3D hydrogel microfibers promote the differentiation of encapsulated neural stem cells and facilitate neuron protection and axon regrowth after complete transactional spinal cord injury.

Spinal cord injury (SCI) could cause permanent impairment to motor or sensory functions. Pre-cultured neural stem cell (NSC) hydrogel scaffolds were demonstrated to be a promising approach to treat SCI with anti-inflammatory effect, axon regrowth and motor function restore. Here in this study, we performed coaxial extrusion process to fabricate a core-shell hydrogel microfiber with high NSC density in the core portion. Oxidized hyaluronic acid (OHA), carboxymethyl chitosan (CMC) and Matrigel blend was used as matrix for NSC growth and to facilitate the fabrication process. During in vitro differentiation culture, it is found that NSC microfiber could differentiate into neuron and astrocyte with higher efficiency compared with NSC cultured in petri dishes. Furthermore, during in vivo transplantation, NSC microfibers were coated with poly lactic acid (PLA) nanosheet by electrospinning for reinforcement. The coated NSC nanofibers showed higher anti-inflammatory effect and lesion cavity filling rate compared with control group. Meanwhile, more neuron- and oligodendrocyte-like cells were visualized in lesion epicenter. Finally, axon regrowth across the whole lesion site was observed, demonstrating the microfiber could guide renascent axon regrowth. Experiment results indicate that the NSC microfiber is a promising bioactive treatment for complete SCI treatment with better outcomes. .

Linc-NSC affects cell differentiation, apoptosis and proliferation in mouse neural stem cells and embryonic stem cells in vitro and in vivo.

BACKGROUND: Stem cell therapy is a promising therapeutic strategy. In a previous study, we evaluated tumorigenicity by the stereotactic transplantation of neural stem cells (NSCs) and embryonic stem cells (ESCs) from experimental mice. Twenty-eight days later, there was no evidence of tumor formation or long-term engraftment in the NSCs transplantation group. In contrast, the transplantation of ESCs caused tumor formation; this was due to their high proliferative capacity. Based on transcriptome sequencing, we found that a long intergenic non-coding RNA (named linc-NSC) with unknown structure and function was expressed at 1100-fold higher levels in NSCs than in ESCs. This finding suggested that linc-NSC is negatively correlated with stem cell pluripotency and tumor development, but positively correlated with neurogenesis. In the present study, we investigated the specific role of linc-NSC in NSCs/ESCs in tumor formation and neurogenesis. METHODS: Whole transcriptome profiling by RNA sequencing and bioinformatics was used to predict lncRNAs that are widely associated with enhanced tumorigenicity. The expression of linc-NSC was assessed by quantitative real-time PCR. We also performed a number of in vitro methods, including cell proliferation assays, differentiation assays, immunofluorescence assays, flow cytometry, along with in vivo survival and immunofluorescence assays to investigate the impacts of linc-NSC on tumor formation and neurogenesis in NSCs and ESCs. RESULTS: Following the knockdown of linc-NSC in NSCs, NSCs cultured in vitro and those transplanted into the cortex of mice showed stronger survival ability (P < 0.0001), enhanced proliferation(P < 0.001), and reduced apoptosis (P < 0.05); the opposite results were observed when linc-NSC was overexpressed in ESCs. Furthermore, the overexpression of linc-NSC in ECSs induced enhanced apoptosis (P < 0.001) and differentiation (P < 0.01), inhibited tumorigenesis (P < 0.05) in vivo, and led to a reduction in tumor weight (P < 0.0001). CONCLUSIONS: Our analyses demonstrated that linc-NSC, a promising gene-edited target, may promote the differentiation of mouse NSCs and inhibit tumorigenesis in mouse ESCs. The knockdown of linc-NSC inhibited the apoptosis in NSCs both in vitro and in vivo, and prevented tumor formation, revealing a new dimension into the effect of lncRNA on low survival NSCs and providing a prospective gene manipulation target prior to transplantation. In parallel, the overexpression of linc-NSC induced apoptosis in ESCs both in vitro and in vivo and attenuated the tumorigenicity of ESCs in vivo, but did not completely prevent tumor formation.

