Phosducin-like 3 is a novel prognostic and onco-immunological biomarker in glioma: A multi-omics analysis with experimental verification.

Malignant glioma is the most frequent primary tumor of the central nervous system. PDCL3 is a member of the phosducin-like protein family, and its imbalance has been shown to be associated with several human diseases. However, the underlying role of PDCL3 in human malignant cancers, especially in malignant gliomas, is unclear. In this study, we combined public database analysis and experimental verification to explore the differential expression, prognostic value and potential functions and mechanisms of PDCL3. The results revealed that PDCL3 is upregulated in multiple cancers and acts as a potential prognostic biomarker of glioma. Mechanistically, PDCL3 expression is associated with epigenetic modifications and genetic mutations. PDCL3 may directly interact with the chaperonin-containing TCP1 complex, regulating cell malignancy, cell communication and the extracellular matrix. More importantly, the association of PDCL3 with the infiltration of immune cells, immunomodulatory genes, immune checkpoints, cancer stemness and angiogenesis suggested that PDCL3 may regulate the glioma immune landscape. Furthermore, PDCL3 interference also decreased the proliferation, invasion and migration of glioma cells. In conclusion, PDCL3 is a novel oncogene and can be adopted as a biomarker with value in assisting clinical diagnosis, predicting patient outcomes and assessing the immune landscape of the tumor microenvironment in glioma.

Prognostic analysis of posterior fossa decompression with or without cerebellar tonsillectomy for Chiari malformation type I: a multicenter retrospective study.

OBJECTIVE: The purpose of this study was to compare the prognosis of patients with Chiari malformation type I (CM-I) treated with posterior fossa decompression with duraplasty (PFDD) and posterior fossa decompression with resection of tonsils (PFDRT). METHODS: The clinical data of patients with CM-I treated using these two procedures in three medical centers between January 2016 and June 2021 were retrospectively analyzed and divided into PFDD and PFDRT groups according to the procedures. The Chicago Chiari Outcome Scale (CCOS) was used to score the patients and compare the prognosis of the two groups. RESULTS: A total of 125 patients with CM-I were included, of whom 90 (72.0%) were in the PFDD group, and 35 (28.0%) were in the PFDRT group. There was no significant difference in the overall essential characteristics of the two groups. Moreover, there was no significant difference in complication rates (3.3% vs 8.6%, p = 0.348), CCOS scores (13.5 ± 1.59 vs 14.0 ± 1.21, p = 0.111), and the probability of poor prognosis (25.6% vs 11.4%, p = 0.096) between the two groups. Nevertheless, a subgroup of patients who had CM-I combined with syringomyelia (SM) revealed higher CCOS scores (13.91 ± 1.12 vs 12.70 ± 1.64, p = 0.002) and a lower probability of poor prognosis (13.0% vs 40.4%, p = 0.028) in the PFDRT than in the PFDD group. Also, SM relief was more significant in patients in the PFDRT compared to the PFDD group. A logistic multifactor regression analysis of poor prognosis in patients with CM-I and SM showed that the PFDRT surgical approach was a protective factor compared to PFDD. Furthermore, by CCOS analysis, it was found that the main advantage of PFDRT in treating patients with CM-I and SM was to improve patients' nonpain and functionality scores. CONCLUSIONS: Compared with PFDD, PFDRT is associated with a better prognosis for patients with CM-I and SM and is a protective factor for poor prognosis. Therefore, the authors suggest that PFDRT may be considered for patients with CM-I and SM.

Kaempferol suppresses glioma progression and synergistically enhances the antitumor activity of gefitinib by inhibiting the EGFR/SRC/STAT3 signaling pathway.

