacral lamina flaps ranged from 756 to 1,052 mm2 (average 906.21 ± 84.04 mm2). We applied a minimum of two (in four cases) and up to four (in four cases) Craniofix clamps in the operation, with three (in 20 cases) being the most common (82.14%, 20/28) and convenient to handle. Excellent sacral canal reconstruction could be confirmed intraoperatively by the surgeons and postoperatively by CT scans. No intraoperative complications occurred. Conclusions: One-stage sacral laminoplasty with absorbable fixation clamps is technically feasible, and applying 3 of these can achieve a stable fixation effect and are easy to operate. Restoring the normal structure of the sacral canal could reduce complications and improve surgical efficacy.

Case Report: Paraganglioma in the sellar region: longitudinal observation and surgical outcome.

Background: Paraganglioma in the sellar region is an extremely rare entity, with a limited number of cases reported in the literature. Due to the paucity of clinical evidence, the diagnosis and treatment of paragangliomas in the sellar region remain challenging. Herein, we reported a case of sellar paraganglioma with parasellar and suprasellar extension. Particularly, the dynamic evolution of this benign tumor within a 7-year longitudinal observation was presented. Additionally, the relevant literature regarding sellar paraganglioma was comprehensively reviewed. Case description: A 70-year-old woman presented with progressive visual deterioration and headache. Brain magnetic resonance imaging demonstrated a mass in the sellar region with parasellar and suprasellar extension. The patient refused surgical treatment. Seven years later, brain magnetic resonance imaging showed the lesion significantly progressed. Neurological examination revealed bilateral tubular contraction of visual fields. Laboratory examinations showed endocrine hormone levels were normal. Surgical decompression was performed via a subfrontal approach, and subtotal resection was achieved. Histopathological examination confirmed a diagnosis of paraganglioma. Postoperatively, she developed hydrocephalus, and ventriculoperitoneal shunting was performed. Eight months later, cranial CT showed no recurrence of the residual tumor, and the hydrocephalus had been relieved. Conclusion: Paraganglioma occurring in the sellar region is rare, and the preoperative differential diagnosis is difficult. Owing to the infiltration to the cavernous sinus and internal carotid, complete surgical resection is usually impracticable. There has been no consensus regarding postoperative adjuvant radiochemotherapy for the tumor residue. In-situ recurrence and metastasis have been reported in the literature, and close follow-up is warranted.

Corrigendum: PHF20 promotes glioblastoma cell malignancies through a WISP1/BGN-dependent pathway.

[This corrects the article DOI: 10.3389/fonc.2020.573318.].

Clinical features and pathogenesis of scoliosis due to spinal astrocytoma.

The aetiology of scoliosis remains unclear. Some studies have focused on the theory of possible muscular imbalance. The role of the spinal cord, which directly innervates the paraspinal muscles, in muscular imbalance has not yet been studied. Spinal astrocytomas often grow on one side of the spinal cord, destroying it asymmetrically. Asymmetrical damage to the spinal cord can lead to asymmetrical changes in paraspinal muscles. The present study investigated the effect of muscular imbalance on scoliosis by observing scoliosis caused by spinal astrocytomas. Patients diagnosed with spinal astrocytomas in a single centre were analysed, and the type and side of the symptoms, sagittal tumour position, scoliosis, end vertebrae and apical vertebrae of scoliosis were recorded. The tumour side was assumed from symptom type and side, and the cross-sectional area of the paraspinal muscles on both sides of the end vertebra was outlined and compared. The incidence of astrocytoma-induced scoliosis was significantly higher in patients with unilateral symptoms. The inferred tumour side was highly consistent with the convex side of scoliosis. The distal vertebral segments of scoliosis were consistent with the spinal cord segments involved in the astrocytomas. The apical vertebrae were more caudal in astrocytoma-induced scoliosis. The cross-sectional area of the multifidus muscle on the convex side of apical-level scoliosis was significantly smaller than that on the concave side. However, no significant differences were observed in the erector spinae muscles. Overall, spinal astrocytomas can cause asymmetric destruction of the corresponding spinal cord segment, resulting in asymmetric atrophy and weakness of the multifidus muscle innervated by the spinal cord segment, thereby causing scoliosis that is convex to the weaker side. This mechanism involves asymmetric lower neuron paralysis of the multifidus muscle. This is a type of scoliosis with several differences from idiopathic scoliosis.

Postoperative Delirium in Neurosurgical Patients: Recent Insights into the Pathogenesis.

