Tumor-derived small extracellular vesicles in cancer invasion and metastasis: molecular mechanisms, and clinical significance.

The production and release of tumor-derived small extracellular vesicles (TDSEVs) from cancerous cells play a pivotal role in the propagation of cancer, through genetic and biological communication with healthy cells. TDSEVs are known to orchestrate the invasion-metastasis cascade via diverse pathways. Regulation of early metastasis processes, pre-metastatic niche formation, immune system regulation, angiogenesis initiation, extracellular matrix (ECM) remodeling, immune modulation, and epithelial-mesenchymal transition (EMT) are among the pathways regulated by TDSEVs. MicroRNAs (miRs) carried within TDSEVs play a pivotal role as a double-edged sword and can either promote metastasis or inhibit cancer progression. TDSEVs can serve as excellent markers for early detection of tumors, and tumor metastases. From a therapeutic point of view, the risk of cancer metastasis may be reduced by limiting the production of TDSEVs from tumor cells. On the other hand, TDSEVs represent a promising approach for in vivo delivery of therapeutic cargo to tumor cells. The present review article discusses the recent developments and the current views of TDSEVs in the field of cancer research and clinical applications.

A novel classification for guiding the surgical approach for cranio-orbital lesions: a single institution case series of 45 cases and a literature review.

We aim to share our experience of the removal of cranio-orbital lesions (COLs) and propose a novel classification to guide the tailored approach selection. We retrospectively reviewed 45 consecutive patients with COLs who underwent surgery performed by the same neurosurgeon between November 2010 and November 2022. The surgical approach was selected according to the anatomical region classification of the COLs. For lesions limited to space A (lateral superior orbital fissure, SOF), the pterion or extended pterion approach (PA or EPA) was used. For lesions limited to space B (extraconal compartment medial SOF, and cavernous sinus CS) and C (intraconal compartment, medial SOF, and CS), the pretemporal transcavernous approach (PTCA) was used. For lesions limited to space D (intraconal compartment and optic canals), the subfrontal approach (SA) was used. For lesions extending into the infratemporal fossa (ITF), the cranio-orbito-zygomatic approach (COZA) was used. For lesions involving pterygopalatine fossa (PPF), the endoscopic transnasal approach (ETNA) was used. We analyzed the clinical manifestations, imaging data, surgical approaches, surgical outcomes, neurological outcomes, and follow-up data. Gross total resection was performed in 35 patients (35/45, 77.8%). SA, PA, EPA, PTCA, COZA, and ETNA were performed in 9, 9, 10, 10, 6, and 1 case(s), respectively. Progression of the residual tumor was observed in 6 cases (1 adenoid cystic carcinoma and 5 meningiomas). Surgical approach selection plays a vital role in patient prognosis. This novel classification based on the involvement of anatomic space could help surgeons select an appropriate approach to remove the COLs.

Preservation of the integrity of facial nerve in vestibular schwannoma microsurgery: A consecutive study of 127 clinical cases focusing on nervus intermedius.