Kaempferol (Kae) is a natural flavonoid that has multiple biological activities, such as anti-inflammatory and antitumor activities. However, few studies have been reported on antiglioma effects of Kae. This study aimed to explore the effects and potential mechanisms of Kae and synergistic antitumor activities with gefitinib (Gef) on glioma. Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays were used to detect cytotoxicity and cell proliferation. Cell apoptosis and the cell cycle were detected by flow cytometry. Transwell assays were used to detect the migratory and invasive abilities of glioma cells. Network pharmacology and molecular docking analysis were used to screen for core targets of Kae in glioma therapy. Xenograft tumor nude mice were established with U251 cells to verify the antiglioma effects of Kae in vivo. A terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to detect apoptosis in tumor tissues. The expression of proteins was detected by immunohistochemistry and western blot analysis. Kae inhibited cell proliferation, promoted apoptosis, and induced cell cycle arrest in the G2/M phase of glioma cells in a concentration-dependent manner. Kae inhibited the migration and invasion of glioma cells at low concentrations. Network pharmacology analyses showed that epidermal growth factor receptor (EGFR) and SRC proto-oncogene (SRC) might be direct molecular-binding targets of Kae. Our results showed that Kae inhibited the levels of phosphorylated EGFR, phosphorylated SRC (p-SRC), and phosphorylated signal transducer and activator of transcription 3 (STAT3). In addition, the combination of Kae with Gef significantly inhibited the proliferation of glioma cells. Kae further inhibited EGFR phosphorylation after treatment with Gef. Similarly, Kae further enhanced the inhibition of p-SRC caused by SU6656. Finally, we demonstrated that Kae exerted great antitumor activities and enhanced the antitumor effect of Gef by inhibiting EGFR/SRC/STAT3 signaling pathway in vivo. Kae played a potential role and synergistic antiglioma effects with Gef by inhibiting the phosphorylation of EGFR/SRC dual targets. Kae is expected to be a candidate drug or chemosensitizer in glioma therapy.

A Modified Dura Puncture Procedure to Reduce Brain Shift in Deep Brain Stimulation Surgery: One Institution's Experience.

Objective: The therapeutic effect of deep brain stimulation (DBS) surgery mainly depends on the accuracy of electrode placement and the reduction in brain shift. Among the standard procedures, cerebrospinal fluid (CSF) loss or pneumocephalus caused by dura incision (DI) is thought to be the main reason for brain shift and inaccuracy of electrode placement. In the current study, we described a modified dura puncture (DP) procedure to reduce brain shift and compare it with the general procedure of DBS surgery in terms of electrode placement accuracy. Materials and Methods: We retrospectively analyzed a series of 132 patients who underwent DBS surgery in Wuhan Union Hospital from December 2015 to April 2021. According to the different surgery procedures, patients were classified into two cohorts: the DI group (DI cohort) had 49 patients who receive the general procedure, and the DP group (DP cohort) had 83 patients who receive the modified procedure. Postoperative pneumocephalus volume (PPV) and CSF loss volume, electrode fusion error (EFE), and trajectory number were calculated. Meanwhile, intraoperative electrophysiological signal length (IESL), electrode implantation duration, and other parameters were analyzed. Results: In the current study, we introduced an improved electrode implantation procedure for DBS surgery named the DP procedure. Compared with the general DI cohort (n = 49), the modified DP cohort (n = 83) had a shorter electrode implantation duration (p < 0.0001), smaller PPV, lower CSF leakage volume (p < 0.0001), and smaller EFE (p < 0.0001). There was no significant difference in IESL (p > 0.05) or adverse events (perioperative cerebral haematoma, skin erosion, epilepsy, p > 0.05) between the two cohorts. Conclusion: The DP procedure is a modified procedure that can reduce brain shift and ensure implantation accuracy during DBS surgery without adverse events.

EDEM2 is a diagnostic and prognostic biomarker and associated with immune infiltration in glioma: A comprehensive analysis.