Postoperative delirium (POD) is a complication characterized by disturbances in attention, awareness, and cognitive function that occur shortly after surgery or emergence from anesthesia. Since it occurs prevalently in neurosurgical patients and poses great threats to the well-being of patients, much emphasis is placed on POD in neurosurgical units. However, there are intricate theories about its pathogenesis and limited pharmacological interventions for POD. In this study, we review the recent insights into its pathogenesis, mainly based on studies within five years, and the five dominant pathological theories that account for the development of POD, with the intention of furthering our understanding and boosting its clinical management.

Multiple dimensions of radiographic reconstruction for the optimal operative strategy of sacral meningeal cysts.

BACKGROUND AND PURPOSE: The contents and subtypes of sacral cysts are sophisticated in many cases. We applied multiple dimensional magnetic resonance imaging (MRI) reconstruction to preoperatively clarify the specific subtype of sacral meningeal cysts. MATERIALS AND METHODS: We preoperatively used multimodal neural reconstruction MRI sequences to evaluate 76 patients with sacral cysts. The linear nerve roots were precisely traced based on sagittal or coronal images processed at various angles and levels which was conducive to the design of the operation strategy. RESULTS: Cysts with nerve passage were detected in 47 cases (62%, 47/76), whereas cysts without nerve roots were detected in 24 cases (32%, 24/76). Five patients had mixed cysts with or without nerve roots. Intraoperative exploration results proved the high accuracy of image reconstruction; only one cyst without a nerve root was misdiagnosed prior to surgery. CONCLUSION: MRI reconstruction based on the three-dimensional fast imaging employing steady-state acquisition T2 sequence precisely tracked the nerve roots of sacral cysts and guided the optimal strategy during surgery.

Pretemporal Transcavernous Approach for Resection of Non-meningeal Tumors of the Cavernous Sinus: Single Center Experience.

OBJECTIVES: To study the outcomes of the pretemporal transcavernous approach in the treatment of non-meningeal tumors involving cavernous sinus and to investigate the surgical strategy for these lesions. METHODS: We conducted a retrospective study of 45 patients with non-meningeal tumors involving cavernous sinus. All 45 patients received microsurgical resection via the pretemporal transcavernous approach from April 2012 to January 2019 by the same neurosurgeon. We analyzed clinical manifestations, image data, perioperative complications, surgical outcomes, functional outcomes, and follow-up data of these patients. RESULTS: Gross total resection was achieved in 38 cases (84.4%) of the 45 patients. Preoperatively, a total of 64 individual cranial nerves were affected. Postoperatively, 92.2% of 64 impaired cranial nerves completely or partially restored function, 7.8% had worsened function compared with their preoperative statuses, and 5 new cranial nerve deficits (CNV) were observed in five patients during the last follow-up. Seven patients presented transient new cranial nerve deficits (5 CNIII and 2 CNVI), three cases suffered transient worsen cranial nerve deficits (3 CNIII and 1 CNVII). There were no cases of intracranial hematoma, intracranial infection, cerebrospinal fluid leaks, and death. The progression of residual tumor was observed in two patients (1 chordoma and 1 pituitary adenoma). CONCLUSIONS: Non-meningeal tumors involving cavernous sinus can be safely and radically removed with less morbidity and mortality. Pretemporal transcavernous approach is an ideal approach to the cavernous sinus and can be tailored individually.

Arachnoidal Diverticula of Sacral Extradural Meningeal Cyst: A Novel Definition and Case Series.

BACKGROUND: Sacral cysts are classically divided into Tarlov cysts and meningeal diverticula. However, the pathogenesis of sacral cysts remains unclear. This study aimed to clarify a novel type of sacral extradural spinal meningeal cyst with a specific arachnoidal structure. METHODS: Nine patients with prophylactic diverticula were included in the study. All patients underwent MRI preoperative reconstruction and traditional neck transfixation. RESULTS: All patients presented with more than one symptom. The major symptom was lower extremity pain, followed by lower extremity numbness (77.8%, 7/9), lower extremity weakness (55.6%, 5/9), bowel/bladder and sexual dysfunction (55.6%, 5/9), and tenesmus (22.2%, 2/9). After long-term follow-up, the outcome was classified as improved in 9 patients (100%). CONCLUSIONS: The clinical findings of this study illustrate a special subtype and may help explain the mechanism of sacral cyst formation.

Cell aging related genes can be used to characterize clinical prognoses and further stratify diffuse gliomas.

Increasing evidence has indicated that senescent cells are associated with the glioma development. Thus, we aimed to explore the relationship between the cellular senescence gene profile and the clinical prognosis of diffuse glioma. In total, 699 gliomas from The Cancer Genome Atlas (TCGA) dataset were used as the training cohort and 693 gliomas from the Chinese Glioma Genome Atlas (CGGA) dataset were used as the validation cohort. Bioinformatics statistical methods are used to develop the risk signature and to study the prognostic value of the risk signature. We identified a 14-gene risk signature and its risk score was an independent prognostic factor (P < 0.001) in the validation dataset. The risk signature had better prognostic value than traditional factors for the 3- and 5-year survival rate. Importantly, the risk signature could further stratify gliomas in specific subgroups of World Health Organization (WHO) classification by the survival rate. Furthermore, the mRNA levels of genes involved in the cell cycle, cell division and other processes were significantly correlated with the risk score. Our study highlighted a 14-gene risk signature for further stratifying the outcomes of patients with gliomas with definite WHO subgroups. These results indicate the potential clinical implications of cell aging-related genes in gliomas.

