The CEBPB+ glioblastoma subcluster specifically drives the formation of M2 tumor-associated macrophages to promote malignancy growth.

Rationale: The heterogeneity of tumor cells within the glioblastoma (GBM) microenvironment presents a complex challenge in curbing GBM progression. Understanding the specific mechanisms of interaction between different GBM cell subclusters and non-tumor cells is crucial. Methods: In this study, we utilized a comprehensive approach integrating glioma single-cell and spatial transcriptomics. This allowed us to examine the molecular interactions and spatial localization within GBM, focusing on a specific tumor cell subcluster, GBM subcluster 6, and M2-type tumor-associated macrophages (M2 TAMs). Results: Our analysis revealed a significant correlation between a specific tumor cell subcluster, GBM cluster 6, and M2-type TAMs. Further in vitro and in vivo experiments demonstrated the specific regulatory role of the CEBPB transcriptional network in GBM subcluster 6, which governs its tumorigenicity, recruitment of M2 TAMs, and polarization. This regulation involves molecules such as MCP1 for macrophage recruitment and the SPP1-Integrin αvß1-Akt signaling pathway for M2 polarization. Conclusion: Our findings not only deepen our understanding of the formation of M2 TAMs, particularly highlighting the differential roles played by heterogeneous cells within GBM in this process, but also provided new insights for effectively controlling the malignant progression of GBM.

NCAPH serves as a prognostic factor and promotes the tumor progression in glioma through PI3K/AKT signaling pathway.

Non-SMC (Structural Maintenance of Chromosomes) condensin I complex subunit H (NCAPH) has been shown to facilitate progression and predict adverse prognostic outcome in many cancer types. However, the function of NCAPH in gliomas is still unclear. Series of experiments were taken to uncover the function of NCAPH in glioma. The expression of NCAPH and potential mechanism regulating progression of glioma was verified by bioinformatics analysis. Lentiviral transfection was used for establishment of loss-of-function and gain-of-function cell lines. CCK-8 assay and Colony-formation assay were used to evaluate proliferation. Transwell assay and Cell wound healing assay were used to assess migration and invasion. Cell cycle and apoptosis were measured by flow cytometry. Protein and RNA were quantified by WB and RT-PCR, respectively. The nude mice model of glioma was used to evaluate the effect of NCAPH in vivo. The expression of NCAPH increased significantly in glioma tissues and correlated with WHO grade, IDH wild-type and non-1p/19q codeletion. Glioma patients with high expression of NCAPH had an undesirable prognosis. Functionally, upregulated NCAPH promotes the malignant hallmarks of glioma cells in vivo and in vitro. NCAPH correlated with DNA damage repair ability of glioma cells and facilitated the proliferation, invasion, and migration of glioma cells by promoting the PI3K/AKT signaling pathway. This study identifies the important pro-tumor role of NCAPH in glioma and suggests that NCAPH is a potential therapeutic target.

IKBKE promotes the ZEB2-mediated EMT process by phosphorylating HMGA1a in glioblastoma.

IKBKE (Inhibitor of Nuclear Factor Kappa-B Kinase Subunit Epsilon) is an important oncogenic protein in a variety of tumors, which can promote tumor growth, proliferation, invasion and drug resistance, and plays a critical regulatory role in the occurrence and progression of malignant tumors. HMGA1a (High Mobility Group AT-hook 1a) functions as a cofactor for proper transcriptional regulation and is highly expressed in multiple types of tumors. ZEB2 (Zinc finger E-box Binding homeobox 2) exerts active functions in epithelial mesenchymal transformation (EMT). In our current study, we confirmed that IKBKE can increase the proliferation, invasion and migration of glioblastoma cells. We then found that IKBKE can phosphorylate HMGA1a at Ser 36 and/or Ser 44 sites and inhibit the degradation process of HMGA1a, and regulate the nuclear translocation of HMGA1a. Crucially, we observed that HMGA1a can regulate ZEB2 gene expression by interacting with ZEB2 promoter region. Hence, HMGA1a was found to promote the ZEB2-related metastasis. Consequently, we demonstrated that IKBKE can exert its oncogenic functions via the IKBKE/HMGA1a/ZEB2 signalling axis, and IKBKE may be a prominent biomarker for the treatment of glioblastoma in the future.