Background: Nervus intermedius (NI) injuries are not given enough attention by neurosurgeons during vestibular schwannoma (VS) surgery. Preservation of NI function is essential for the integrity and continuity of the facial nerve, although this can be challenging. We identified the risk factors for NI injury and proposed our experience for optimizing NI preservation based on our cases. Methods: We retrospectively analyzed clinical data from a consecutive series of 127 patients with VS who underwent microsurgery via the retrosigmoid approach from 2017 to 2021 at our institution. The baseline characteristics of the patients were collected from the medical records, and the incidence of NI dysfunction symptoms was obtained by outpatient and online video follow-up 6 months after surgery. The surgical procedures and techniques used were described in detail. The data were analyzed in relation to sex, age, tumor location (left or right), Koos grading scale, internal acoustic canal (IAC) invasion (TFIAC Classification), brainstem adhesion, tumor characteristics (cystic or solid), tumor necrosis, and preoperative House-Brackmann (HB) grading by univariate and multivariate analyses. Results: Gross tumor removal was achieved in 126 (99.21%) patients. Subtotal removal was performed on one patient (0.79%). Twenty-three of our cases exhibited facial nerve palsy preoperatively; 21 patients had HB grade II facial palsy, and two had HB grade III. Two months after surgery, 97 (76.38%) patients had normal function of the motor portion of the facial nerve; 25 (19.69%) patients had HB Grade II facial palsy, five had Grade III (3.94%), and zero (0%) had Grade IV. Postoperatively, 15 patients experienced newly gained dry eyes (11.81%), whereas 21 cases of lacrimal disturbances (16.54%), nine of taste disturbances (7.09%), seven of xerostomia (5.51%), five of nasal hypersecretions (3.94%), and seven of hypersalivation (5.51%) were identified in our cases. Univariate and multivariate analyses revealed that the Koos grading scale and tumor characteristics (solid or cystic) were correlated with NI injury (p <0.01). Conclusion: The data in this study demonstrate that although the motor function of the facial nerve is well preserved, NI disturbance is still common after VS surgery. Maintaining the integrity and continuity of the facial nerve is key to NI function. Performing bidirectional and subperineurium dissection based on even and adequate debulking is beneficial for NI preservation in VS surgery. Higher Koos grading and cystic characteristics of VS are associated with postoperative NI injuries. These two parameters can be used to guide the delineation of surgical strategy and predict the prognosis of NI function preservation.

Positive regulators of T cell proliferation as biomarkers for predicting prognosis and characterizing the immune landscape in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the one of the most prevalent and fatal form of malignant tumors worldwide. Recently, immunotherapy is widely used in the treatment of patients with LUAD and has proved to be clinically effective in improve the prognosis of patients. But there still has been a tremendous thrust to further improve the efficacy of immunotherapy in individual patients with LUAD. The suppression of T cells and their effector functions in the tumor microenvironment (TME) of LUAD is one of the primary reasons for the low efficacy of immunotherapy in some patients with LUAD. Therefore, identifying positive regulators of T cell proliferation (TPRs) may offer novel avenues for LUAD immunotherapy. In this study, we comprehensively evaluated the infiltration patterns of TPRs in 1,066 patients with LUAD using unsupervised consensus clustering and identified correlations with genomic and clinicopathological characteristics. Three infiltrating TPR clusters were defined, and a TPR-related risk signature composed of nine TPRs was constructed using least absolute shrinkage and selection operator-Cox regression algorithms to classify the individual TPR infiltration patterns. Cluster 1 exhibited high levels of T cell infiltration and activation of immune-related signaling pathways, whereas cluster 2 was characterized by robust T cell immune infiltration and enrichment of pathways associated with carcinogenic gene sets and tumor immunity. Cluster 3 was characterized as an immune-desert phenotype. Moreover, the TPR signature was confirmed as an independent prognostic biomarker for drug sensitivity in patients with LUAD. In conclusion, the TPR signature may serve as a novel tool for effectively characterizing immune characteristics and evaluating the prognosis of patients with LUAD.

Identification of SSBP1 as a ferroptosis-related biomarker of glioblastoma based on a novel mitochondria-related gene risk model and in vitro experiments.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor that leads to lethality. Several studies have demonstrated that mitochondria play an important role in GBM and that mitochondria-related genes (MRGs) are potential therapeutic targets. However, the role of MRGs in GBM remains unclear. METHODS: Differential expression and univariate Cox regression analyses were combined to screen for prognostic differentially-expressed (DE)-MRGs in GBM. Based on LASSO Cox analysis, 12 DE-MRGs were selected to construct a risk score model. Survival, time dependent ROC, and stratified analyses were performed to evaluate the performance of this risk model. Mutation and functional enrichment analyses were performed to determine the potential mechanism of the risk score. Immune cell infiltration analysis was used to determine the association between the risk score and immune cell infiltration levels. CCK-8 and transwell assays were performed to evaluate cell proliferation and migration, respectively. Mitochondrial reactive oxygen species (ROS) levels and morphology were measured using a confocal laser scanning microscope. Genes and proteins expression levels were investigated by quantitative PCR and western blotting, respectively. RESULTS: We identified 21 prognostic DE-MRGs, of which 12 DE-MRGs were selected to construct a prognostic risk score model for GBM. This model presented excellent performance in predicting the prognosis of patients with GBM and acted as an independent predictive factor. Functional enrichment analysis revealed that the risk score was enriched in the inflammatory response, extracellular matrix, and pro-cancer-related and immune related pathways. Additionally, the risk score was significantly associated with gene mutations and immune cell infiltration in GBM. Single-stranded DNA-binding protein 1 (SSBP1) was considerably upregulated in GBM and associated with poor prognosis. Furthermore, SSBP1 knockdown inhibited GBM cell progression and migration. Mechanistically, SSBP1 knockdown resulted in mitochondrial dysfunction and increased ROS levels, which, in turn, increased temozolomide (TMZ) sensitivity in GBM cells by enhancing ferroptosis. CONCLUSION: Our 12 DE-MRGs-based prognostic model can predict the GBM patients prognosis and 12 MRGs are potential targets for the treatment of GBM. SSBP1 was significantly upregulated in GBM and protected U87 cells from TMZ-induced ferroptosis, which could serve as a prognostic and therapeutic target/biomarker for GBM.