Classification of and individual treatment strategies for complex tethered cord syndrome.

Objective: To study the classification, diagnosis, and treatment strategies of complex tethered cord syndrome (C-TCS) on the basis of the patients' clinical symptoms, imaging findings, and therapeutic schedule. Methods: The clinical data of 126 patients with C-TCS admitted to our department from January 2015 to December 2020 were retrospectively analyzed. Classification criteria for C-TCS were established by analyzing the causes of C-TCS. Different surgical strategies were adopted for different types of C-TCS. The Kirollos grading, visual analogue scale (VAS), critical muscle strength, and Japanese Orthopaedic Association (JOA) scores were used to evaluate the surgical outcomes and explore individualized diagnosis and treatment strategies for C-TCS. Results: C-TCS was usually attributable to three or more types of tether-causing factors. The disease mechanisms could be categorized as pathological thickening and lipomatosis of the filum terminal (filum terminal type), arachnoid adhesion (arachnoid type), spina bifida with lipomyelomeningocele/meningocele (cele type), spinal lipoma (lipoma type), spinal deformity (bone type), and diastomyelia malformation (diastomyelia type). Patients with different subtypes showed complex and varied symptoms and required individualized treatment strategies. Conclusion: Since C-TCS is attributable to different tether-related factors, C-TCS classification can guide individualized surgical treatment strategies to ensure complete release of the tethered cord and reduce surgical complications.

The clinical outcome of emergency superficial temporal artery-to-middle cerebral artery bypass in acute ischemic stroke with large vessel occlusion.

The role of superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass in acute ischemic stroke (AIS) is contentious, with no evidence in patients with AIS and large vessel occlusion (AIS-LVO). We conducted a cohort study to assess emergency STA-MCA outcomes in AIS-LVO and a meta-analysis to evaluate STA-MCA outcomes in early AIS treatment. From January 2018 to March 2021, we consecutively recruited newly diagnosed AIS-LVO patients, dividing them into STA-MCA and non-STA-MCA groups. To evaluate the neurological status and outcomes, we employed the National Institutes of Health Stroke Scale (NIHSS) during the acute phase and the modified Rankin Scale (mRS) during the follow-up period. Additionally, we conducted a meta-analysis encompassing all available clinical studies to assess the impact of STA-MCA on patients with AIS. In the cohort study (56 patients), we observed more significant neurological improvement in the STA-MCA group at two weeks (p = 0.030). However, there was no difference in the clinical outcomes between the two groups. Multivariable logistic regression identified the NIHSS at two weeks (OR: 0.840; 95% CI: 0.754-0.936, p = 0.002) as the most critical predictor of a good outcome. Our meta-analysis of seven studies indicated a 67% rate for achieving a good outcome (mRS < 3) at follow-up points (95% CI: 57%-77%, I2 = 44.1%). In summary, while the meta-analysis suggested the potential role of STA-MCA bypass in mild to moderate AIS, our single-center cohort study indicated that STA-MCA bypass does not seem to improve the prognosis of patients who suffer from AIS-LVO.

An inflammatory gene-related prognostic risk score model for prognosis and immune infiltration in glioblastoma.

