Lycorine hydrochloride interferes with energy metabolism to inhibit chemoresistant glioblastoma multiforme cell growth through suppressing PDK3.

Glioblastoma multiforme (GBM) is the highest grade of glioma. Tumours, including GBM, possess reprogrammed metabolism, such as altered aerobic glycolysis and aberrant energy production. Lycorine hydrochloride (LH) was extracted from the bulb of Lycoris radiata. The previous study indicated that LH exerts antiviral, anti-inflammatory and antitumour effects. However, the effect of LH on GBM and the underlying molecular mechanism remain unclear. Our study revealed that LH restrained chemoresistant GBM cells growth by inhibiting PDK3 expression in vitro and in vivo. Functionally, LH inhibited the proliferation and invasive capacity of chemoresistant GBM cells in dose-dependent manner. Metabolomics and cellular energy analyses showed that LH decreased extracellular acidification rates while increased oxidative respiration and ROS levels. Mechanistically, LH inhibits the growth of GBM chemoresistant cells by regulating the expression of apoptosis-related proteins, while overexpression of of PDK3 can reverse the antitumor effect of LH. In conclusion, our study revealed that LH could reprogramme cell energy metabolism, including aerobic glycolysis suppression and oxidative phosphorylation hyperactivation by inhibiting PDK3. PDK3 may be a candidate therapeutic target for chemoresistant GBM treatment with LH.

Amino acid formula induces microbiota dysbiosis and depressive-like behavior in mice.

Amino acid formula (AAF) is increasingly consumed in infants with cow's milk protein allergy; however, the long-term influences on health are less described. In this study, we established a mouse model by subjecting neonatal mice to an amino acid diet (AAD) to mimic the feeding regimen of infants on AAF. Surprisingly, AAD-fed mice exhibited dysbiotic microbiota and increased neuronal activity in both the intestine and brain, as well as gastrointestinal peristalsis disorders and depressive-like behavior. Furthermore, fecal microbiota transplantation from AAD-fed mice or AAF-fed infants to recipient mice led to elevated neuronal activations and exacerbated depressive-like behaviors compared to that from normal chow-fed mice or cow's-milk-formula-fed infants, respectively. Our findings highlight the necessity to avoid the excessive use of AAF, which may influence the neuronal development and mental health of children.

Exosomal circZNF800 Derived from Glioma Stem-like Cells Regulates Glioblastoma Tumorigenicity via the PIEZO1/Akt Axis.

Exosomes play a crucial role in regulating crosstalk between tumor and tumor stem-like cells through their cargo molecules. Circular RNAs (circRNAs) have recently been demonstrated to be critical factors in tumorigenesis. This study focuses on the molecular mechanism by which circRNAs from glioma stem-like cell (GSLC) exosomes regulate glioblastoma (GBM) tumorigenicity. In this study, we validated that GSLC exosomes accelerated the malignant phenotype of GBM. Subsequently, we found that circZNF800 was highly expressed in GSLC exosomes and was negatively associated with GBM patients. CircZNF800 promoted GBM cell proliferation and migration and inhibited GBM cell apoptosis in vitro. Silencing circZNF800 could improve the GBM xenograft model survival rate. Mechanistic studies revealed that circZNF800 activated the PIEZO1/Akt signaling pathway by sponging miR-139-5p. CircZNF800 derived from GSLC exosomes promoted GBM cell tumorigenicity and predicted poor prognosis in GBM patients. CircZNF800 has the potential to serve as a promising target for further therapeutic exploration.

Short-term outcomes of robot-assisted minimally invasive surgery for brainstem hemorrhage: A case-control study.