Tumor antigens and immune subtypes of glioblastoma: the fundamentals of mRNA vaccine and individualized immunotherapy development.

Purpose: Glioblastoma (GBM) is the most common primary brain tumor in adults and is notorious for its lethality. Given its limited therapeutic measures and high heterogeneity, the development of new individualized therapies is important. mRNA vaccines have exhibited promising performance in a variety of solid tumors, those designed for glioblastoma (GBM) need further development. The aim of this study is to explore tumor antigens for the development of mRNA vaccines against GBM and to identify potential immune subtypes of GBM to identify the patients suitable for different immunotherapies. Methods: RNA-seq data and the clinical information of 143 GBM patients was extracted from the TCGA database; microarray data and the clinical information of 181 GBM patients was obtained from the REMBRANDT cohort. A GBM immunotherapy cohort of 17 patients was obtained from a previous literature. GEPIA2, cBioPortal, and TIMER2 were used to identify the potential tumor antigens. Immune subtypes and gene modules were identified using consensus clustering; immune landscape was constructed using graph-learning-based dimensionality reduction analysis. Results: Nine potential tumor antigens associated with poor prognosis and infiltration of antigen-presenting cells were identified in GBM: ADAMTSL4, COL6A1, CTSL, CYTH4, EGFLAM, LILRB2, MPZL2, SAA2, and LSP1. Four robust immune subtypes and seven functional gene modules were identified and validated in an independent cohort. Immune subtypes had different cellular and molecular characteristics, with IS1, an immune cold phenotype; IS2, an immune hot and immunosuppressive phenotype; IS3, a relatively immune cold phenotype, second only to IS1; IS4, having a moderate tumor immune microenvironment. Immune landscape revealed the immune distribution of the GBM patients. Additionally, the potential value of immune subtypes for individualized immunotherapy was demonstrated in a GBM immunotherapy cohort. Conclusions: ADAMTSL4, COL6A1, CTSL, CYTH4, EGFLAM, LILRB2, MPZL2, SAA2, and LSP1 are the candidate tumor antigens for mRNA vaccine development in GBM, and IS1 GBM patients are best suited for mRNA vaccination, IS2 patients are best suited for immune checkpoint inhibitor. This study provides a theoretical framework for GBM mRNA vaccine development and individualized immunotherapy strategies. Supplementary Information: The online version contains supplementary material available at 10.1186/s40537-022-00643-x.

Individualized surgical treatment of giant tuberculum sellae meningioma: Unilateral subfrontal approach vs. endoscopic transsphenoidal approach.