Glioma is a highly common pathological brain tumor. Misfolded protein response, which is strongly associated with the growth of cancerous tumors, is mediated by the gene, endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein 2. However, this gene has not been linked to glioma. To assess the same, we used The Cancer Genome Atlas, Chinese Glioma Genome Atlas, and Genotype-Tissue Expression datasets. The gene was overexpressed in gliomas. This overexpression was linked to unfavorable clinical characteristics, such as the World Health Organization grade, isocitrate dehydrogenase mutation, and the combined loss of the short arm chromosome 1 and the long arm of chromosome 19. Quantitative polymerase chain reaction experiments and immunohistochemistry on clinical samples from our institution verified the gene's expression and clinical importance. The Human Protein Atlas website verified the messenger ribonucleic acid expression of the gene in glioma cell lines, and immunohistochemistry verified the presence of its protein. A previous survival study indicated that its high expression is substantially related to a bad prognosis. It was identified as an independent predictor of primary glioma prognosis using multivariate Cox regression analysis. To forecast individual survival, we created a nomogram based on this (concordance-index = 0.847). Additionally, functional annotation demonstrated its major role in the control of the extracellular matrix and immune system. The scratch assay and transwell migration assay confirmed the decreased invasive ability of U251 glioma cells with the gene knockdown. Its increased expression was found to be related to the extent of macrophage infiltration using the CIBERSORT, ESTIMATE, Single-sample Gene Set Enrichment Analysis, and Tumor Immune Single-Cell Hub (TISCH) algorithms. The Tumor Immune Dysfunction and Exclusion algorithm revealed that the gene can accurately predict the response of immunotherapy (area under the receiver operating characteristic curve = 0.857). Further, isocitrate dehydrogenase 1 mutation is typically more frequent when the gene expression is high. Finally, five medicines targeting this gene were discovered utilizing the molecular docking program and drug sensitivity analysis of the RNAactDrug website. Low expression of the gene inhibited glioma cell invasion. Therefore, the gene is helpful for the diagnosis, prognosis, and case-specific immunotherapy of glioma.

CD90low glioma-associated mesenchymal stromal/stem cells promote temozolomide resistance by activating FOXS1-mediated epithelial-mesenchymal transition in glioma cells.

BACKGROUND: The tumour microenvironment contributes to chemotherapy resistance in gliomas, and glioma-associated mesenchymal stromal/stem cells (gaMSCs) are important stromal cell components that play multiple roles in tumour progression. However, whether gaMSCs affect chemotherapy resistance to the first-line agent temozolomide (TMZ) remains unclear. Herein, we explored the effect and mechanism of gaMSCs on resistance to TMZ in glioma cells. METHODS: Human glioma cells (cell line U87MG and primary glioblastoma cell line GBM-1) were cultured in conditioned media of gaMSCs and further treated with TMZ. The proliferation, apoptosis and migration of glioma cells were detected by Cell Counting Kit-8 (CCK-8), flow cytometry and wound-healing assays. The expression of FOXS1 in glioma cells was analysed by gene microarray, PCR and Western blotting. Then, FOXS1 expression in glioma cells was up- and downregulated by lentivirus transfection, and markers of the epithelial-mesenchymal transformation (EMT) process were detected. Tumour-bearing nude mice were established with different glioma cells and treated with TMZ to measure tumour size, survival time and Ki-67 expression. Finally, the expression of IL-6 in gaMSC subpopulations and its effects on FOXS1 expression in glioma cells were also investigated. RESULTS: Conditioned media of gaMSCs promoted the proliferation, migration and chemotherapy resistance of glioma cells. The increased expression of FOXS1 and activation of the EMT process in glioma cells under gaMSC-conditioned media were detected. The relationship of FOXS1, EMT and chemotherapy resistance in glioma cells was demonstrated through the regulation of FOXS1 expression in vitro and in vivo. Moreover, FOXS1 expression in glioma cells was increased by secretion of IL-6 mainly from the CD90low gaMSC subpopulation. CONCLUSIONS: CD90low gaMSCs could increase FOXS1 expression in glioma cells by IL-6 secretion, thereby activating epithelial-mesenchymal transition and resistance to TMZ in glioma cells. These results indicate a new role of gaMSCs in chemotherapy resistance and provide novel therapeutic targets.

Cell fusion in cancer hallmarks: Current research status and future indications.

