Bibliometric analysis of emerging trends and research foci in brainstem tumor field over 30 years (1992-2023).

PURPOSE: Over the past several decades, numerous articles have been published on brainstem tumors. However, there has been limited bibliometric analysis in this field. Therefore, we conducted a bibliometric analysis to elucidate the evolution and current status of brainstem tumor research. METHODS: We retrieved 5525 studies published in English between 1992 and 2023 from the Web of Science Core Collection database. We employed bibliometric tools and VOSviewer to conduct the analysis. RESULTS: We included a total of 5525 publications for further analysis. The annual publications have exhibited steady growth over time. The United States accounted for the highest number of publications and total citations. Among individual researchers, Liwei Zhang had the highest number of publications, while Cynthia Hawkins and Chris Jones shared the most citations, closely followed by Eric Bouffet in this field. The study titled "Diffuse brainstem glioma in children: critical review of clinical trials" stood out as the most cited work in this field. Keyword analysis revealed that immune therapy and epigenetic research are the focal points of this field. CONCLUSIONS: Our bibliometric analysis underscores the enduring significance of brainstem tumors in the realm of neuro-oncology research. The field's hotspots have transitioned from surgery and radiochemotherapy to investigating epigenetic mechanisms and immune therapy.

Apoptotic Bodies Derived from Fibroblast-Like Cells in Subcutaneous Connective Tissue Inhibit Ferroptosis in Ischaemic Flaps via the miR-339-5p/KEAP1/Nrf2 Axis.

Preventing and treating avascular necrosis at the distal end of the flaps are critical to surgery success, but current treatments are not ideal. A recent study shows that apoptotic bodies (ABs) generated near the site of apoptosis can be taken up and promote cell proliferation. The study reveals that ABs derived from fibroblast-like cells in the subcutaneous connective tissue (FSCT cells) of skin flaps promoted ischaemic flap survival. It is also found that ABs inhibited cell death and oxidative stress and promoted M1-to-M2 polarization in macrophages. Transcriptome sequencing and protein level testing demonstrated that ABs promoted ischaemic flap survival in endothelial cells and macrophages by inhibiting ferroptosis via the KEAP1-Nrf2 axis. Furthermore, microRNA (miR) sequencing data and in vitro and in vivo experiments demonstrated that ABs inhibited KEAP1 by delivering miR-339-5p to exert therapeutic effects. In conclusion, FSCT cell-derived ABs inhibited ferroptosis, promoted the macrophage M1-to-M2 transition via the miR-339-5p/KEAP1/Nrf2 axis and promoted ischaemic flap survival. These results provide a potential therapeutic strategy to promote ischaemic flap survival by administering ABs.

Effects of electroconvulsive therapy on functional brain networks in patients with schizophrenia.