Objective: Giant tuberculum sellae meningiomas (TSMs) are deeply located in the suprasellar region and extensively compressed or encased in the surrounding neurovascular structures, making gross total resection (GTR) without postoperative visual impairment challenging. The authors presented individualized unilateral subfrontal approach and endoscopic transsphenoidal approach (ETSA) in a series of patients and elaborated on their advantages and indications in resecting giant TSMs. Methods: A total of 38 patients with giant TSMs operated by a single surgeon between March 2012 and November 2021 were retrospectively reviewed. Patients underwent unilateral subfrontal approach and ETSA according to preoperative imaging characteristics. Tumor characteristics, surgical details, preoperative symptoms, and neurological outcomes of TSMs patients were collected and analyzed. Results: In 31 patients operated with the unilateral subfrontal approach, total resection (Simpson grade I or II) was achieved in 27 patients (87.0%), while 6 patients (85.7%) achieved GTR in 7 patients using ETSA. The postoperative visual improvement was maintained in 22 (81.5%) and 5 patients (83.3%). Recurrence or progression was only observed in 2 (7.4%) patients operated with the unilateral subfrontal approach. There was no mortality in our series. Conclusions: Preoperative imaging and visual function are important for surgical approach selection. Maximum tumor resection and optic nerve protection can be achieved concurrently by taking advantage of these surgical approaches. The cerebral artery protection strategies and individualized surgical techniques provide great utility in improving a patient's quality of life.

Individualized Cerebral Artery Protection Strategies for the Surgical Treatment of Parasellar Meningiomas on the Basis of Preoperative Imaging.

OBJECTIVE: Parasellar meningiomas (PMs) represent a cohort of skull base tumors that are localized in the parasellar region. PMs tend to compress, encase, or even invade the cerebral arteries and their perforating branches. The surgical resection of PMs without damaging neurovascular structures is challenging. This study aimed to analyze functional outcomes in a series of patients who underwent surgery with individualized cerebral artery protection strategies based on preoperative imaging. METHODS: A retrospective review was performed on a single surgeon's experience of the microsurgical removal of PMs in 163 patients between January 2012 and March 2020. Individualized approaches with a bidirectional dissection strategy were used. Cerebral artery invasion classification, neurological outcomes, MRC Scale for muscle strength, and Karnofsky performance scale were used to assess tumor vascular invasion, functional outcome, and patient quality-of-life outcomes, respectively. RESULTS: Total resection (Simpson grade I or II) was achieved in 114 patients (69.9%) in our study. A total of 44.7% of patients had improved vision at consecutive follow-ups, 51.1% were stable, and 3.8% deteriorated. Improvements in cranial nerves III, IV, and VI were observed in 41.1%, 36.2%, and 44.8% of patients, respectively. The mean follow-up time was (38.8 ± 27.9) months, and the KPS at the last follow-up was 89.6 ± 8.5. Recurrence was observed in eight patients (13.8%) with cavernous sinus meningiomas, and the recurrence rates in anterior clinoid meningiomas and medial sphenoid wing meningiomas were 3.8% and 2.8%, respectively. CONCLUSIONS: Preoperative imaging is important in the selection of surgical approaches. Maximum tumor resection and cerebral artery protection can be achieved concurrently by utilizing the bidirectional dissection technique. Individualized cerebral artery protection strategies provide great utility in improving a patient's quality of life.

Efficacy of the Suboccipital Paracondylar-Lateral Cervical Approach: The Series of 64 Jugular Foramen Tumors Along With Follow-Up Data.

OBJECTIVE: Complete resection of jugular foramen tumors with minimal cranial nerve complications remains challenging even for skilled neurosurgeons. Here, we introduce a modified paracondylar approach, named the suboccipital paracondylar-lateral cervical (SPCLC) approach for this purpose. We also share the follow-up data of our series and discuss the advantages and limitations of this modified paracondylar approach. METHODS: We included 64 patients with jugular foramen tumors who underwent surgery by the same senior neurosurgeon between November 2011 and August 2020. All patients were treated with the SPCLC approach, which aimed for gross total tumor removal in a single-stage operation. The clinical characteristics, including preoperative and postoperative neurological status, the extent of surgical resection, and follow-up data were retrospectively acquired and evaluated. RESULTS: There were 48 schwannomas, nine meningiomas, three paragangliomas, one hemangiopericytoma, one chordoma, one endolymphatic sac tumor, and one Langerhans' cell histiocytosis. The median age of our patients was 43 years (range: 21-77 years). Dysphagia, hoarseness, and tongue deviation were observed in 36, 26, and 28 patients, respectively. Thirty-two patients had hearing function impairments, including hearing loss or tinnitus. Gross total resection was achieved in 59 patients (59/64, 92.2%). Gamma Knife treatment was used to manage residual tumors in five patients. Postoperatively, new-onset or aggravative dysphagia and hoarseness occurred in 26 and 18 cases, respectively. Nine patients developed new-onset facial palsy, and one patient developed new-onset hearing loss. There were no cases of intracranial hematoma, re-operation, tracheostomy, or death. At the latest follow-up, hearing loss and tinnitus had improved in 20 cases (20/32, 62.5%), dysphagia alleviated in 20 cases (20/36, 55.6%), and hoarseness improved in 14 cases (14/26, 53.8%). Over a mean follow-up period of 27.8 ± 19.5 months (range: 3-68 months), tumor recurrence was observed in one patient. CONCLUSION: The SPCLC approach, modified from the paracondylar approach, and was less invasive, safe, and efficient for certain jugular foramen tumors. Taking advantage of the anatomic understanding, clear operational vision, and appropriate surgical skills, it is possible to achieve gross total tumor removal and the preservation of neurological function.