PDIA4 Correlates with Poor Prognosis and is a Potential Biomarker in Glioma.

PURPOSE: Gliomas, characterized by aggressiveness and invasiveness, remain incurable after conventional therapies. The molecular mechanisms driving the progression and maintenance of glioma are still poorly understood. METHODS: The TCGA and CGGA databases were chosen for bioinformatics analysis. Gene expression profiling interactive analysis (GEPIA) was performed for differential analysis. The Kaplan-Meier method was chosen for survival analysis. Analysis of stromal and immune infiltration was performed using the ESTIMATE algorithm and xCell package. qPCR and Western blotting were performed to measure the expression of PDIA4 at the mRNA and protein levels. IHC was performed to detect the expression of PDIA4 in glioma tissues. The viability of glioma cells was evaluated by the CCK8 assay. RESULTS: In this study, we identified high PDIA4 expression in gliomas that correlated with poor prognosis. The association between IDH1 and different glioma patterns also indicated the potential biological role of PDIA4 in tumor development. Mechanistically, PDIA4 interacted with multiple immunological components to promote an immunosuppressive tumor microenvironment (TME). Knockdown of PDIA4 significantly impaired the proliferation of GBM cells. CONCLUSION: Our results confirm that PDIA4 is an efficient biomarker of gliomas, with clinical implications for prognosis and therapeutic strategies.

PHF20 Promotes Glioblastoma Cell Malignancies Through a WISP1/BGN-Dependent Pathway.

Glioblastoma (GBM) stem cells are resistant to cancer therapy, and therefore responsible for tumor progression and recurrence after conventional therapy. However, the molecular mechanisms driving the maintenance of stemness and dedifferentiation are poorly understood. In this study, we identified plant homeodomain finger-containing protein 20 (PHF20) as a crucial epigenetic regulator for sustaining the stem cell-like phenotype of GBM. It is highly expressed in GBM and tightly associated with high levels of aggressiveness of tumors and potential poor prognosis in GBM patients. Knockout of PHF20 inhibits GBM cell proliferation, as well as its invasiveness and stem cell-like traits. Mechanistically, PHF20 interacts with WDR5 and binds to the promoter regions of WISP1 for its expression. Subsequently, WISP1 and BGN act in concert to regulate the degradation of ß-Catenin. Our findings have identified PHF20 as a key driver of GBM malignant behaviors, and provided a potential target for developing prognosis and therapy.

Identification of a Tumor Microenvironment-Related Eight-Gene Signature for Predicting Prognosis in Lower-Grade Gliomas.

Lower-grade gliomas (LrGG), characterized by invasiveness and heterogeneity, remain incurable with current therapies. Clinicopathological features provide insufficient information to guide optimal individual treatment and cannot predict prognosis completely. Recently, an increasing amount of studies indicate that the tumor microenvironment plays a pivotal role in tumor malignancy and treatment responses. However, studies focusing on the tumor microenvironment (TME) of LrGG are still limited. In this study, taking advantage of the currently popular computational methods for estimating the infiltration of tumor-associated normal cells in tumor samples and using weighted gene co-expression network analysis, we screened the co-expressed gene modules associated with the TME and further identified the prognostic hub genes in these modules. Furthermore, eight prognostic hub genes (ARHGDIB, CLIC1, OAS3, PDIA4, PARP9, STAT1, TAP2, and TAGLN2) were selected to construct a prognostic risk score model using the least absolute shrinkage and selection operator method. Univariate and multivariate Cox regression analysis demonstrated that the risk score was an independent prognostic factor for LrGG. Moreover, time-dependent ROC curves indicated that our model had favorable efficiency in predicting both short- and long-term prognosis in LrGG patients, and the stratified survival analysis demonstrated that our model had prognostic value for different subgroups of LrGG patients. Additionally, our model had potential value for predicting the sensitivity of LrGG patients to radio- and chemotherapy. Besides, differential expression analysis showed that the eight genes were aberrantly expressed in LrGG compared to normal brain tissue. Correlation analysis revealed that the expression of the eight genes was significantly associated with the infiltration levels of six types of immune cells in LrGG. In summary, the TME-related eight-gene signature was significantly associated with the prognosis of LrGG patients. They might act as potential prognostic biomarkers for LrGG patients, offer better stratification for future clinical trials, and be candidate targets for immunotherapy, thus deserving further investigation.