BACKGROUND: Schizophrenia is a kind of intractable brain disorder. Electroconvulsive therapy (ECT) has been used to rapidly improve the clinical symptoms of patients with schizophrenia, but the effect of ECT on topological attributes of brain functional network in patients with schizophrenia has not been clear. The purpose of this study was to investigate the brain functional network mechanism of ECT against schizophrenia. METHODS: Thirty-one patients with schizophrenia and fifty healthy controls matching age, gender, and years of education were included. All participants underwent general data collection and magnetic resonance imaging scanning before ECT, and clinical symptoms were assessed using the Positive And Negative Syndrome Scale (PANSS). MRI and clinical symptoms were collected again after the first and eighth ECT application. The functional brain network was constructed on the basis of magnetic resonance imaging, and the global and node topological properties were analyzed. Repeated measure variance analysis was used to explore the changes of the topological attribute values and clinical symptom scores before and after ECT, and Bonferroni post hoc analysis was performed. The independent sample t-test was used to compare the differences in the topological attribute values between patients and healthy controls at three time points before and after ECT. Partial correlation analysis was performed for topological attribute values and clinical symptom scores of abnormal brain regions in the patient groups and their changes during ECT. A general linear regression model was used to predict the outcome after the final eighth ECT using the patient's response to the first ECT. RESULTS: (1) One ECT can restore the gamma(γ), lamuda(λ), sigma(σ), nodal global efficiency (Ne) of right insular gyrus ventral agranular insula (INS_R_vIa) and nodal local efficiency (NLe) of bilateral fusiform gyrus medioventral area37 (FuG_A37mv). Eight ECT can also restore the NLe of cortex rostral lingual gyrus (MVOcC _R_rLinG). Eight ECT did not improve the Ne of right superior parietal lobule rostral area 7 (SPL_R_A7r) and NLe of left superior frontal gyrus medial area 6 (SFG_L_A6m). (2) Even after only the first use of ECT, total PANSS scores began to decrease (mean ΔPANSSECT1 was 11.7%; Range, 2%-32.8%), decreased significantly after the eighth application (mean ΔPANSSECT8 was 86.0%; Range,72.5% to 97.9%). Five patients met the response criteria after ECT1 (20% reduction in PANSS total score), and all patients met the response criteria after ECT8. (3) Linear regression analysis showed that ΔPANSSECT1 was a significant predictor of ΔPANSSECT8 (F=5.387, P=0.028), and ΔPANSSECT1 explained 15.7% of the variance of ΔPANSSECT8 (R2=0.157). CONCLUSIONS: ECT was able to normalize γ, λ, σ, Ne of INS_R_vIa, NLe of bilateral FuG_A37mv in SZ patients after the first treatment, and NLe of MVOcC_R_rLinG after the eighth ECT. ECT significantly alleviates psychotic symptoms in patients with SZ, and its efficacy after eight sessions can be predicted by the patient's response to the first session of ECT.

Activating MC4R Promotes Functional Recovery by Repressing Oxidative Stress-Mediated AIM2 Activation Post-spinal Cord Injury.

Spinal cord injury (SCI) is a destructive neurological trauma that induces permanent sensory and motor impairment as well as a deficit in autonomic physiological function. Melanocortin receptor 4 (MC4R) is a G protein-linked receptor that is extensively expressed in the neural system and contributes to inhibiting inflammation, regulating mitochondrial function, and inducing programmed cell death. However, the effect of MC4R in the modulation of oxidative stress and whether this mechanism is related to the role of absent in melanoma 2 (AIM2) in SCI are not confirmed yet. In the current study, we demonstrated that MC4R is significantly increased in the neurons of spinal cords after trauma and oxidative stimulation of cells. Further, activation of MC4R by RO27-3225 effectively improved functional recovery, inhibited AIM2 activation, maintained mitochondrial homeostasis, repressed oxidative stress, and prevented Drp1 translocation to the mitochondria. Meanwhile, treating Drp1 inhibitors would be beneficial in reducing AIM2 activation, and activating AIM2 could abolish the protective effect of MC4R on neuron homeostasis. In conclusion, we demonstrated that MC4R protects against neural injury through a novel process by inhibiting mitochondrial dysfunction, oxidative stress, as well as AIM2 activation, which may serve as an available candidate for SCI therapy.

FGF-18 Protects the Injured Spinal cord in mice by Suppressing Pyroptosis and Promoting Autophagy via the AKT-mTOR-TRPML1 axis.

Spinal cord injury (SCI) is a severe medical condition with lasting effects. The efficacy of numerous clinical treatments is hampered by the intricate pathophysiological mechanism of SCI. Fibroblast growth factor 18 (FGF-18) has been found to exert neuroprotective effects after brain ischaemia, but its effect after SCI has not been well explored. The aim of the present study was to explore the therapeutic effect of FGF-18 on SCI and the related mechanism. In the present study, a mouse model of SCI was used, and the results showed that FGF-18 may significantly affect functional recovery. The present findings demonstrated that FGF-18 directly promoted functional recovery by increasing autophagy and decreasing pyroptosis. In addition, FGF-18 increased autophagy, and the well-known autophagy inhibitor 3-methyladenine (3MA) reversed the therapeutic benefits of FGF-18 after SCI, suggesting that autophagy mediates the therapeutic effects of FGF-18 on SCI. A mechanistic study revealed that after stimulation of the protein kinase B (AKT)-transient receptor potential mucolipin 1 (TRPML1)-calcineurin signalling pathway, the FGF-18-induced increase in autophagy was mediated by the dephosphorylation and nuclear translocation of transcription factor E3 (TFE3). Together, these findings indicated that FGF-18 is a robust autophagy modulator capable of accelerating functional recovery after SCI, suggesting that it may be a promising treatment for SCI in the clinic.