Cell fusion is involved in several physiological processes, such as reproduction, development and immunity. Although cell fusion in tumors was reported 130 years ago, it has recently attracted great interest, with recent progress in tumorigenesis research. However, the role of cell fusion in tumor progression remains unclear. The pattern of cell fusion and its role under physiological conditions are the basis for our understanding of the pathological role of cell fusion. However, the role of cell fusion in tumors and its functions are complicated. Cell fusion can directly increase tumor heterogeneity by forming polyploids or aneuploidies. Several studies have reported that cell fusion is associated with tumorigenesis, metastasis, recurrence, drug resistance and the formation of cancer stem cells. Given the diverse roles cell fusion plays in different tumor phenotypes, methods based on targeted cell fusion have been designed to treat tumors. Research on cell fusion in tumors may provide novel ideas for further treatment.

Efficacy and safety of general anesthesia deep brain stimulation for dystonia: an individual patient data meta-analysis of 341 cases.

OBJECTIVE: The efficacy and safety of deep brain stimulation (DBS) under general anesthesia for the treatment of dystonia have not yet been confirmed with high level of evidence. This meta-analysis with pooled individual patient data aims to assess the clinical outcomes and identify the potential prognostic factors of dystonia patients who underwent general anesthesia DBS. METHODS: We searched PubMed, Web of Science, and Embase for articles describing patients with dystonia who underwent asleep DBS and had individual Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores. The relative improvement in BFMDRS scores was considered the primary outcome. Pearson correlation analyses and multivariate linear regression analysis were conducted to explore the prognostic factors. RESULTS: A total of 34 studies involving 341 patients were included. The mean postoperative improvement in BFMDRS-M (BFMDRS movement subscale) and BFMDRS-D (BFMDRS disability subscale) scores were 58.6±36.2% and 48.5±38.7% at the last follow-up visit, respectively, with a mean follow-up time of 22.4±27.6 months. Age at surgery and disease duration showed a negative correlation with the percent improvement of BFMDRS-M (%) at the last visit (r=-0.134, P=0.013; r=-0.165, P=0.006). In the stepwise multivariate regression, only disease duration remained a relevant factor. Additionally, the adverse events were acceptable. CONCLUSION: General anesthesia DBS is a safe, effective, and feasible option for dystonia patients in the long term. Shorter disease duration predicts better clinical outcomes.

Growth factors contribute to the mediation of angiogenic capacity of glioma-associated mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are important components of stromal cell populations and serve a crucial role in tumor growth and progression. Previously, our laboratory successfully isolated and cultured MSCs from human glioma issues and demonstrated that glioma-associated mesenchymal stem cells (gb-MSCs) participate in and maintain tumor angiogenesis. Furthermore, growth factors, such as fibroblast growth factor and vascular endothelial cell growth factor, were demonstrated to be associated with endothelial cell tube formation. However, the effect of transforming growth factor ß1 (TGF-ß1) and platelet-derived growth factor-BB (PDGF-BB) on the angiogenic activity of gb-MSCs remains unknown. The present study aimed therefore to explore their effects in gb-MSCs angiogenesis. In the present study, gb-MSCs were isolated from patients with glioma and were characterized using flow cytometry and differentiation experiments. Furthermore, the results from tube formation assay revealed that TGF-ß1 and PDGF-BB could mediate the angiogenic capacity of gb-MSCs in vitro. In addition, results from immunofluorescence demonstrated that gb-MSCs expressed TGF-ß1R and PDGFR, which are the receptors for TGF-ß1 and PDGF-BB, respectively. Taken together, these findings indicated that TGF-ß1 and PDGF-BB may serve a crucial role in mediating gb-MSC angiogenesis, which might provide a therapeutic strategy for targeting the angiogenic capacity of gb-MSCs in patients with glioma.

Roles of long non-coding RNAs in the hallmarks of glioma.