This study aimed to screen for key genes related to the prognosis of patients with glioblastoma (GBM). First, bioinformatics analysis was performed based on databases such as TCGA and MSigDB. Inflammatory-related genes were obtained from the MSigDB database. The TCGA-tumor samples were divided into cluster A and B groups based on consensus clustering. Multivariate Cox regression was applied to construct the risk score model of inflammatory-related genes based on the TCGA database. Second, to understand the effects of model characteristic genes on GBM cells, U-87 MG cells were used for knockdown experiments, which are important means for studying gene function. PLAUR is an unfavorable prognostic biomarker for patients with glioma. Therefore, the model characteristic gene PLAUR was selected for knockdown experiments. The prognosis of cluster A was significantly better than that of cluster B. The verification results also demonstrate that the risk score could predict overall survival. Although the immune cells in cluster B and high-risk groups increased, no matching survival advantage was observed. It may be that stromal activation inhibits the antitumor effect of immune cells. PLAUR knockdown inhibits tumor cell proliferation, migration, and invasion, and promoted tumor cell apoptosis. In conclusion, a prognostic prediction model for GBM composed of inflammatory-related genes was successfully constructed. Increased immune cell expression may be linked to a poor prognosis for GBM, as stromal activation decreased the antitumor activity of immune cells in cluster B and high-risk groups. PLAUR may play an important role in tumor cell proliferation, migration, invasion, and apoptosis.

Effect of Optic Canal Opening on Postoperative Visual Acuity in Patients with Tuberculum Sellae Meningiomas.

BACKGROUND: Tuberculum sellae meningiomas (TSMs) account for 5 to 10% of all intracranial meningiomas. They typically invade the optic canal and displace the optic nerve upward and laterally. The transcranial approach has been the standard surgical approach, while the transsphenoidal approach has been proposed for its minimally invasive nature; however, some reservations concerning this approach remain. METHODS: From January 2000 to December 2018, a total of 97 patients who were diagnosed with TSM with invasion of the optic canal were enrolled and underwent microsurgery for tumor removal with optic canal opening. A retrospective analysis was performed on the effect of optic canal opening on postoperative visual acuity improvement. The median follow-up was 17.4 months (range: 3-86 months). RESULTS: Among the 97 patients with TSM involving the optic canal, optic canal invasion was seen on preoperative imaging in 73 patients and during intraoperative exploration in all patients. In total, 87/97 patients (89.7%) underwent optic canal opening to remove tumors involving the optic canal, and the rate of total macroscopic resection of tumors invading the optic canal was 100%. Among the 10 patients who did not undergo optic canal opening, the rate of total resection of tumors involving the optic canal was 80% (8/10, p < 0.001). There were no deaths or serious complications. The postoperative visual acuity improvement rate was 64.4%, 23.7% maintained the preoperative level, and the visual acuity deteriorated 11.9%. CONCLUSION: Intraoperative optic canal opening is the key to total resection of TSMs involving the optic canal and improving postoperative visual acuity.

3D color multimodality fusion imaging as an augmented reality educational and surgical planning tool for extracerebral tumors.

Extracerebral tumors often occur on the surface of the brain or at the skull base. It is important to identify the peritumoral sulci, gyri, and nerve fibers. Preoperative visualization of three-dimensional (3D) multimodal fusion imaging (MFI) is crucial for surgery. However, the traditional 3D-MFI brain models are homochromatic and do not allow easy identification of anatomical functional areas. In this study, 33 patients with extracerebral tumors without peritumoral edema were retrospectively recruited. They underwent 3D T1-weighted MRI, diffusion tensor imaging (DTI), and CT angiography (CTA) sequence scans. 3DSlicer, Freesurfer, and BrainSuite were used to explore 3D-color-MFI and preoperative planning. To determine the effectiveness of 3D-color-MFI as an augmented reality (AR) teaching tool for neurosurgeons and as a patient education and communication tool, questionnaires were administered to 15 neurosurgery residents and all patients, respectively. For neurosurgical residents, 3D-color-MFI provided a better understanding of surgical anatomy and more efficient techniques for removing extracerebral tumors than traditional 3D-MFI (P < 0.001). For patients, the use of 3D-color MFI can significantly improve their understanding of the surgical approach and risks (P < 0.005). 3D-color-MFI is a promising AR tool for extracerebral tumors and is more useful for learning surgical anatomy, developing surgical strategies, and improving communication with patients.

A controllable gelatin-based microcarriers fabrication system for the whole procedures of MSCs amplification and tissue engineering.