DADLE promotes motor function recovery by inhibiting cytosolic phospholipase A2 mediated lysosomal membrane permeabilization after spinal cord injury.

BACKGROUND AND PURPOSE: Autophagy is a protective factor for controlling neuronal damage, while necroptosis promotes neuroinflammation after spinal cord injury (SCI). DADLE (D-Ala2 , D-Leu5 ]-enkephalin) is a selective agonist for delta (δ) opioid receptor and has been identified as a promising drug for neuroprotection. The aim of this study was to investigate the mechanism/s by which DADLE causes locomotor recovery following SCI. EXPERIMENTAL APPROACH: Spinal cord contusion model was used and DADLE was given by i.p. (16 mg·kg-1 ) in mice for following experiments. Motor function was assessed by footprint and Basso mouse scale (BMS) score analysis. Western blotting used to evaluate related protein expression. Immunofluorescence showed the protein expression in each cell and its distribution. Network pharmacology analysis was used to find the related signalling pathways. KEY RESULTS: DADLE promoted functional recovery after SCI. In SCI model of mice, DADLE significantly increased autophagic flux and inhibited necroptosis. Concurrently, DADLE restored autophagic flux by decreasing lysosomal membrane permeabilization (LMP). Additionally, chloroquine administration reversed the protective effect of DADLE to inhibit necroptosis. Further analysis showed that DADLE decreased phosphorylated cPLA2 , overexpression of cPLA2 partially reversed DADLE inhibitory effect on LMP and necroptosis, as well as the promotion autophagy. Finally, AMPK/SIRT1/p38 pathway regulating cPLA2 is involved in the action DADLE on SCI and naltrindole inhibited DADLE action on δ receptor and on AMPK signalling pathway. CONCLUSION AND IMPLICATION: DADLE causes its neuroprotective effects on SCI by promoting autophagic flux and inhibiting necroptosis by decreasing LMP via activating δ receptor/AMPK/SIRT1/p38/cPLA2 pathway.

Abnormal caudate nucleus activity in patients with depressive disorder: Meta-analysis of task-based functional magnetic resonance imaging studies with behavioral domain.

During task-based functional magnetic resonance imaging (t-fMRI) patients with depressive disorder (DD) have shown abnormal caudate nucleus activation. There have been no meta-analyses that are conducted on the caudate nucleus using Activation Likelihood Estimation (ALE) in patients with DD, and the relationships between abnormal caudate activity and different behavior domains in patients with DD remain unclear. There were 24 previously published t-fMRI studies included in the study with the caudate nucleus as the region of interest. Meta-analyses were performed using the method of ALE. Included five ALE meta-analyses: (1) the hypoactivated caudate nucleus relative to healthy controls (HCs); (2) the hyper-activated caudate nucleus; (3) the abnormal activation in the caudate nucleus in the emotion domain; (4) the abnormal activation in cognition domain; (5) the abnormal activation in the affective cognition domain. Results revealed that the hypo-/hyper-activity in the caudate subregions is mainly located in the caudate body and head, while the relationships between abnormal caudate subregions and different behavior domains are complex. The hypoactivation of the caudate body and head plays a key role in the emotions which indicates there is a positive relationship between the decreased caudate activity and depressed emotional behaviors in patients with DD.

Hybrid surgery can improve neurocognitive function in patients with internal carotid artery occlusion.