Objective: This work focused on investigating if robot-assisted minimally invasive surgery improved middle term vital outcome for primary brainstem hemorrhage (PBSH). Methods: This work obtained clinical data from patients with PBSH admitted from July 2019 to August 2021. All cases were classified as surgical or conservative treatment group. The general information, Glasgow coma scale (GCS) score, Glasgow outcome score (GOS), along with survival time in patients 60 days after robot-assisted surgery were recorded and analyzed. Results: A prospective analysis was performed on 82 cases meeting eligibility criteria, including 36 from surgical group whereas 46 from the conservative group. Sixty days after onset, the death rate was found to be 19.44% and 50.00% of surgical and conservative groups, separately (cases versus controls, P < 0.05). Furthermore, postoperative GOS and GCS scores of surgical group were significantly higher, and hydrocephalus was lower compared with conservative group. Central fever incidence did not exhibit any significant difference between two groups. Conclusion: Robot-assisted PBSH drainage may improve survivorship and reduce the occurrence of hydrocephalus.

Stabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells.

The peptidyl-prolyl cis-trans isomerase Pin1 is a pivotal therapeutic target in cancers, but the regulation of Pin1 protein stability is largely unknown. High Pin1 expression is associated with SUMO1-modified protein hypersumoylation in glioma stem cells (GSCs), but the underlying mechanisms remain elusive. Here we demonstrate that Pin1 is deubiquitinated and stabilized by USP34, which promotes isomerization of the sole SUMO E2 enzyme Ubc9, leading to SUMO1-modified hypersumoylation to support GSC maintenance. Pin1 interacts with USP34, a deubiquitinase with preferential expression and oncogenic function in GSCs. Such interaction is facilitated by Plk1-mediated phosphorylation of Pin1. Disruption of USP34 or inhibition of Plk1 promotes poly-ubiquitination and degradation of Pin1. Furthermore, Pin1 isomerizes Ubc9 to upregulate Ubc9 thioester formation with SUMO1, which requires CDK1-mediated phosphorylation of Ubc9. Combined inhibition of Pin1 and CDK1 with sulfopin and RO3306 most effectively suppresses orthotopic tumor growth. Our findings provide multiple molecular targets to induce Pin1 degradation and suppress hypersumoylation for cancer treatment.

Vascularization ability of glioma stem cells in different three-dimensional microenvironments.

Glioblastoma (GBM) is among the most common and aggressive adult central nervous system tumors. One prominent characteristic of GBM is the presence of abnormal microvessels. A significant correlation between angiogenesis and prognosis has been observed. Accurately reconstructing this neovascularization and tumor microenvironment through personalized in vitro disease models presents a significant challenge. However, it is crucial to develop new anti-angiogenic therapies for GBM. In this study, 3D bioprinted glioma stem cell (GSC)-laden hydrogel scaffolds, hybrid GSC hydrogels and cell-free hydrogel scaffolds were manufactured to investigate the vascularization ability of GSCs in varying 3D microenvironments. Our results demonstrated that the bioactivity of GSCs in the 3D bioprinted GSC-laden hydrogel scaffold was preferable and stable, and the amounts of vascular endothelial growth factor A and basic fibroblast growth factor were the highest in the microenvironment. When the three different models were co-cultured with human umbilical vein endothelial cells, the expression of angiogenesis-related markers was the most abundant in the bioprinted GSC-laden hydrogel scaffold. Additionally, xenograft tumors formed by bioprinted GSC-laden hydrogel scaffolds more closely resembled human gliomas regarding color, texture and vascularization. Notably, in xenograft tumors derived from 3D bioprinted GSC-laden hydrogel scaffolds, the number of human CD105+ cells was significantly higher, and human endothelial vascular lumen-like structures were observed. This indicates that the 3D bioprinted GSC-laden hydrogel scaffold is a suitable model for mimicking the glioma microenvironment and studying tumor angiogenesis.

A case report of bilateral lateral ventricle calcified pseudoneoplasm of the neuraxins.

BACKGROUND: Calcifying pseudoneoplasm of the neuraxis (CAPNON) is indeed a rare central nervous system lesion that can occur in central nervous system (CNS). Due to its infrequency and limited literature reports, it is challenging to diagnose and manage CAPNON. CASE PRESENTATION: In this intriguing study, we embarked on a quest to uncover the story of a 16-year-old girl who experienced bothersome headaches. Through advanced imaging techniques like computed tomography (CT) and magnetic resonance imaging (MRI), we glimpsed a delicate calcified growth within the lateral ventricles' posterior horn. Motivated by our unwavering commitment to solving mysteries, we embarked on a surgical journey that not only freed the young patient from her ailment but also shed light on the true nature of her puzzling adversary-a remarkable CAPNON. CONCLUSIONS: For patients with CAPNON who have multiple or non-respectable lesions, the primary goal is to alleviate symptoms. After alleviating the symptoms with partial resection, close monitoring of any residual lesions is essential. If there is no evidence for disease progression, a strategy of continued close observation is appropriate.