Biopolymer microbeads present substantial benefits for cell expansion, tissue engineering, and drug release applications. However, a fabrication system capable of producing homogeneous microspheres with high precision and controllability for cell proliferation, passaging, harvesting and downstream application is limited. Therefore, we developed a co-flow microfluidics-based system for the generation of uniform and size-controllable gelatin-based microcarriers (GMs) for mesenchymal stromal cells (MSCs) expansion and tissue engineering. Our evaluation of GMs revealed superior homogeneity and efficiency of cellular attachment, expansion and harvest, and MSCs expanded on GMs exhibited high viability while retaining differentiation multipotency. Optimization of passaging and harvesting protocols was achieved through the addition of blank GMs and treatment with collagenase, respectively. Furthermore, we demonstrated that MSC-loaded GMs were printable and could serve as building blocks for tissue regeneration scaffolds. These results suggested that our platform held promise for the fabrication of uniform GMs with downstream application of MSC culture, expansion and tissue engineering.

Reactive A1 Astrocyte-Targeted Nucleic Acid Nanoantiepileptic Drug Downregulating Adenosine Kinase to Rescue Endogenous Antiepileptic Pathway.

Resistance to traditional antiepileptic drugs is a major challenge in chronic epilepsy treatment. MicroRNA-based gene therapy is a promising alternative but has demonstrated limited efficacy due to poor blood-brain barrier permeability, cellular uptake, and targeting efficiency. Adenosine is an endogenous antiseizure agent deficient in the epileptic brain due to elevated adenosine kinase (ADK) activity in reactive A1 astrocytes. We designed a nucleic acid nanoantiepileptic drug (tFNA-ADKASO@AS1) based on a tetrahedral framework nucleic acid (tFNA), carrying an antisense oligonucleotide targeting ADK (ADKASO) and A1 astrocyte-targeted peptide (AS1). This tFNA-ADKASO@AS1 construct effectively reduced brain ADK, increased brain adenosine, mitigated aberrant mossy fiber sprouting, and reduced the recurrent spontaneous epileptic spike frequency in a mouse model of chronic temporal lobe epilepsy. Further, the treatment did not induce any neurotoxicity or major organ damage. This work provides proof-of-concept for a novel antiepileptic drug delivery strategy and for endogenous adenosine as a promising target for gene-based modulation.

Inhibition of ACSL4 Alleviates Parkinsonism Phenotypes by Reduction of Lipid Reactive Oxygen Species.

Ferroptosis is a programmed cell death pathway that is recently linked to Parkinson's disease (PD), where the key genes and molecules involved are still yet to be defined. Acyl-CoA synthetase long-chain family member 4 (ACSL4) esterifies polyunsaturated fatty acids (PUFAs) which is essential to trigger ferroptosis, and is suggested as a key gene in the pathogenesis of several neurological diseases including ischemic stroke and multiple sclerosis. Here, we report that ACSL4 expression in the substantia nigra (SN) was increased in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated model of PD and in dopaminergic neurons in PD patients. Knockdown of ACSL4 in the SN protected against dopaminergic neuronal death and motor deficits in the MPTP mice, while inhibition of ACSL4 activity with Triacsin C similarly ameliorated the parkinsonism phenotypes. Similar effects of ACSL4 reduction were observed in cells treated with 1-methyl-4-phenylpyridinium (MPP+) and it specifically prevented the lipid ROS elevation without affecting the mitochondrial ROS changes. These data support ACSL4 as a therapeutic target associated with lipid peroxidation in PD.

The signature of immune-subtype specific driving transcription factors suggest potential drugs for refractory glioblastoma.