Internal carotid artery occlusion (ICAO) is a relatively uncommon but important cause of transient ischaemic attack and cerebral infarction. Hybrid surgery (HS) improves cerebral perfusion, but its impact on neurocognitive function has been controversial. Patients with symptomatic chronic ICAO treated by hybrid surgery or medical treatment from 2016 to 2019 were included. We recorded and analysed the clinical characteristics, angiographic data, outcomes and cognitive status. Functional assessments, including the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index, and a battery of neuropsychological tests, including the Mini-Mental State Examination (MMSE), Alzheimer Disease Assessment Scale-Cognitive Subtest (ADAS-cog), verbal fluency, and Colour Trail test Parts 1 and 2, were administered. Significant improvements in the ADAS (before, 7.5 ± 6.2 versus after, 5.2 ± 5.7; P = 0.022), MMSE (before, 25.5 ± 2.8 versus after, 28.1 ± 2.3; P = 0.013), and Colour Trail test Part 1 (before, 118.3 ± 26.5 versus after, 96.2 ± 23.1; P = 0.016) were observed six months after HS. Moreover, the abovementioned postprocedure scales were ameliorated in the HS group. This study found that in patients with multiple symptomatic ICAO and objective ipsilateral ischaemia, successful HS leads to improvement in the scores of three cognitive tests.

How to predict the outcome of primary brainstem hemorrhage: Six-year results of a single-center retrospective analysis.

Primary brainstem hemorrhage (PBH) is one of the most fatal intracranial hemorrhages, evaluating the prognosis in the early stage is vital for appropriate therapeutic planning. Our study aimed to identify risk factors for 30-day mortality and 90-day functional recovery of PBH. Data from 63 patients with PBH admitted to Beijing Chaoyang Hospital between 2016 and 2022 were retrieved for this study. We grouped the patients according to 30-day survival or 90-day functional recovery. Independent risk factors of 30-day mortality and 90-day functional recovery were identified by univariate and multivariate logistic regression analyses. 31 patients (49.2%) died within 30 days and 22 patients (34.9%) achieved better functional recovery. By multivariate analysis, Glasgow coma scale <9 on admission and tachycardia were significantly associated with 30-day mortality, while the hematoma volume >5 mL was an independent risk factor for 90-day functional recovery. Initial level of consciousness, tachycardia, massive hematoma were risk factors for prognosis, which must be seriously evaluated for therapeutic planning.

Clinical outcome and prognostic factors of patients with non-traumatic angiography-negative subarachnoid hemorrhage.

Purpose: The cause of spontaneous subarachnoid hemorrhage (SAH) is unknown in 10% of cases. The aim of this study was to demonstrate the characteristics of patients with angiography-negative subarachnoid hemorrhage (anSAH) and to analyze factors influencing the clinical outcome in patients suffering from anSAH. Methods: A retrospective cohort of 75 patients with anSAH [26 perimesencephalic (pmSAH) and 49 non-perimesencephalic SAH (npmSAH)] admitted between January 2016 and June 2022 was included. We analyzed demographic, clinical data and 6-month functional outcomes. Enter regression analysis was performed to identify factors associated with outcomes. Results: Unfavorable outcome was achieved in 10 of 75 patients (13.3%). Unfavorable outcome was associated with senior adults (p = 0.008), Hijdra cistern score (HCS) elevation (p = 0.015), long-time lumbar cistern continuous drainage (LCFD; p = 0.029) and hydrocephalus (p = 0.046). The only significant risk factor for unfavorable outcome after npmSAH was the HCS (OR 1.213 (95%CI 1.007-1.462), p = 0.042). Conclusion: Our study provides valuable information on both SAH patterns and functional outcome in patients suffering from anSAH and should be taken into consideration during management of these patients.

Cyclic helix B peptide alleviates proinflammatory cell death and improves functional recovery after traumatic spinal cord injury.