GTF2E2 downregulated by miR-340-5p inhibits the malignant progression of glioblastoma.

Glioblastoma is the most common malignant tumor in the central nervous system. The general transcription factor IIE subunit beta (GTF2E2) is crucial for physiological and pathological functions, but its roles in the malignant biological function of glioma remain ambiguous. CCK-8, colony formation assays, TUNEL assays, cell migration assays, wound-healing assays, and xenograft model were established to investigate the biological functions of GTF2E2 both in vitro and in vivo. GTF2E2 was overexpressed in glioma and was associated with poor prognosis of glioma patients. Biological functions of GTF2E2 were investigated both in vitro and in vi0vo by multiple experiments. Moreover, we explored the possible mechanisms of GTF2E2. In our results, we demonstrated that GTF2E2 could be regulated by miR-340-5p directly or indirectly. CCND1 was transcriptionally affected by GTF2E2 and glioma progression was then regulated. Our data presented the overexpression of GTF2E2 in glioma and indicated the association between GTF2E2 and glioma prognosis. GTF2E2 was found to be regulated by miR-340-5p and thus affect downstream gene expressions and glioma progression. Our results indicate that GTF2E2 might be a potential target in the diagnosis and treatments of glioblastoma.

Functional Connectivity and Anxiety Improvement After Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease.

Background: Anxiety is one of the most common and disturbing non-motor symptoms of Parkinson's disease (PD). However, few studies have explored the relationship between functional connectivity (FC) and the rate of anxiety improvement after subthalamic nucleus deep brain stimulation (STN-DBS). Therefore, in this study, we aimed to explore the correlation between FC and the rate of anxiety improvement in patients with PD who underwent STN-DBS. Methods: The resting-state functional magnetic resonance imaging (rs-fMRI) data of 62 patients with anxious PD (aPD), 68 patients with PD without anxiety (naPD), and 64 healthy controls (HCs) were analyzed according to FC. Intergroup comparison and correlation analyses of anxiety improvement rates were performed. Results: The HC, aPD and naPD groups of zFCs were then used for the ANOVA test, and the results were FDR-corrected. There were 24 significant differences in FCs between the three groups. Post tests were conducted between groups found that 15 significantly different FCs were observed between the naPD and aPD groups. In addition, the two FCs in patients with aPD were significantly correlated with the rate of improvement in anxiety. Conclusion: We found that the two FCs in patients with aPD (olfactory cortex and inferior frontal gyrus [IFG] pars orbitalis; inferior temporal gyrus and posterior orbital gyrus) were significantly correlated with the rate of improvement in anxiety. Our study may help us understand the underlying mechanisms by which STN-DBS improves anxiety in PD patients and identify more effective treatment strategies.

Comparison of endoscopic evacuation, craniotomy, and puncture aspiration for the treatment of spontaneous basal ganglia intracerebral hematoma.