Immunocharacteristics-based typing strategies can be used to reflect the similar status of tumors. Therefore, we aimed to demonstrate whether the immune subtypes of GBM have independent prognostic efficacy and whether these subtypes can be used as clinical guidance for predicting the progression of GBM and determining drug sensitivity. In this study, we found that patients with GBM were divided into three conserved immune-related subtypes based on the infiltration level of immune cells, including immunosuppressed, moderate immunoactivity, and high immunoactivity. Regarding the relevant clinical significance, the high immunoactivity in GBM indicates the worst survival, which exhibited the highest levels of oncogenic activity, including angiogenesis, tumor-associated macrophages and tumor-associated fibroblasts, indicated worst survival. The immunosuppressive subtype of GBM was more likely to carry epidermal growth factor receptor mutations and MGMT methylation, and belong to the classical and proneural subtypes; however, but the high immunoactivity subtype was not. The immune subtype-specific transcription factors (TFs) regulatory network indicates that specific TFs drive the construction of each immune subtype, and that these subtype-specific TFs are more prone to internal TFs regulation. Furthermore, the immunosuppressed and moderate immunoactivity subtypes were significantly correlated with the drugs sensitivity, whereas the high immunoactivity subtype was not, indicating that GBMs with high immunoactivity were refractory. We also found that obatoclax mesylate, NPK76-II-72-1, gemcitabine, TAK-715 are potential drugs for the treatment of refractory GBM based on drug sensitivity models of different immune subtypes. Therefore, we demonstrated that the immune subtypes of GBM have independent prognostic efficacy and can be used as clinical guidance for predicting the progression of GBM and drug sensitivity. Most importantly, this study is expected to provide a pathway for the development of effective drugs for treatment of refractory GBM.

Uncover DNA damage and repair-related gene signature and risk score model for glioma.

BACKGROUND: Glioma is a common primary central nervous system tumor with complex pathogenesis. DNA damage and repair (DDR) is widely involved in regulating cell proliferation and tumorigenesis by correcting and repairing DNA damage mechanisms. Recent studies have reported the following properties in cancer cells in glioma, increased DNA damage and reduced DNA repair capacity. However, the relationship between glioma and DDR-related genes was unclear. METHODS: DDR-related risk score model was built. The validity of this model was validated in detail through the Kaplan-Meier survival analysis, tumor mutational burden (TMB) analysis, immune cell infiltration, sensitivity to treatment regimens. Moreover, the model's adaptability was validated in different glioma data cohorts and different glioma subgroups. To further investigate the molecular mechanism of one of DDR-related gene (NUDT1) in glioma, U251 cell was used for the knockdown experiment, followed by MTT, wound healing and transwell analysis. RESULTS: Ten prognostic-related DDR-related signature genes were obtained, including EID3, MGMT, YWHAG, PMS1, SHPRH, HUS1, NUDT1, GADD45G, APEX1 and FAM175A. The RT-qPCR results suggested that the latter five genes were highly expressed in glioma patients. Interestingly, high TMB score had longer survival. In high-risk score groups, reduced immune cell infiltration in the tumor microenvironment lead to poorer patient outcomes. Sensitivity to treatment regimens analysis indicated that low-risk score groups were more sensitive to chemotherapeutics. Moreover, the risk score model had a good prediction effect on different glioma datasets and different glioma subgroups. In vitro mechanism study showed that knockdown of NUDT1 reduced tumorigenesis. Furthermore, knockdown of NUDT1 remarkably reduced the expression level of HIF-1α. CONCLUSION: DDR-related risk score model built-in this work has good predictive performance for glioma.Key messagesTen prognostic-related DDR-related signature genes were obtained, including EID3, MGMT, YWHAG, PMS1, SHPRH, HUS1, NUDT1, GADD45G, APEX1 and FAM175A.In high-risk score groups, reduced immune cell infiltration in the tumor microenvironment leads to poorer patient outcomes.The risk score model had a good prediction effect on different glioma datasets and different glioma subgroups.Knockdown of NUDT1 reduced tumorigenesis of glioma and remarkably reduced the expression level of HIF-1α.

The factors influencing postoperative efficacy of anterior clinoidal meningioma treatment and an analysis of best-suited surgical strategies.