BACKGROUND: Necroptosis and pyroptosis, two types of proinflammatory programmed cell death, were recently found to play important roles in spinal cord injury (SCI). Moreover, cyclic helix B peptide (CHBP) was designed to maintain erythropoietin (EPO) activity and protect tissue against the adverse effects of EPO. However, the protective mechanism of CHBP following SCI is still unknown. This research explored the necroptosis- and pyroptosis-related mechanism underlying the neuroprotective effect of CHBP after SCI. METHODS: Gene Expression Omnibus (GEO) datasets and RNA sequencing were used to identify the molecular mechanisms of CHBP for SCI. A mouse model of contusion SCI was constructed, and HE staining, Nissl staining, Masson staining, footprint analysis and the Basso Mouse Scale (BMS) were applied for histological and behavioural analyses. qPCR, Western blot analysis, immunoprecipitation and immunofluorescence were utilized to analyse the levels of necroptosis, pyroptosis, autophagy and molecules associated with the AMPK signalling pathway. RESULTS: The results revealed that CHBP significantly improved functional restoration, elevated autophagy, suppressed pyroptosis, and mitigated necroptosis after SCI. 3-Methyladenine (3-MA), an autophagy inhibitor, attenuated these beneficial effects of CHBP. Furthermore, CHBP-triggered elevation of autophagy was mediated by the dephosphorylation and nuclear translocation of TFEB, and this effect was due to stimulation of the AMPK-FOXO3a-SPK2-CARM1 and AMPK-mTOR signalling pathways. CONCLUSION: CHBP acts as a powerful regulator of autophagy that improves functional recovery by alleviating proinflammatory cell death after SCI and thus might be a prospective therapeutic agent for clinical application.

A multimodal imaging-based classification for pediatric diffuse intrinsic pontine gliomas.

OBJECT: Pediatric diffuse intrinsic pontine glioma (DIPG) is a radiologically heterogeneous disease entity, here we aim to establish a multimodal imaging-based radiological classification and evaluate the outcome of different treatment strategies under this classification frame. METHODS: This retrospective study included 103 children diagnosed with DIPGs between January 2015 and August 2018 in Beijing Tiantan Hospital (Beijing, China). Multimodal radiological characteristics, including conventional magnetic resonance imaging (MRI), diffuse tensor imaging/diffuse tensor tractography (DTI/DTT), and positron emission tomography (PET) were reviewed to construct the classification. The outcome of different treatment strategies was compared in each DIPG subgroup using Kaplan-Meier method (log-rank test) to determine the optimal treatment for specific DIPGs. RESULTS: Four radiological DIPG types were identified: Type A ("homocentric", n=13), Type B ("ventral", n=41), Type C ("eccentric", n=37), and Type D ("dorsal", n=12). Their treatment modalities were grouped as observation (43.7%), cytoreductive surgery (CRS) plus radiotherapy (RT) (24.3%), RT alone (11.7%), and CRS alone (20.4%). CRS+RT mainly fell into type C (29.7%), followed by type B1 (21.9%) and type D (50%). Overall, CRS+RT exhibited a potential survival advantage compared to RT alone, which was more pronounced in specific type, but this did not reach statistical significance, due to limited sample size and unbalanced distribution. CONCLUSION: We proposed a multimodality imaging-based radiological classification for pediatric DIPG, which was useful for selecting optimal treatment strategies, especially for identifying candidates who may benefit from CRS plus RT. This classification opened a window into image-guided integrated treatment for pediatric DIPG.

3,4-Dimethoxychalcone, a caloric restriction mimetic, enhances TFEB-mediated autophagy and alleviates pyroptosis and necroptosis after spinal cord injury.