TCAF2 drives glioma cellular migratory/invasion properties through STAT3 signaling.

Glioma is an intracranial tumor characterized by high mortality and recurrence rates. In the present study, the association of TRPM8 channel-associated factor 2 (TCAF2) in glioma was investigated using bioinformatics, showing significant relationships with age, WHO grade, IDH, and 1p/19q status, as well as being an independent predictor of prognosis. Immunohistochemistry of a glioma sample microarray showed markedly increased TCAF2 expression in glioblastoma relative to lower-grade glioma, with elevated expression predominating in the tumor center. Raised TCAF2 levels promote glioma cell migratory/invasion properties through the epithelial-to-mesenchymal transition-like (EMT-like) process, shown by Transwell and scratch assays and western blotting. It was further found that the effects of TCAF2 were mediated by the activation of STAT3. These results suggest that TCAF2 promotes glioma cell migration and invasion, rendering it a potential drug target in glioma therapy.

Ultra high b-value diffusion weighted imaging enables better molecular grading stratification over histological grading in adult-type diffuse glioma.

PURPOSE: Accurate preoperative radiological staging of adult-type diffuse glioma is crucial for effective prognostic stratification and selection of appropriate therapeutic interventions. The purpose of this study was to compare the effectiveness of apparent diffusion coefficient (ADC) maps generated from ultrahigh b-value diffusion-weighted imaging (DWI) for molecular grading with that for histological grading of adult-type diffuse glioma, and to evaluate the correlation between these ADC maps and molecular and histological biomarkers. METHODS: This study retrospectively enrolled forty adult-type diffuse glioma patients, diagnosed using the 2021 WHO classification criteria. Preoperative imaging data, including multiple b-value DWI and conventional magnetic resonance imaging, were collected. Tumors were graded using both histological and molecular criteria. Histogram analysis was conducted to generate 14 parameters for each tumor. Receiver operating characteristic curves and the area under the curve (AUC) were used to evaluate tumor grading and molecular status differentiation. Analysis of histological biomarkers was performed by calculating the Pearson and Spearman correlation coefficients of continuous and hierarchical variables, respectively. RESULTS: The intensity-related parameters for molecular grading were found to be superior to those for histological grading for the identification of WHO grade 4 (WHO4) adult-type diffuse glioma. The AUC of both grading systems increased with increasing b-values, with ADC8000-based histogram parameters showing the best results (molecular grading, square root: AUC = 0.897; histological grading, median: AUC = 0.737). The intensity-related parameters could also differentiate molecular WHO4 gliomas from histologically lower-grade gliomas (ADC8000-based square root: AUC = 0.919), and different ADC8000-based kurtosis was observed between molecular and histological WHO4 gliomas (AUC = 0.833). Significant correlations between the Ki-67 index and molecular status prediction for IDH, CDKN2A, and EGFR were also demonstrated. CONCLUSION: The histogram parameters derived from high b-value ADC maps were found to be more effective for differentiating molecular grades of WHO4 adult-type diffuse glioma than for differentiating histological grades.

The mechanism by which Naru 3 pill protects against intervertebral disc cartilage endplate degeneration based on network pharmacology and experimental verification.