Objective: To explore the influence of the type of anterior clinoidal meningioma on surgical strategy planning, surgical approach selection, and postoperative efficacy. Patients and methods: We conducted a retrospective analysis of the clinical data of 63 cases, including data on visual function, extent of tumor resection, and postoperative follow-up. Grade I and II approaches were selected according to the type of tumor. A univariate analysis of the factors influencing the extent of tumor resection, postoperative visual function, and postoperative relapse and complications was conducted. Results: Simpson Grade I-II total resection was seen in 48 cases (76.2%), with an overall relapse/progression rate of 12.7%. The tumor type and texture and the relationship between the tumors and adjacent structures were the main factors influencing total tumor resection (P < 0.01). The overall postoperative visual acuity improvement, stabilization rate, and deterioration rate were 76.2, 15.9, and 7.9%, respectively. Postoperative visual acuity level was significantly correlated with preoperative visual acuity level and tumor type (P < 0.01). Conclusions: Determining the type of tumor at a preoperative level and whether the optic canal and cavernous sinus are invaded can aid in the planning of detailed individualized surgical strategies.

Neural circuit changes in neurological disorders: Evidence from in vivo two-photon imaging.

Neural circuits, such as synaptic plasticity and neural activity, are critical components of healthy brain function. The consequent dynamic remodeling of neural circuits is an ongoing procedure affecting neuronal activities. Disruption of this essential process results in diseases. Advanced microscopic applications such as two-photon laser scanning microscopy have recently been applied to understand neural circuit changes during disease since it can visualize fine structural and functional cellular activation in living animals. In this review, we have summarized the latest work assessing the dynamic rewiring of postsynaptic dendritic spines and modulation of calcium transients in neurons of the intact living brain, focusing on their potential roles in neurological disorders (e.g. Alzheimer's disease, stroke, and epilepsy). Understanding the fine changes that occurred in the brain during disease is crucial for future clinical intervention developments.

[Clinical Features and Surgical Outcomes of 15 Cases of Intracranial Alveolar Echinococcosis]. / 15ä¾‹é¢ å† æ³¡åž‹æ£˜çƒèš´ç— çš„ä¸´åºŠç‰¹ç‚¹åŠæ‰‹æœ¯ç–—æ•ˆåˆ†æž.

Objective: To investigate the surgical treatment strategy of intracranial alveolar echinococcosis (AE) and the clinical outcomes. Methods: The clinical and follow-up data of 15 intracranial AE patients who underwent surgical treatment in the Departments of Neurosurgery of Sichuan Provincial People's Hospital (SPPH) and People's Hospital of Aba Tibetan and Qiang Autonomous Prefecture (a branch hospital of SPPH) between March 2017 and January 2021 were retrospectively analyzed. Full follow-up data were available for each of the 15 cases. The clinical and imaging characteristics, general surgical information, and surgical outcomes were analyzed. Results: In the 15 patients, there were a total of 50 intracranial lesions, with an average of (3.3±3.1)/case. Four cases had solitary intracranial lesions, while 11 cases had multiple lesions, with the number of intracranial lesions per case ranging from 2 to 13. All patients with solitary intracranial lesions received total resection. In 6 patients with multiple intracranial lesions, only the largest lesion was surgically removed, and in 5 patients, 2 to 3 adjacent lesions were surgically removed. All but one patient had extracranial lesions in their liver, lungs, kidneys, adrenal glands, and thoracic vertebrae. The patients were followed up for 12 to 58 months after surgery, with the mean follow-up time being (28.1±13.4) months. Among the 15 cases, 13 showed stable intracranial condition during postoperative follow-up. Intracranial lesions recurred in 2 patients who had deep lesions accompanied by dissemination to the subarachnoid space. Two patients died during follow-up. Conclusion: Microsurgical treatment of intracranial AE is effective, but total surgical resection is difficult to accomplish when patients have echinococcosis lesions located at a depth, especially when the lesions are spreading to the subarachnoid space. The prognosis of patients is closely associated with the extent of lesion invasion and the control of systemic hydatid lesions, especially those in the liver.