Interplay of m6 A and histone modifications contributes to temozolomide resistance in glioblastoma.

BACKGROUND: Despite the development of new treatment protocols for glioblastoma (GBM), temozolomide (TMZ) resistance remains a primary hindrance. Previous studies, including our study, have shown that aberrant N6-methyladenosine (m6 A) modification is implicated in GBM pathobiology. However, the roles and precise mechanisms of m6 A modification in the regulation of TMZ resistance in GBM remain unclear. METHODS: m6 A individual-nucleotide-resolution cross-linking and immunoprecipitation sequencing (miCLIP-seq) was performed to identify m6 A modification of transcripts in TMZ-resistant and -sensitive tumors. To explore the role of METTL3 in TMZ resistance, TMZ-resistant GBM cells were transfected with METTL3 shRNA or overexpression lentivirus and then assessed by cell viability, tumor sphere formation, and apoptosis assays. An intracranial GBM xenograft model was developed to verify the effect of METTL3 depletion during TMZ treatment in vivo. ATAC-seq, ChIP-qPCR, and dual-luciferase reporter assays were carried out to verify the role of SOX4/EZH2 in the modulation of METTL3 expression upon TMZ treatment. RESULTS: We demonstrated that TMZ treatment upregulated the expression of the m6 A methyltransferase METTL3, thereby increasing m6 A modification of histone modification-related gene transcripts. METTL3 is required to maintain the features of GBM stem cells. When combined with TMZ, METTL3 silencing suppressed orthotopic TMZ-resistant xenograft growth in a cooperative manner. Mechanistically, TMZ induced a SOX4-mediated increase in chromatin accessibility at the METTL3 locus by promoting H3K27ac levels and recruiting RNA polymerase II. Moreover, METTL3 depletion affected the deposition of m6 A on histone modification-related gene transcripts, such as EZH2, leading to nonsense-mediated mRNA decay. We revealed an important role of EZH2 in the regulation of METTL3 expression, which was via an H3K27me3 modification-independent manner. CONCLUSIONS: Our findings uncover the fundamental mechanisms underlying the interplay of m6 A RNA modification and histone modification in TMZ resistance and emphasize the therapeutic potential of targeting the SOX4/EZH2/METTL3 axis in the treatment of TMZ-resistant GBM.

Novel Molecular Hallmarks of Group 3 Medulloblastoma by Single-Cell Transcriptomics.

Medulloblastoma (MB) is a highly heterogeneous and one of the most malignant pediatric brain tumors, comprising four subgroups: Sonic Hedgehog, Wingless, Group 3, and Group 4. Group 3 MB has the worst prognosis of all MBs. However, the molecular and cellular mechanisms driving the maintenance of malignancy are poorly understood. Here, we employed high-throughput single-cell and bulk RNA sequencing to identify novel molecular features of Group 3 MB, and found that a specific cell cluster displayed a highly malignant phenotype. Then, we identified the glutamate receptor metabotropic 8 (GRM8), and AP-1 complex subunit sigma-2 (AP1S2) genes as two critical markers of Group 3 MB, corresponding to its poor prognosis. Information on 33 clinical cases was further utilized for validation. Meanwhile, a global map of the molecular cascade downstream of the MYC oncogene in Group 3 MB was also delineated using single-cell RNA sequencing. Our data yields new insights into Group 3 MB molecular characteristics and provides novel therapeutic targets for this relentless disease.