CONTEXT: Naru 3 pill is a traditional Mongolian medicine for the treatment of intervertebral disc degeneration (IDD), but the mechanism is not yet clear. OBJECTIVE: This study investigated the mechanism of Naru 3 pill in the treatment of IDD. MATERIALS AND METHODS: Active ingredients and related targets of Naru 3 pill, as well as IDD-related genes, were collected from public databases. The analysis was performed by protein‒protein interaction network analysis, gene ontology and Kyoto Gene and Genome Encyclopedia (KEGG) functional enrichment analysis, molecular docking and molecular dynamics simulations. Finally, the network pharmacology results were validated by in vitro experiments. RESULTS: Network analysis showed that sesamin, piperine and ellagic acid were potential key components and CASP3, BAX and BCL2 were key targets. KEGG analysis indicated the apoptotic pathway as a potential pathway. Molecular docking showed that sesamin interacted better with the targets than the other components. The results of molecular dynamics simulations indicated that the three systems BAX-sesamin, BCL2-sesamin and CASP3-sesamin were stable and reasonable during the simulation. In vitro experiments showed that sesamin had the least effect on cell growth and the most pronounced proliferation-promoting effect, and so sesamin was considered the key component. The experiments confirmed that sesamin had antiapoptotic effects and reversed the expression of CASP3, BAX and BCL2 in degeneration models, which was consistent with the network pharmacology results. Furthermore, sesamin alleviated extracellular matrix (ECM) degeneration and promoted cell proliferation in the IDD model. CONCLUSION: The present study suggested that Naru 3 pill might exert its therapeutic and antiapoptotic effects on IDD by delaying ECM degradation and promoting cell proliferation, which provides a new strategy for the treatment of IDD.

Diffusion tensor imaging versus intraoperative subcortical mapping for glioma resection: a systematic review and meta-analysis.

Maintaining the integrity of crucial fiber tracts allows functional preservation and improved recovery in patients with glioma resection. Diffusion tensor imaging (DTI) and intraoperative subcortical mapping (ISM) are commonly required for pre- and intraoperative assessment of white matter fibers. This study investigated differences of clinical outcomes in glioma resection aided by DTI or ISM. A comprehensive literature retrieval of the PubMed and Embase databases identified several DTI or ISM studies in 2000-2022. Clinical data, including extent of resection (EOR) and postoperative neurological deficits, was collected and statistically analyzed. Heterogeneity was regressed by a random effect model and the Mann-Whitney U test was used to test statistical significance. Publication bias was assessed by Egger test. A total of 14 studies with a pooled cohort of 1837 patients were included. Patients undergoing DTI-navigated glioma surgery showed a higher rate of gross total resection (GTR) than ISM-assisted surgical resection (67.88%, [95% CI 0.55-0.79] vs. 45.73%, [95% CI 0.29-0.63], P = 0.032). The occurrence of early postoperative functional deficit (35.45%, [95% CI 0.13-0.61] vs. 35.60% [95% CI 0.20-0.53], P = 1.000), late postoperative functional deficit (6.00%, [95% CI 0.02-0.11] vs. 4.91% [95% CI 0.03-0.08], P = 1.000) and severe postoperative functional deficit (2.21%, [95% CI 0-0.08] vs. 5.93% [95% CI 0.01-0.16], P = 0.393) were similar between the DTI and ISM group, respectively. While DTI-navigation resulted in a higher rate of GTR, the occurrence of postoperative neurological deficits between DTI and ISM groups was comparable. Together, these data indicate that both techniques could safely facilitate glioma resection.

Erratum: KLF4 suppresses the migration of hepatocellular carcinoma by transcriptionally upregulating monoglyceride lipase.

[This corrects the article on p. 1019 in vol. 8, PMID: 30034939.].

Emotional Problems, Quality of Life and Symptom Burden in Patients with Chordoma.

Chordomas are very rare malignant bone tumors. Following surgery, their effects on neurological, physical, psychological, social, and emotional functioning are substantial and can have a major impact on a patients' quality of life (QOL). In this survey, we aimed to characterize the postoperation health-related QOL and emotional problem in patients with chordoma using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQ-C30) and Hamilton Depression Rating Scale (HAMD). The cohort included 100 patients who underwent resection surgery between 2014 and 2020. Being single or divorced, living in a rural area, receiving a diagnosis of sacrococcygeal chordoma, Karnofsky performance status (KPS) ≤ 70, and weight loss were associated with increased likelihood of depression (p < 0.05). Patients who were single or divorced, with KPS ≤ 70, and experiencing weight loss had a higher likelihood of a worse QOL (p < 0.05). The uni- and multivariate logistic regression analyses indicated that the KPS level (p = 0.000) and postoperative radiation therapy (p = 0.009) were related to depression; marital status (p = 0.029), KPS level (p = 0.006), and tumor location (p = 0.033) were related to worse QOL. Certain characteristics placed patients with chordoma at increased risk of emotional problems, which are associated with a lowered QOL and a higher symptom burden. Further knowledge regarding emotional problems is key to improving the QOL for patients with chordoma.