OBJECTIVE: To compare the prognosis of patients with spontaneous basal ganglia intracerebral hematoma treated by endoscopic evacuation, craniotomy, or puncture aspiration. METHODS: This retrospective observational study included information from patients with basal ganglia hematoma who received craniotomy, endoscopic evacuation, or puncture aspiration in the Department of Neurosurgery of the First Affiliated Hospital of USTC between January 2016 and May 2021. Patients were grouped according to their treatment method for comparison. RESULTS: From a total of 184 patients, 62 cases (51 males, aged 54.44 ± 9.92 years) received craniotomy, 64 cases (45 males, aged 53.97 ± 11.87 years) received endoscopic evacuation, and 58 cases (43 males, aged 54.25 ± 10.35 years) received puncture aspiration. No significant difference was found in baseline characteristics among three surgical procedures. Patients in the endoscopy group had the shortest hospital stay (15.16 ± 4.89 days vs. 17.88 ± 5.97 and 20.77 ± 6.96 days), lowest infectious meningitis [1(1.6 %) vs. 2(3.4%) and 8(12.9%)] and pulmonary infection [3(4.7%) vs. 5(8.6%) and 13(21.0%)] rates, and highest hematoma removal rate (90.39 ± 5.22% vs. 35.87 ± 6.23 and 84.76 ± 4.91%) and Glasgow outcome scale 6 months after surgery (4.41 ± 0.53 vs. 3.74 ± 1.09 and 3.81 ± 1.03). The occurrence of gastrointestinal bleeding, epilepsy, and mortality were similar (all p > 0.05) among the groups. CONCLUSION: Patients with spontaneous basal ganglia intracerebral hematoma who received endoscopic evacuation might have better prognosis than those treated with craniotomy or puncture aspiration. In future, endoscopic surgery could become the most common method for treating spontaneous basal ganglia hemorrhages.

CircSOBP suppresses the progression of glioma by disrupting glycolysis and promoting the MDA5-mediated immune response.

Glioma, an aggressively growing and highly malignant brain tumor, poses substantial therapeutic challenges due to its resistance to radiotherapy and chemotherapy. Recent research has identified circRNAs as pivotal players in glioma formation and development. However, the roles of circRNA in the metabolic and immune regulation of glioma are unclear. In this study, circSOBP expression was significantly downregulated in glioma cells and specimens. Functionally, enhanced circSOBP expression mitigated cell proliferation, invasion, migration, and glycolysis in gliomas. Mechanistically, circSOBP inhibited glycolysis and activated the MDA5-mediated IKKε/TBK1/IRF3 signaling pathway by binding TKFC proteins. Furthermore, the elevated levels of IFN-I induced by the MDA5 pathway increased the number and activity of CD8+ T and NK cells in the immune response of the animal models. In summary, our findings have emphasized the critical role of circSOBP in binding and modulating TKFC protein, offering potential therapeutic avenue for targeting glioma metabolism and immunological reprogramming.

MGCG regulates glioblastoma tumorigenicity via hnRNPK/ATG2A and promotes autophagy.

Glioblastoma (GBM) is the most common malignant primary brain cancer in adults and has constantly been a focus of research. Long noncoding RNAs (lncRNAs) play important roles in the development of cancers. To illustrate the role of lncRNAs in the development of glioblastoma, high-throughput RNA sequencing was performed to obtain the transcripts using three freshly isolated tumor tissue samples from GBM patients and three normal brain tissue samples from the traumatic brain of patients. Then, a lncRNA, MGCG (MGC70870 is expressed at a high level in glioblastoma), which has not been reported previously in GBM, was found to be associated with the prognosis of patients. The results of bioinformatic analysis showed that MGCG was correlated with autophagy and positively correlated with the expression of the autophagy-related gene ATG2A. The data of mass spectrometry demonstrated that the hnRNPK protein was a direct target interacting with MGCG, and MGCG/hnRNPK promoted the development of GBM by enhancing the translation of ATG2A and autophagy. In conclusion, the present study showed that MGCG has the potential to promote the development of GBM and may become a candidate for molecular diagnostics and treatment of tumors.

Shunt-Dependent Post-Traumatic Hydrocephalus: Predictors and Long-Term Functional Outcomes.