Brain-invasive meningiomas: molecular mechanisms and potential therapeutic options.

Meningiomas are the most commonly diagnosed benign intracranial adult tumors. Subsets of meningiomas that present with extensive invasion into surrounding brain areas have high recurrence rates, resulting in difficulties for complete resection, substantially increased mortality of patients, and are therapeutically challenging for neurosurgeons. Exciting new data have provided insights into the understanding of the molecular machinery of invasion. Moreover, clinical trials for several novel approaches have been launched. Here, we will highlight the mechanisms which govern brain invasion and new promising therapeutic approaches for brain-invasive meningiomas, including pharmacological approaches targeting three major aspects of tumor cell invasion: extracellular matrix degradation, cell adhesion, and growth factors, as well as other innovative treatments such as immunotherapy, hormone therapy, Tumor Treating Fields, and biodegradable copolymers (wafers), impregnated chemotherapy. Those ongoing studies can offer more diversified possibilities of potential treatments for brain-invasive meningiomas, and help to increase the survival benefits for patients.

Prognostic value and immune cell infiltration of hypoxic phenotype-related gene signatures in glioblastoma microenvironment.

Glioblastoma (GBM) is a malignant intracranial tumour with the highest proportion and lethality. It is characterized by invasiveness and heterogeneity. However, the currently available therapies are not curative. As an essential environmental cue that maintains glioma stem cells, hypoxia is considered the cause of tumour resistance to chemotherapy and radiation. Growing evidence shows that immunotherapy focusing on the tumour microenvironment is an effective treatment for GBM; however, the current clinicopathological features cannot predict the response to immunotherapy and provide accurate guidance for immunotherapy. Based on the ESTIMATE algorithm, GBM cases of The Cancer Genome Atlas (TCGA) data set were classified into high- and low-immune/stromal score groups, and a four-gene tumour environment-related model was constructed. This model exhibited good efficiency at forecasting short- and long-term prognosis and could also act as an independent prognostic biomarker. Additionally, this model and four of its genes (CLECL5A, SERPING1, CHI3L1 and C1R) were found to be associated with immune cell infiltration, and further study demonstrated that these four genes might drive the hypoxic phenotype of perinecrotic GBM, which affects hypoxia-induced glioma stemness. Therefore, these might be important candidates for immunotherapy of GBM and deserve further exploration.

Multidisciplinary Therapy Managed Recurrent Glioblastoma in a BRAF-V600E Mutant Pregnant Female: A Case Report and Review of the Literature.

Background: Glioblastoma (GBM) is the most malignant intracranial tumor in adults. However, the overall management of GBM in pregnancy is rarely reported. How to balance the therapeutic benefits to the mother and risks to the fetus remains hugely challenging for clinicians. The application of specific targeting therapy combined with conventional treatment sheds light on a longer lifetime for the patients suffering from GBM. Case Presentation: We present a pregnant female at 20 weeks gestation diagnosed with GBM. Surgical resection was initially performed without adjuvant therapy, and the tumor recurred de novo 2 months later. A secondary craniotomy and cesarean section were performed simultaneously at 32 weeks gestation, both the patient and infant were survived. She was subsequently treated with traditional chemo-radiotherapy. No other identified genetic alterations indicating an optimistic prognosis were detected except for BRAF V600E mutation. Thus, the BRAF inhibitor was placed on her with achieving a good clinical outcome of more than 2-year survival without recurrence. Conclusion: Personalized multidisciplinary therapy should be considered when GBMs occur in pregnancy. Response to the therapy in this presenting case suggests that BRAF V600E mutation is a favorable biomarker for GBM. The mortality of GBM might be reduced through genetic testing and targeted treatment. However, more studies must be conducted to confirm our observation.

LINC00470 promotes tumour proliferation and invasion, and attenuates chemosensitivity through the LINC00470/miR-134/Myc/ABCC1 axis in glioma.