Salvianolic acid B attenuates tubulointerstitial fibrosis by inhibiting EZH2 to regulate the PTEN/Akt pathway.

CONTEXT: Salvianolic acid B (SAB) can alleviate renal fibrosis and improve the renal function. OBJECTIVE: To investigate the effect of SAB on renal tubulointerstitial fibrosis and explore its underlying mechanisms. MATERIALS AND METHODS: Male C57 mice were subjected to unilateral ureteric obstruction (UUO) and aristolochic acid nephropathy (AAN) for renal fibrosis indication. Vehicle or SAB (10 mg/kg/d, i.p.) were given consecutively for 2 weeks in UUO mice while 4 weeks in AAN mice. The serum creatinine (Scr) and blood urine nitrogen (BUN) were measured. Masson's trichrome staining and the fibrotic markers (FN and α-SMA) were used to evaluate renal fibrosis. NRK-49F cells exposed to 2.5 ng/mL TGF-ß were treated with SAB in the presence or absence of 20 µM 3-DZNep, an inhibitor of EZH2. The protein expression of EZH2, H3k27me3 and PTEN/Akt signaling pathway in renal tissue and NRK-49F cells were measured by Western blots. RESULTS: SAB significantly improved the levels of Scr by 24.3% and BUN by 35.7% in AAN mice. SAB reduced renal interstitial collagen deposition by 34.7% in UUO mice and 72.8% in AAN mice. Both in vivo and in vitro studies demonstrated that SAB suppressed the expression of FN and α-SMA, increased PTEN and decreased the phosphorylation of Akt, which were correlated with the down-regulation of EZH2 and H3k27me3. The inhibition of EZH2 attenuated the anti-fibrotic effects of SAB in NRK-49Fs. CONCLUSION: SAB might have therapeutic potential on renal fibrosis of CKD through inhibiting EZH2, which encourages further clinical trials.

PDPN contributes to constructing immunosuppressive microenvironment in IDH wildtype glioma.

The tumor immunosuppressive microenvironment (IME) significantly affects tumor occurrence, progression, and prognosis, but the underlying molecular mechanisms remain to make known. We investigated the prognostic significance of PDPN and its role in IME in glioma. Weighted gene co-expression network analysis (WGCNA) found PDPN closely related to IDH wildtype status and higher immune score. Correlation analysis suggested PDPN was highly positively relevant to immune checkpoints expression and immune checkpoints block responding status. Correlation analysis together with verification in vitro suggested PDPN highly positively relevant tumor-associated neutrophils (TANs) and tumor-associated macrophages (TAMs). Least absolute shrinkage and selection operator (LASSO) regression employed to develop the prediction model with TANs and TAMs markers showed that high risk scores predicted worse prognosis. We highlight that PDPN overexpression is an independent prognostic indicator, and promotes macrophage M2 polarization and neutrophil degranulation, ultimately devotes to the formation of an immunosuppressive tumor microenvironment. Our findings contribute to re-recognizing the role of PDPN in IDH wildtype gliomas and implicate promising target therapy combined with immunotherapy for this highly malignant tumor.

The crosstalk between intestinal bacterial microbiota and immune cells in colorectal cancer progression.