Glioma is one of the most common types of tumor of the central nervous system. Due to the aggressiveness and invasiveness of high-level gliomas, the survival time of patients with these tumors is short, at ~15 months, even after combined treatment with surgery, radiotherapy and/or chemotherapy. Recently, a number of studies have demonstrated that long non-coding RNA (lncRNAs) serve crucial roles in the multistep development of human gliomas. Gliomas acquire numerous biological abilities during multistep development that collectively constitute the hallmarks of glioma. Thus, in this review, the roles of lncRNAs associated with glioma hallmarks and the current and future prospects for their development are summarized.

CD90 determined two subpopulations of glioma-associated mesenchymal stem cells with different roles in tumour progression.

Human glioma-associated mesenchymal stem cells (gbMSCs) are the stromal cell components that contribute to the tumourigenesis of malignant gliomas. Recent studies have shown that gbMSCs consist of two distinct subpopulations (CD90+ and CD90- gbMSCs). However, the different roles in glioma progression have not been expounded. In this study, we found that the different roles of gbMSCs in glioma progression were associated with CD90 expression. CD90high gbMSCs significantly drove glioma progression mainly by increasing proliferation, migration and adhesion, where as CD90low gbMSCs contributed to glioma progression chiefly through the transition to pericytes and stimulation of vascular formation via vascular endothelial cells. Furthermore, discrepancies in long non-coding RNAs and mRNAs expression were verified in these two gbMSC subpopulations, and the potential underlying molecular mechanism was discussed. Our data confirm for the first time that CD90high and CD90low gbMSCs play different roles in human glioma progression. These results provide new insights into the possible future use of strategies targeting gbMSC subpopulations in glioma patients.

Current status and potential challenges of mesenchymal stem cell-based therapy for malignant gliomas.

Glioma, which accounts for more than 30% of primary central nervous system tumours, is characterised by symptoms such as headaches, epilepsy, and blurred vision. Glioblastoma multiforme is the most aggressive, malignant, and lethal brain tumour in adults. Even with progressive combination treatment with surgery, radiotherapy, and chemotherapy, the prognosis for glioma patients is still extremely poor. Compared with the poor outcome and slowly developing technologies for surgery and radiotherapy, the application of targeted chemotherapy with a new mechanism has become a research focus in this field.Moreover, targeted therapy is promising for most solid tumours. The tumour-tropic ability of stem cells, including neural stem cells and mesenchymal stem cells, provides an alternative therapeutic approach. Thus, mesenchymal stem cell-based therapy is based on a tumour-selective capacity and has been thought to be an effective anti-tumour option over the past decades. An increasing number of basic studies on mesenchymal stem cell-based therapy for gliomas has yielded complex outcomes.In this review, we summarise the biological characteristics of human mesenchymal stem cells, and the current status and potential challenges of mesenchymal stem cell-based therapy in patients with malignant gliomas.

Human Glioblastoma-Derived Mesenchymal Stem Cell to Pericytes Transition and Angiogenic Capacity in Glioblastoma Microenvironment.

BACKGROUND/AIMS: Tumor vascular formation and maintenance are crucial events in glioblastoma development. Mesenchymal stem cells (MSCs) have been shown to differentiate into pericytes and contribute to neovascularization in the glioma microenvironment. Moreover, glioblastoma-derived mesenchymal stem cells (gb-MSCs), which consist of CD90-MSCs and CD90+MSCs, are a subpopulation of MSCs that are more active in glioma vascularization. However, the functions of gb-MSCs and the microRNA (miRNA) modifications in the glioblastoma microenvironment have not yet been fully elucidated. Here, we focus on the pericyte differentiation potential of gb-MSCs and miRNA modifications in gb-MSCs during new vascular formation and glioblastoma growth. METHODS: In vitro, surface markers of gb-MSCs were detected by flow cytometry; the differentiation potential was evaluated by Oil Red O staining, Alizarin Red staining and Alcian blue staining; the proliferation and migration of gb-MSCs in different conditioned media were analyzed by the cck8 test and wound-healing assay, respectively; gb-MSC to pericyte transition was detected by immunofluorescence staining and western blot assay; angiogenetic capacity was analyzed by tube formation assay; and levels of cytokines in different supernatant were determined by ELISA. Additionally, RNA was isolated from gb-MSCs, and miRNA modifications were analyzed using the RAffymetrix miRNA microarray Results: We showed that glioblastoma-conditioned medium increased gb-MSC proliferation and migration and was capable of inducing gb-MSC differentiation into pericytes. Glioblastoma secreted angiogenic factors and gb-MSCs incubated in malignant glioblastoma-conditioned medium formed more tube-like structures, and these cells also adhered to tube-like vessels formed by human umbilical vein endothelial cells (HUVECs) on Matrigel to maintain tumor vascular structure in vitro. miRNA expression were also modified in gb-MSCs cultured in malignant glioblastoma-conditioned medium in vitro. CONCLUSION: These results provide new insight into the functional effects of a subpopulation of MSCs in glioblastoma and may help in the development of novel therapies for solid tumors.