Glioma is the most common primary malignant tumour in the brain; temozolomide (TMZ) is the most prevalent chemotherapeutic drug currently used to combat this cancer. We reported previously that the long intergenic non-protein coding RNA 470 (LINC00470) is a novel prognostic biomarker for glioma and promotes the tumour growth in an intracranial transplantation mouse model. However, the effects of LINC00470 on glioma cell proliferation, invasion and TMZ chemosensitivity, as well as its molecular mechanism, remain unclear. In this study, we found elevated expression levels of LINC00470 and MYC in glioma tissues and cells and decreased expression of microRNA-134 (miR-134). Functional studies have shown that LINC00470 promotes proliferation and invasion, and attenuates chemosensitivity of glioma cells, while miR-134 exerts the opposite effect. In the rescue experiments, the tumorigenic effect of LINC00470 was offset by miR-134. In the mechanism study, we found that LINC00470 was a competitive endogenous RNA (ceRNA) of miR-134 and that miR-134 can directly target MYC and negatively regulate its expression. Furthermore, MYC was positively correlated with ATP-binding cassette subfamily C member 1 (ABCC1) expression in glioma cells and MYC up-regulated ABCC1 expression. Further studies found that LINC00470 regulated MYC by sponging miR-134 to regulate the expression of ABCC1. We concluded that LINC00470 promoted the expression of MYC and ABCC1 by suppressing miR-134, thus promoting glioma cell proliferation and invasion, and attenuating TMZ chemosensitivity. Moreover, the LINC00470/miR-134/MYC/ABCC1 axis constitutes a potential therapeutic target.

Identification and validation of a three-gene signature as a candidate prognostic biomarker for lower grade glioma.

BACKGROUND: Lower grade glioma (LGG) are a heterogeneous tumor that may develop into high-grade malignant glioma seriously shortens patient survival time. The clinical prognostic biomarker of lower-grade glioma is still lacking. The aim of our study is to explore novel biomarkers for LGG that contribute to distinguish potential malignancy in low-grade glioma, to guide clinical adoption of more rational and effective treatments. METHODS: The RNA-seq data for LGG was downloaded from UCSC Xena and the Chinese Glioma Genome Atlas (CGGA). By a robust likelihood-based survival model, least absolute shrinkage and selection operator regression and multivariate Cox regression analysis, we developed a three-gene signature and established a risk score to predict the prognosis of patient with LGG. The three-gene signature was an independent survival predictor compared to other clinical parameters. Based on the signature related risk score system, stratified survival analysis was performed in patients with different age group, gender and pathologic grade. The prognostic signature was validated in the CGGA dataset. Finally, weighted gene co-expression network analysis (WGCNA) was carried out to find the co-expression genes related to the member of the signature and enrichment analysis of the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were conducted for those co-expression network. To prove the efficiency of the model, time-dependent receiver operating characteristic curves of our model and other models are constructed. RESULTS: In this study, a three-gene signature (WEE1, CRTAC1, SEMA4G) was constructed. Based on the model, the risk score of each patient was calculated with LGG (low-risk vs. high-risk, hazard ratio (HR) = 0.198 (95% CI [0.120-0.325])) and patients in the high-risk group had significantly poorer survival results than those in the low-risk group. Furthermore, the model was validated in the CGGA dataset. Lastly, by WGCNA, we constructed the co-expression network of the three genes and conducted the enrichment of GO and KEGG. Our study identified a three-gene model that showed satisfactory performance in predicting the 1-, 3- and 5-year survival of LGG patients compared to other models and may be a promising independent biomarker of LGG.

Surgical Management of Tentorial Notch Meningioma Guided by Further Classification: A Consecutive Study of 53 Clinical Cases.