INTRODUCTION: As a disorder of the brain in adults and children, traumatic brain injury (TBI) is considered the major cause of mortality and morbidity. As a serious complication of TBI, post-traumatic hydrocephalus (PTH) is commonly identified and significantly associated with neurocognitive impairment, motor dysfunction, and growth impairment. The long-term functional outcomes after shunt dependence are totally not clear. METHODS: This study included 6279 patients between 2012 and 2022. To identify the unfavorable functional outcomes and the PTH-related factors, we carried out univariable logistic regression analyses. To identify the occurrence time of PTH, we conducted the log-rank test and Kaplan-Meier analysis. RESULTS: Mean patient age was 51.03 ± 22.09 years. Of the 6279 patients with TBI, 327 developed PTH (5.2%). Several PTH development-associated factors, such as intracerebral hematoma, diabetes, longer initial hospital stay, craniotomy, low GCS (Glasgow Coma Scale), EVD (external ventricular drain), and DC (decompressive craniectomy) (p < 0.01), were identified. We also analyzed the factors of unfavorable outcomes after TBI including > 80 years, repeated operations, hypertension, EVD, tracheotomy, and epilepsy (p < 0.01). Ventriculoperitoneal shunt (VPS) itself is not an independent factor of the unfavorable outcome but shunt complication is a strong independent factor of unfavorable outcome (p < 0.05). CONCLUSION: We should emphasize the practices that can minimize the risks of shunt complications. Additionally, the rigorous radiographic and clinical surveillance will benefit those patients at high risk of developing PTH. TRIAL REGISTRATION: ClinicalTrials.gov identifier, ChiCTR2300070016.

Relationship between serum uric acid levels and the outcome of STN-DBS in Parkinson's disease.

BACKGROUND: Uric acid is a natural antioxidant and it has been shown that low levels of uric acid may be a risk factor for the development of Parkinson's disease. We aimed to investigate the relationship between uric acid and improvement of motor symptoms in patients with Parkinson's disease after subthalamic nucleus deep brain stimulation. METHODS: We analyzed the correlation between serum uric acid levels in 64 patients with Parkinson's disease and the rate of improvement of motor symptoms 2 years after subthalamic nucleus deep brain stimulation. RESULTS: A non-linear correlation was observed between uric acid levels and the rate of motor symptom improvement after subthalamic nucleus deep brain stimulation, during both the drug-off and drug-on periods. CONCLUSIONS: Uric acid is positively associated with the rate of motor symptom improvement in subthalamic nucleus deep brain stimulation within a certain range.

Single-cell landscape of primary central nervous system diffuse large B-cell lymphoma.

Understanding tumor heterogeneity and immune infiltrates within the tumor-immune microenvironment (TIME) is essential for the innovation of immunotherapies. Here, combining single-cell transcriptomics and chromatin accessibility sequencing, we profile the intratumor heterogeneity of malignant cells and immune properties of the TIME in primary central nervous system diffuse large B-cell lymphoma (PCNS DLBCL) patients. We demonstrate diverse malignant programs related to tumor-promoting pathways, cell cycle and B-cell immune response. By integrating data from independent systemic DLBCL and follicular lymphoma cohorts, we reveal a prosurvival program with aberrantly elevated RNA splicing activity that is uniquely associated with PCNS DLBCL. Moreover, a plasmablast-like program that recurs across PCNS/activated B-cell DLBCL predicts a worse prognosis. In addition, clonally expanded CD8 T cells in PCNS DLBCL undergo a transition from a pre-exhaustion-like state to exhaustion, and exhibit higher exhaustion signature scores than systemic DLBCL. Thus, our study sheds light on potential reasons for the poor prognosis of PCNS DLBCL patients, which will facilitate the development of targeted therapy.

Development and Validation of a Prediction Model for Anxiety Improvement after Deep Brain Stimulation for Parkinson Disease.

BACKGROUND: Parkinson's disease (PD) represents one of the most frequently seen neurodegenerative disorders, while anxiety accounts for its non-motor symptom (NMS), and it has greatly affected the life quality of PD cases. Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) can effectively treat PD. This study aimed to develop a clinical prediction model for the anxiety improvement rate achieved in PD patients receiving STN-DBS. METHODS: The present work retrospectively enrolled 103 PD cases undergoing STN-DBS. Patients were followed up for 1 year after surgery to analyze the improvement in HAMA scores. Univariate and multivariate logistic regression were conducted to select factors affecting the Hamilton Anxiety Scale (HAMA) improvement. A nomogram was established to predict the likelihood of achieving anxiety improvement. Receiver operating characteristic (ROC) curve analysis, decision curve analysis (DCA), and calibration curve analysis were conducted to verify nomogram performance. RESULTS: The mean improvement in HAMA score was 23.9% in 103 patients; among them, 68.9% had improved anxiety, 25.2% had worsened (Preop) anxiety, and 5.8% had no significant change in anxiety. Education years, UPDRS-III preoperative score, and HAMA preoperative score were independent risk factors for anxiety improvement. The nomogram-predicted values were consistent with real probabilities. CONCLUSIONS: Collectively, a nomogram is built in the present work for predicting anxiety improvement probability in PD patients 1 year after STN-DBS. The model is valuable for determining expected anxiety improvement in PD patients undergoing STN-DBS.