LCTL Is a Prognostic Biomarker and Correlates With Stromal and Immune Infiltration in Gliomas.

Immune evasion in glioma strongly correlates with clinical outcomes; however, the molecular mechanisms driving the maintenance of immunosuppression remain largely unknown. Recently studies demonstrate that Klothos are aberrantly expressed in several cancers and are potential therapeutic targets in cancers. However, their roles are still unclear in glioma. Here, we show that LCTL is highly expressed in gliomas and that its expression is regulated by DNA methylation status at the promoter. LCTL expression is also found to be significantly associated with high tumor aggressiveness and poor outcomes for glioma patients. Mechanistically, results suggested that LCTL might play an important immunosuppressive role by recruiting immunosuppressive cells and regulating tumor-associated macrophages polarization, T cell exhaustion, and epithelial-mesenchymal transition through FGF signaling in glioma. Our results establish LCTL as a key biomarker for prognosis that could be considered a potential epigenetic and immunotherapeutic target for treatment.

Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis.

Development of central nervous system (CNS) is regulated by both intrinsic and peripheral signals. Previous studies have suggested that environmental factors affect neurological activities under both physiological and pathological conditions. Although there is anatomical separation, emerging evidence has indicated the existence of bidirectional interaction between gut microbiota, i.e., (diverse microorganisms colonizing human intestine), and brain. The cross-talk between gut microbiota and brain may have crucial impact during basic neurogenerative processes, in neurodegenerative disorders and tumors of CNS. In this review, we discuss the biological interplay between gut-brain axis, and further explore how this communication may be dysregulated in neurological diseases. Further, we highlight new insights in modification of gut microbiota composition, which may emerge as a promising therapeutic approach to treat CNS disorders.

The Chance of Permanent Cure for Micro- and Macroprolactinomas, Medication or Surgery? A Systematic Review and Meta-Analysis.

Background: This meta-analysis aims to evaluate the long-term efficacy of medication treatment vs. surgery treatment in patients with prolactinomas. Methods: An electronic literature search was performed using MEDLINE, EMBASE and Web of Science databases for studies dated before July in 2018. Patients with prolactinomas received primary dopamine agonists (DAs) treatment or primary surgical interventions were included in this study. A systematic review and meta-analysis were performed in pertinent studies meeting eligible criteria. The clinical outcome was measured by the long-term remission rate of prolactin (PRL) in each cohort. The pooled data was analyzed according to a random effect model. Results: Thirteen publications with total 809 patients were included in the final meta-analysis. In the overall patients with prolactinomas, long-term remission rate was achieved in 88% patients treated with surgeries and in 52% patients treated with DAs (P = 0.001). The long-term remission rates in surgery cohort were also significantly higher than medication cohort in both microprolactinomas and macroprolactinomas (91 vs. 60%, P = 0.002; 77 vs. 43%, P = 0.003). Conclusions: Patients with prolactinomas, especially microprolactinomas, can consider transsphenoidal surgery as an alternative first-line treatment strategy. After receiving primary surgical intervention, administration of DAs should be considered based on the postoperative PRL level to achieve the best long-term remission rate.

PHF20 collaborates with PARP1 to promote stemness and aggressiveness of neuroblastoma cells through activation of SOX2 and OCT4.

The differentiation status of neuroblastoma (NB) strongly correlates with its clinical outcomes; however, the molecular mechanisms driving maintenance of stemness and differentiation remain poorly understood. Here, we show that plant homeodomain finger-containing protein 20 (PHF20) functions as a critical epigenetic regulator in sustaining stem cell-like phenotype of NB by using CRISPR/Cas9-based targeted knockout (KO) for high-throughput screening of gene function in NB cell differentiation. The expression of PHF20 in NB was significantly associated with high aggressiveness of the tumor and poor outcomes for NB patients. Deletion of PHF20 inhibited NB cell proliferation, invasive migration, and stem cell-like traits. Mechanistically, PHF20 interacts with poly(ADP-ribose) polymerase 1 (PARP1) and directly binds to promoter regions of octamer-binding transcription factor 4 (OCT4) and sex determining region Y-box 2 (SOX2) to modulate a histone mark associated with active transcription, trimethylation of lysine 4 on histone H3 protein subunit (H3K4me3). Overexpression of OCT4 and SOX2 restored growth and progression of PHF20 KO tumor cells. Consistently, OCT4 and SOX2 protein levels in clinical NB specimens were positively correlated with PHF20 expression. Our results establish PHF20 as a key driver of NB stem cell-like properties and aggressive behaviors, with implications for prognosis and therapy.