BACKGROUND: Management of tentorial notch meningiomas (TNM) remains a challenge for neurosurgeons. We demonstrate the clinical characteristics and surgical experiences of TNM based on our cases according to a proposed further classification. METHODS: We retrospectively analyzed clinical and follow-up data in a consecutive series of 53 TNM patients who underwent microsurgical operation from 2011 to 2019 in our institution. The operations were performed using various approaches. Clinical history, preoperative and postoperative neurofunction, imaging results, and surgical outcomes were collected for further classification of TNM. RESULTS: All TNM cases were divided into anterior (T1), middle (T2), and posterior notch (T3). According to the direction of tumor extension and correlation with the neurovascular structures, detailed subtypes of anterior TNMs were identified as the central (T1a), posterior (T1b), and medial type (T1c). The middle TNMs were divided into the infratentorial (T2a), supratentorial (T2b), and supra-infratentorial type (T2c). The posterior TNMs were divided into superior (T3a), inferior (T3b), lateral (T3c), and straight sinus type (T3d) in reference to Bassiouni's classification. Total removal of the tumor was achieved in 46 cases, with five cases of subtotal and two cases of partial removal without any recorded deaths in our series. In total, five subtotal resected cases underwent gamma-knife treatment and achieved stable disease. Postoperative aggravation or new onset cranial nerve dysfunction occurred in some individual cases, with incidences ranging from 3.77 to 15.10% and improved preoperative neurological deficits ranging from 0 to 100%. CONCLUSION: Further, TNM classification based on the intracranial location, extension direction, relationship with brainstem, and neurovascular structures guides preoperative evaluation, rational surgical approach selection, and surgical strategy formulation. Taking microsurgery as the main body, a satisfactory outcome of TNM treatment can be achieved for complicated tumors by combining stereotactic radiotherapy. This study demonstrates the surgical outcomes and complications in detail. Further classification might be helpful for treatment decisions in the future.

circCPA4 acts as a prognostic factor and regulates the proliferation and metastasis of glioma.

Circular RNAs (circRNAs) are reported to play vital roles in tumour process and might be potential prognostic biomarkers and therapeutic targets for tumours. But the expression and function of circRNAs in glioma remain unclear. Here, we performed circRNA microarray analysis of glioma tissues and matched normal brain tissue samples to explore the circRNA profile in glioma. GO analysis, KEGG and Reactom pathway analysis of linear mRNA transcripts corresponding to circRNAs were performed to study the involved biological process and pathways. The clinical significance of the selected circRNA was investigated by Kaplan-Meier survival analysis. Relevant biological function, such as cell proliferation and metastasis, was detected in vitro and in vivo. And possible mechanism of the regulatory function of the selected circRNA in glioma was explored. We found that circCPA4 (hsa_circ_0082374) up-regulated the most in glioma tissues and high levels of circCPA4 were positively related to poor outcome of glioma. And knockdown of circCPA4 suppresses cell proliferation and metastasis in glioma. Moreover, circCPA4 interacts with let-7 and serves as a sponge for let-7. Through the competitive endogenous RNA (ceRNA) mechanism, circCPA4 sponges let-7 to regulate the expression of CPA4 and glioma progression. The circCPA4/let-7/CPA4 axis regulates glioma progression by ceRNA mechanism, and circCPA4 could be a novel prognostic biomarker and target for glioma treatment.

Overexpression of the phospholipase A2 group V gene in glioma tumors is associated with poor patient prognosis.

Purpose: Gliomas are the most common primary malignant neoplasms of the central nervous system. Secreted phospholipases A2 (sPLA2s) are known to play an important role in various physiological processes, including bioactive lipid production, defense mechanisms, and cell signaling. However, their roles and clinical importance in gliomas remain unclear. Patients and methods: In this study, we analyzed the association between the expression of various sPLA2-encoding genes and the clinicopathology of gliomas, using the data of 1047 patients obtained from a public database. Immunohistochemical analysis of 82 glioma tissues was also carried out to assess the relationship between phospholipase A2 group V (PLA2G5) protein expression and the World Health Organization (WHO) glioma grades. Results: We found that high PLA2G5 gene expression was associated with unfavorable prognosis in both low-grade and high-grade gliomas. The immunohistochemistry of the 82 glioma tissues further confirmed that PLA2G5 protein expression was dependent on the WHO glioma grade. In addition, we found a correlation between PLA2G5 gene expression and both epithelial-mesenchymal transition and the isocitrate dehydrogenase 1 mutation status in these tumors. Conclusion: Our results indicate that PLA2G5 could be a potential biomarker for predicting poor prognosis in patients with gliomas.