Background: Caloric restriction mimetics (CRMs) mimic the favourable effects of caloric restriction (CR) and have been shown to have therapeutic effects in neuroinflammatory disease. However, whether CRMs improve the functional recovery from spinal cord injury (SCI) and the underlying mechanism of action remain unclear. In this study, we used the CRMs 3,4-dimethoxychalcone (3,4-DC) to evaluate the therapeutic value of CRMs for SCI. Methods: HE, Masson and Nissl staining; footprint analysis; and the Basso mouse scale were used to determine the functional recovery from SCI after 3,4-DC treatment. RNA sequencing was used to identify the mechanisms of 3,4-DC in SCI. Western blotting, qPCR and immunofluorescence were used to detect the levels of pyroptosis, necroptosis, autophagy and the AMPK-TRPML1-calcineurin signalling pathway. We employed a dual-luciferase reporter assay in vitro and applied AAV vectors to inhibit TFEB in vivo to explore the mechanism of 3,4-DC. Results: 3,4-DC reduced glial scar area and motor neuron death and improved functional recovery after SCI. RNA-sequencing results indicated that oxidative stress, pyroptosis, necroptosis, and autophagy may be involved in the ability of 3,4-DC to improve functional recovery. Furthermore, 3,4-DC inhibited pyroptosis and necroptosis by enhancing autophagy. We also found that 3,4-DC enhances autophagy by promoting TFEB activity. A decrease in the TFEB level abolished the protective effect of 3,4-DC. In addition, 3,4-DC partially regulated TFEB activity through the AMPK-TRPML1-calcineurin signalling pathway. Conclusions: 3,4-DC promotes functional recovery by upregulating TFEB-mediated autophagy and inhibiting pyroptosis and necroptosis after SCI, which may have potential clinical application value.

Abnormal brain gray matter volume in patients with major depressive disorder: Associated with childhood trauma?

BACKGROUND: Patients with major depressive disorders (MDD) have abnormalities in the frontal-limbic structures of the brain. Childhood trauma is a risk factor for both structural brain alterations and MDD. However, the relationships among the three have not been confirmed. METHODS: Sixty-four patients with MDD and sixty-one healthy controls (HC) were checked by using MRI, the Hamilton Depression Scale (HAMD) and Childhood Trauma Questionnaire (CTQ). Voxel-based morphometry (VBM) was used to compare gray matter volume (GMV) differences between the two groups. Moreover, partial correlation and mediation analyses were conducted to test for potential associations between CTQ scores, different GMV, and clinical variables. RESULTS: Compared to the HC group, the MDD patients showed decreased GMV in the right middle frontal gyrus (rMFG) and right precentral gyrus (rPreCG). In the patient group, reduced GMV in rMFG was associated with CTQ scores (r = -0.30, P = 0.019) and HAMD scores (r = -0.53, P < 0.001). Finally, in the patient group, mediation analysis revealed that the indirect effect of rMFG GMV in CTQ scores and HAMD scores was 0.115 and the proportion of indirect effect to total effect was 23.86%. LIMITATIONS: This study used a cross-sectional collection, and it is unclear whether at the longitudinal level the brain GMV mediates the relationship between childhood trauma and depression. CONCLUSIONS: Abnormalities in the frontal GMV were presented in the MDD patients. It is possible that childhood traumatic experiences cause inefficient GMV and ultimately lead to an increased susceptibility to depression.

Primary Squamous Cell Carcinomas Arising in Intracranial Epidermoid Cysts: A Series of Nine Cases and Systematic Review.

OBJECTIVE: Primary squamous cell carcinomas (PSCCs) arising in intracranial epidermoid cysts (IECs) are very rare, and their management and prognostic factors remain unclear. This study aimed to enunciate the clinical features and suggest a treatment protocol based on cases from the literature and the cases from our institution. METHODS: The clinicoradiological data were obtained from nine patients with PSCCs arising in IECs, who underwent surgical treatment at Beijing Tiantan Hospital between July 2012 and June 2018. We also searched the PubMed database using the keywords "epidermoid cyst(s)" or "epidermoid tumor(s)" combined with "malignant" or "malignancy" or "intracranial" or "brain" or "squamous cell carcinoma" between 1960 and 2020. Risk factors for overall survival (OS) were evaluated in the pooled cohort. RESULTS: The mean age of our cohort was 51.2 ± 8.3 years (range: 39-61 years), which included eight males and one female. Gross total resection (GTR) was achieved in three patients, while non-GTR was achieved in six patients. Radiotherapy was administered to five patients. After a median follow-up of 16.7 ± 21.6 months (range: 3-72 months), eight patients died with a mean OS time of 9.75 ± 6.6 months (range: 3-23 months). In the literature between 1965 and 2020, 45 cases of PSCCs arising in IECs were identified in 23 males and 22 females with a mean age of 55.2 ± 12.4 years. GTR, non-GTR, and biopsy were achieved in six (13.3%), 36 (80%), and three (6.7%) cases, respectively. After a mean follow-up of 12.7 ± 13.4 months (range: 0.33-60 months), 54.1% (20/37) patients died, and recurrence occurred in 53.6% (15/28) patients. A multivariate analysis demonstrated that postoperative radiotherapy (p = 0.002) was the only factor that favored OS. The Kaplan-Meier analysis showed that, compared with no radiotherapy (median survival time: 4 months), radiotherapy (median survival time: 24 months) had significantly prolonged OS (p = 0.0011), and GTR could not improve OS (p = 0.5826), compared with non-GTR. The 1-year OS of patients with or without radiotherapy was 72.5% or 18.2%, respectively. CONCLUSION: Malignant transformation of IEC into PSCC was prevalent in elderly patients, with slight male predominance. GTR of previous benign IECs is recommended. For remnant benign IECs, close follow-up should be performed. Postoperative radiotherapy for PSCCs could bring survival benefit. GTR of these malignant intracranial tumors is difficult when they involve important brain structures. Future studies with larger cohorts are necessary to verify our findings.