Different types of cells that are involved in tumor immunity play a significant part in antitumor therapy. The intestinal microbiota consist of the trillions of diverse microorganisms that inhabit the gastrointestinal tract. Recently, much emphasis has been paid to the link between these symbionts and colorectal cancer (CRC). This association might be anything from oncogenesis and cancer development to resistance or susceptibility to chemotherapeutic medicines. Cancer patients have a significantly different microbial composition in their guts compared to healthy persons. The microbiome may play a role in the development and development of cancer through the modulation of tumor immunosurveillance, as shown by these studies; however, the specific processes underlying this role are still poorly understood. This review focuses on the relationship between the intestinal bacterial microbiota and immune cells to determine how the commensal microbiome influences the initiation and development of CRC.

Combinatorial Application of Papain and CD66B for Isolating Glioma- Associated Neutrophils.

BACKGROUND: Stromal cells in the tumor microenvironment play crucial roles in glioma development. Current methods for isolating tumor-associated stromal cells (such as neutrophils) are inefficient due to the conflict between tissue dissociation and cell surface protein protection, which hampers the research on patient-derived stromal cells. Our study aims to establish a novel method for isolating glioma-associated neutrophils (GANs). METHODS: To observe neutrophil-like polymorphonuclear cells, we performed Hematoxylin-Eosin staining on glioma tissues. For isolating single cells from glioma tissues, we evaluated the efficiency of tissue dissociation with FastPrep Grinder-mediated homogenization or proteases (trypsin or papain) digestion. To definite specific markers of GANs, fluorescence-activated cell sorting (FACS) and immunofluorescence staining were performed. FACS and Ficoll were performed for the separation of neutrophils from glioma tissue-derived single-cell or whole blood pool. To identify the isolated neutrophils, FACS and RT-PCR were carried out. RESULTS: Neutrophil-like cells were abundant in high-grade glioma tissues. Among the three tissue dissociation methods, papain digestion produced a 5.1-fold and 1.7-fold more living cells from glioma mass than physical trituration and trypsin digestion, respectively, and it preserved over 97% of neutrophil surface protein markers. CD66B could be adopted as a unique neutrophil surface protein marker for FACS sorting in glioma. Glioma-derived CD66B+ cells specifically expressed neutrophil marker genes. CONCLUSION: A combination of papain-mediated tissue dissociation and CD66B-mediated FACS sorting is an effective novel method for the isolation of GANs from glioma tissues.

Chinese guideline on the application of anti-seizure medications in the perioperative period of supratentorial craniocerebral surgery.

Seizures are a common symptom of craniocerebral diseases, and epilepsy is one of the comorbidities of craniocerebral diseases. However, how to rationally use anti-seizure medications (ASMs) in the perioperative period of craniocerebral surgery to control or avoid seizures and reduce their associated harm is a problem. The China Association Against Epilepsy (CAAE) united with the Trauma Group of the Chinese Neurosurgery Society, Glioma Professional Committee of the Chinese Anti-Cancer Association, Neuro-Oncology Branch of the Chinese Neuroscience Society, and Neurotraumatic Group of Chinese Trauma Society, and selected experts for consultancy regarding outcomes from evidence-based medicine in domestic and foreign literature. These experts referred to the existing research evidence, drug characteristics, Chinese FDA-approved indications, and expert experience, and finished the current guideline on the application of ASMs during the perioperative period of craniocerebral surgery, aiming to guide relevant clinical practice. This guideline consists of six sections: application scope of guideline, concepts of craniocerebral surgery-related seizures and epilepsy, postoperative application of ASMs in patients without seizures before surgery, application of ASMs in patients with seizures associated with lesions before surgery, emergency treatment of postoperative seizures, and 16 recommendations.

Targeting Heat-Shock Protein 90 in Cancer: An Update on Combination Therapy.