Prediction of STN-DBS for Parkinson's disease by uric acid-related brain function connectivity: A machine learning study based on resting state function MRI.

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder characterized by dyskinesia and is closely related to oxidative stress. Uric acid (UA) is a natural antioxidant found in the body. Previous studies have shown that UA has played an important role in the development and development of PD and is an important biomarker. Subthalamic nucleus deep brain stimulation (STN-DBS) is a common treatment for PD. Methods: Based on resting state function MRI (rs-fMRI), the relationship between UA-related brain function connectivity (FC) and STN-DBS outcomes in PD patients was studied. We use UA and DC values from different brain regions to build the FC characteristics and then use the SVR model to predict the outcome of the operation. Results: The results show that PD patients with UA-related FCs are closely related to STN-DBS efficacy and can be used to predict prognosis. A machine learning model based on UA-related FC was successfully developed for PD patients. Discussion: The two biomarkers, UA and rs-fMRI, were combined to predict the prognosis of STN-DBS in treating PD. Neurosurgeons are provided with effective tools to screen the best candidate and predict the prognosis of the patient.

Neuropsychological Alterations of Prolactinomas' Cognitive Flexibility in Task Switching.

Prolactinomas have been reported to impair cognition in broad aspects. However, few studies investigated the influence of prolactinomas on cognitive flexibility never mentioning the underlying neural and electrophysiological mechanism. We recorded scalp electroencephalography (EEG) in a colour-shape switching task. Patients with prolactinomas showed longer reaction time in switch trials and larger switch costs relative to healthy controls (HCs). Compared to HCs who showed stronger frontal theta activity in switch trials, the generally weak frontal theta activity in patients implied that they could not afford the executive control to configure task sets. Meanwhile, machine-learning based classification revealed that patients manifested non-selective brain patterns in response to different task types (colour vs. shape task) and different task states (switch vs. repeat state), which collectively suggested the cognitive dysfunction in preparation for a changing environment. Compared to HCs who showed stronger frontoparietal synchronization in switch trials, this enhanced frontoparietal connectivity was disrupted among patients with severe prolactinomas. This finding implicated greater hyperprolactinemia was linked to a larger decrease in cognitive performance. Taken together, the present study highlighted frontal theta power, and frontoparietal connectivity at theta band as the electrophysiological markers of the impaired cognitive flexibility and task control in patients with prolactinomas.

First ground-based, high-field, cryogen-free, mobile intraoperative magnetic resonance imaging system.

BACKGROUND/OBJECTIVE: Accurately targeting specific regions of interest in the brain is pivotal for the success of neurosurgical procedures. For example, the outcome of brain tumor resection is improved dramatically when surgeons are better able to define surgical borders. Intraoperative magnetic resonance imaging (iMRI) helps reduce the risk of damaging critical areas of the brain and makes it possible to confirm a successful resection or determine the need for further resection prior to closing a patient's head and finalizing the surgery. Here we present a ground-based, iMRI system with a mobile 1-T cryogen-free imager. METHODS: An ex-vivo experimental test of the novel iMRI system is performed to demonstrate preoperative and intraoperative imaging. RESULTS: The ground-based, mobile iMRI system presented here was successfully used to obtain intraoperative MR images without moving the imaging target or compromising conventional surgical techniques. CONCLUSION: The success of this experiment constitutes a major milestone towards the installation of a ground-based, high-field, mobile iMRI system in a hospital setting.