Cooperative treatment effectiveness of ATR and HSP90 inhibition in Ewing's sarcoma cells.

INTRODUCTION: Ewing's sarcoma is an aggressive childhood malignancy whose outcome has not substantially improved over the last two decades. In this study, combination treatments of the HSP90 inhibitor AUY922 with either the ATR inhibitor VE821 or the ATM inhibitor KU55933 were investigated for their effectiveness in Ewing's sarcoma cells. METHODS: Effects were determined in p53 wild-type and p53 null Ewing's sarcoma cell lines by flow cytometric analyses of cell death, mitochondrial depolarization and cell-cycle distribution as well as fluorescence and transmission electron microscopy. They were molecularly characterized by gene and protein expression profiling, and by quantitative whole proteome analysis. RESULTS: AUY922 alone induced DNA damage, apoptosis and ER stress, while reducing the abundance of DNA repair proteins. The combination of AUY922 with VE821 led to strong apoptosis induction independent of the cellular p53 status, yet based on different molecular mechanisms. p53 wild-type cells activated pro-apoptotic gene transcription and underwent mitochondria-mediated apoptosis, while p53 null cells accumulated higher levels of DNA damage, ER stress and autophagy, eventually leading to apoptosis. Impaired PI3K/AKT/mTOR signaling further contributed to the antineoplastic combination effects of AUY922 and VE821. In contrast, the combination of AUY922 with KU55933 did not produce a cooperative effect. CONCLUSION: Our study reveals that HSP90 and ATR inhibitor combination treatment may be an effective therapeutic approach for Ewing's sarcoma irrespective of the p53 status.

PODNL1 promotes cell proliferation and migration in glioma via regulating Akt/mTOR pathway.

Background and Aims: Emerging studies have determined that the small leucine-rich proteoglycan (SLRP) family can aggravate tumor progression. However, the biological function of podocan-like protein 1 (PODNL1), a novel member of the SLRP family, has not been investigated. Therefore, our study focused on the function and regulatory mechanism of PODNL1 in glioma. Methods: Both the Gene Expression Profiling Interactive Analysis (GEPIA) and the Chinese Glioma Genome Atlas (CGGA) database were used to analyze the expression level and survival risk of PODNL1 in glioma. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were applied to detect the mRNA and protein expression, respectively. Celltiter-Glo and colony formation assays were used to evaluate cell proliferation. Migration capacity was measured by Transwell and wound healing assays. Flow cytometry was utilized to assess the apoptotic rate. Results: The expression of PODNL1 predicted the poor prognosis in glioma patients. Silencing of PODNL1 inhibited cell proliferation, migration, and induced epithelial-like phenotype. In addition, knockdown of PODNL1 also induced cell apoptosis. Moreover, the cell growth and migration inhibited by PODNL1 knockdown could be partially rescued with Akt activator. Conversely, PODNL1 overexpression promoted cell growth and migration, which were suppressed by Akt inhibitor. Conclusions: PODNL1, a promising predictive indicator of poor prognosis, resulted in greater proliferation, migration and epithelial-mesenchymal transition (EMT) process. Moreover, PODNL1 promoted aggressive glioma behavior by activating Akt/mTOR pathway, providing a novel therapeutic target for glioma.