Heat-shock protein 90 (HSP90) is an important molecule chaperone associated with tumorigenesis and malignancy. HSP90 is involved in the folding and maturation of a wide range of oncogenic clients, including diverse kinases, transcription factors and oncogenic fusion proteins. Therefore, it could be argued that HSP90 facilitates the malignant behaviors of cancer cells, such as uncontrolled proliferation, chemo/radiotherapy resistance and immune evasion. The extensive associations between HSP90 and tumorigenesis indicate substantial therapeutic potential, and many HSP90 inhibitors have been developed. However, due to HSP90 inhibitor toxicity and limited efficiency, none have been approved for clinical use as single agents. Recent results suggest that combining HSP90 inhibitors with other anticancer therapies might be a more advisable strategy. This review illustrates the role of HSP90 in cancer biology and discusses the therapeutic value of Hsp90 inhibitors as complements to current anticancer therapies.

Calcium-Related Gene Signatures May Predict Prognosis and Level of Immunosuppression in Gliomas.

Gliomas are the most common primary brain cancer. While it has been known that calcium-related genes correlate with gliomagenesis, the relationship between calcium-related genes and glioma prognosis remains unclear. We assessed TCGA datasets of mRNA expressions with differentially expressed genes (DEGs) and enrichment analysis to specifically screen for genes that regulate or are affected by calcium levels. We then correlated the identified calcium-related genes with unsupervised/supervised learning to classify glioma patients into 2 risk groups. We also correlated our identified genes with immune signatures. As a result, we discovered 460 calcium genes and 35 calcium key genes that were associated with OS. There were 13 DEGs between Clusters 1 and 2 with different OS. At the same time, 10 calcium hub genes (CHGs) signature model were constructed using supervised learning, and the prognostic risk scores of the 3 cohorts of samples were calculated. The risk score was confirmed as an independent predictor of prognosis. Immune enrichment analysis revealed an immunosuppressive tumor microenvironment with upregulation of checkpoint markers in the high-risk group. Finally, a nomogram was generated with risk scores and other clinical prognostic independent indicators to quantify prognosis. Our findings suggest that calcium-related gene expression patterns could be applicable to predict prognosis and predict levels of immunosuppression.

A Novel Prognostic Signature Based on Glioma Essential Ferroptosis-Related Genes Predicts Clinical Outcomes and Indicates Treatment in Glioma.

Background: Ferroptosis is a form of programmed cell death (PCD) that has been implicated in cancer progression, although the specific mechanism is not known. Here, we used the latest DepMap release CRISPR data to identify the essential ferroptosis-related genes (FRGs) in glioma and their role in patient outcomes. Methods: RNA-seq and clinical information on glioma cases were obtained from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). FRGs were obtained from the FerrDb database. CRISPR-screened essential genes (CSEGs) in glioma cell lines were downloaded from the DepMap portal. A series of bioinformatic and machine learning approaches were combined to establish FRG signatures to predict overall survival (OS) in glioma patients. In addition, pathways analysis was used to identify the functional roles of FRGs. Somatic mutation, immune cell infiltration, and immune checkpoint gene expression were analyzed within the risk subgroups. Finally, compounds for reversing high-risk gene signatures were predicted using the GDSC and L1000 datasets. Results: Seven FRGs (ISCU, NFS1, MTOR, EIF2S1, HSPA5, AURKA, RPL8) were included in the model and the model was found to have good prognostic value (p < 0.001) in both training and validation groups. The risk score was found to be an independent prognostic factor and the model had good efficacy. Subgroup analysis using clinical parameters demonstrated the general applicability of the model. The nomogram indicated that the model could effectively predict 12-, 36-, and 60-months OS and progression-free interval (PFI). The results showed the presence of more aggressive phenotypes (lower numbers of IDH mutations, higher numbers of EGFR and PTEN mutations, greater infiltration of immune suppressive cells, and higher expression of immune checkpoint inhibitors) in the high-risk group. The signaling pathways enriched closely related to the cell cycle and DNA damage repair. Drug predictions showed that patients with higher risk scores may benefit from treatment with RTK pathway inhibitors, including compounds that inhibit RTKs directly or indirectly by targeting downstream PI3K or MAPK pathways. Conclusion: In summary, the proposed cancer essential FRG signature predicts survival and treatment response in glioma.