Dehydrocavidine attenuates d-galactose induced learning and memory impairment in rats.

OBJECTIVE: Dehydrocavidine (DEH) is the major component of a plant corydalis saxicola Bunting, which is used to treat the patients with hepatic disorders, there is still no report about the effect of DEH on the brain disorder. In this study, the effect and mechanism of DEH on d-galactose (d-gala) induced learning and memory impairment in rats was investigated. METHODS: A learning and memory impairment rat model was employed by chronic intraperitoneal injection of d-gala and intragastric administration of DEH, then Morris water maze test was used to investigate the effect of DEH on learning and memory impairment, Golgi stain and biochemical methods, real time PCR were used to investigate underlying mechanism. RESULTS: Intraperitoneal injection of d-gala could induced severe learning and memory impairment in rats, intragastric administration of DEH could effectively attenuates these deficits. Golgi staining showed DEH supplementary could restored the density of spines to 5.7±1.16 spines per 10µm in the DEH+d-gala group (p<0.05). DEH supplementary administration reversed the lipid peroxides and restored the enzymes activities to reduce oxidative damage (p<0.05). DEH supplementary administration could reduced the production of NO and PGE2 and the mRNA expression of iNOS and COX-2 (p<0.05). CONCLUSIONS: DEH could attenuates d-gala induced learning and memory impairment in rats by enhancing synaptic plasticity, reducing oxidative damage and limiting the neuroinflammation.

Effect of microRNA-128 on cisplatin resistance of glioma SHG-44 cells by targeting JAG1.

This current study intends to investigate the effect of microRNA-128 (miR-128) on cisplatin (DDP) resistance in glioma SHG-44 cells. SHG-44/DDP cells were transfected with miR-128 antisense oligonucleotide (ASO) and assigned into blank, resistance, NC, anti-miR-128, miR-128 mimic, si-JAG1, and anti-miR-128 + si-JAG1 groups. qRT-PCR and Western blotting were employed for determining expression of miR-128, JAG1, Bax and Bcl-2. MTT assay, Giemsa staining, and flow cytometry were applied to detect DDP resistance, cellular morphology, and cell cycle, respectively. JAG1 is targeted and negatively regulated by miR-128. In in vitro experiments, compared with the blank group, the rest groups exhibited declined miR-28 and Bax expression, lowered cell inhibition rate and apoptosis rate, but elevated JAG1 and Bcl-2 expression with cells arrested in the S phase. Compared with the resistance group, the anti-miR-128 group showed decreasedBax expression along with a lowered cell inhibition rate and apoptosis rate, but increased JAG1 and Bcl-2 expression with reduced cells arrested in the S phase; while the miR-128 mimic group showed an opposite trend; the si-JAG1 group showed decreased Bcl-2 expression and reduced cells in the S phase. In in vivo experiments, compared with the resistance group, the tumor growth rate, tumor volume, and weight as well as JAG1 expression accelerated in the anti-miR-128 group; whereas the miR-128 mimic and si-JAG1 groups exhibited an opposite trend. Our findings demonstrated that miR-128 ASO transfection might down-regulate the expression of miR-128 in SHG-44/DDP and up-regulate the DDP resistance in SHG-44/DDP cells, providing a potential treatment target for glioma.