Long Non-Coding RNA LINC00662 Regulated Proliferation and Migration by Targeting miR-34a-5p/LMAN2L Axis in Glioma.

BACKGROUND: Numerous studies suggest that long non-coding RNAs (lncRNAs) participate in the biological process of diverse malignancies, including glioma. Although many differentially expressed lncRNAs have been identified in glioma, to our best knowledge, the role of LINC00662 and its potential underlying mechanism in glioma progression remains unclear. This study aimed to explore the function and regulatory network of LINC00662 in glioma. METHODS: Expressions of LINC00662, miR-34a-5p and lectin mannose-binding 2-like (LMAN2L) in glioma tissues were analyzed using The Cancer Genome Atlas Program (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases. Colony formation, Celltiter-Glo and BrdU (5-bromo-2'-deoxyuridine) incorporation assays were used to detect cell proliferation in vitro. Xenograft mouse models were established to determine cell proliferation in vivo. Transwell and wound healing assay was used to detect cell migration. In addition, epithelial-mesenchymal transition (EMT) markers were detected by Western blot. Annexin V and 7-AAD were used to stain apoptotic cells. Interactions between miR-34a-5p and LINC00662 or the 3'-UTR of LMAN2L were predicted and determined by bioinformatics analysis, luciferase reporter assay and RNA immunoprecipitation (RIP) assays. RESULTS: High LINC00662 level predicted poor overall survival of glioma patients. Functional studies revealed that suppression of LINC00662 remarkably inhibited cell proliferation, clonogenicity and EMT pathway. Mechanistically, LINC00662 sponged miR-34a-5p to regulate LMAN2L expression. Furthermore, miR-34a-5p inhibitor reversed the anti-proliferation and anti-migration effect of LINC00662 knockdown, which could be rescued by downregulation of LMAN2L in glioma cells. CONCLUSION: Our study was the first to report that LINC00662 acted as a competing endogenous RNA (ceRNA) to regulate glioma progression by targeting miR-34a-5p/LMAN2L axis, providing a new therapeutic target for glioma.

Quiescin Sulfhydryl Oxidase 1 Regulates the Proliferation, Migration and Invasion of Human Glioblastoma Cells via PI3K/Akt Pathway.

BACKGROUND: Quiescin sulfhydryl oxidase 1 (QSOX1) involves in the formation of disulfide bonds and participates in the protein folding process. In recent years, accumulating evidences have shown that QSOX1 is a biomarker for tumor development and prognosis. However, the biological function of QSOX1 in glioblastoma (GBM) remains unclear. MATERIALS AND METHODS: QSOX1 expression in glioma and overall survival of glioma patients were analyzed through The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases. shRNAs were used to decrease the expression of QSOX1 in U87 and U251 cells. Celltiter-Glo and colony formation assays were used to assess cell proliferation. Transwell and scratch assays were utilized to determine cell migration and invasion, the xenograft mouse models were established to evaluate the effect of QSOX1 knockdown in vivo. Western blot assays were used to detect the changes of E-cadherin/N-cadherin/vimentin and PI3K/Akt pathway. RESULTS: We found that QSOX1 was upregulated in glioma, especially in GBM. Upregulation of QSOX1 was correlated with poor prognosis in glioma patients. We discovered for the first time that suppression of QSOX1 expression inhibited proliferation, migration and invasion, as well as epithelial-mesenchymal transition (EMT) in GBM cell lines. In addition, phosphorylated PI3K and Akt were downregulated in the QSOX1-knockdown groups. Moreover, QSOX1 knockdown-impaired cell growth was partially rescued by Akt activator. CONCLUSION: Our findings revealed that QSOX1 was a novel biomarker for GBM patients and QSOX1 promoted cell proliferation, migration and invasion through regulating PI3K/Akt pathway in GBM.