Machine-learning-based risk stratification for probability of dying in patients with basal ganglia hemorrhage.

To confirm whether machine learning algorithms (MLA) can achieve an effective risk stratification of dying within 7 days after basal ganglia hemorrhage (BGH). We collected patients with BGH admitted to Sichuan Provincial People's Hospital between August 2005 and August 2021. We developed standard ML-supervised models and fusion models to assess the prognostic risk of patients with BGH and compared them with the classical logistic regression model. We also use the SHAP algorithm to provide clinical interpretability. 1383 patients with BGH were included and divided into the conservative treatment group (CTG) and surgical treatment group (STG). In CTG, the Stack model has the highest sensitivity (78.5%). In STG, Weight-Stack model achieves 58.6% sensitivity and 85.1% specificity, and XGBoost achieves 61.4% sensitivity and 82.4% specificity. The SHAP algorithm shows that the predicted preferred characteristics of the CTG are consciousness, hemorrhage volume, prehospital time, break into ventricles, brain herniation, intraoperative blood loss, and hsCRP were also added to the STG. XGBoost, Stack, and Weight-Stack models combined with easily available clinical data enable risk stratification of BGH patients with high performance. These ML classifiers could assist clinicians and families to identify risk states timely when emergency admission and offer medical care and nursing information.

BACE1 Aptamer-Modified Tetrahedral Framework Nucleic Acid to Treat Alzheimer's Disease in an APP-PS1 Animal Model.

Alzheimer's disease is a neurodegenerative disease caused by excessive amyloid ß protein-induced neurotoxicity. However, drugs targeting amyloid ß protein production face many problems, such as the low utilization rate of drugs by cells and the difficulty of drugs in penetrating the blood-brain barrier. A tetrahedral framework nucleic acid is a new type of nanonucleic acid structure that functions as a therapy and drug carrier. Here, we synthesized a BACE1 aptamer-modified tetrahedral framework nucleic acid and tested its therapeutic effect on Alzheimer's disease in vitro and in vivo. Our results demonstrated that the tetrahedral framework nucleic acid could be used as a carrier to deliver the BACE1 aptamer to the brain to reduce the production of amyloid ß proteins. It also played an antiapoptotic role by reducing the production of reactive oxygen species. Thus, this nanomaterial is a potential drug for Alzheimer's disease.

Negative effects of brain regulatory T cells depletion on epilepsy.

The infiltration of immune cells is observed in the epileptogenic zone; however, the relationship between epilepsy and regulatory T cells (Tregs) remains only partially understood. We aimed to investigate brain-infiltrating Tregs to reveal their underlying role in epilepsy. We analyzed the infiltration of Tregs in the epileptogenic zones from patients with epilepsy and a pilocarpine-induced temporal lobe epilepsy (TLE) model. Next, we evaluated the effects of brain Treg depletion on neuroinflammation, neuronal loss, oxidative stress, seizure activity and behavioral changes in the pilocarpine model. We also explored the impact of Treg expansion in the brain on seizure activity. There were a large number of Tregs in the epileptogenic zones of human and experimental epilepsy. The number of brain Tregs was negatively correlated with the frequency of seizures in patients with epilepsy. Our further findings demonstrated that brain Treg depletion promoted astrocytosis, microgliosis, inflammatory cytokine production, oxidative stress, and neuronal loss in the hippocampus after status epilepticus (SE). Moreover, brain Treg depletion increased seizure activity and contributed to behavioral impairments in experimental chronic TLE. Interestingly, intracerebroventricular injection of CCL20 amplified Tregs in brain tissue, thereby inhibiting seizure activity. Taken together, our study highlights the therapeutic potential of regulating Tregs in epileptic brain tissue.

Paeoniflorin Inhibits EMT and Angiogenesis in Human Glioblastoma via K63-Linked C-Met Polyubiquitination-Dependent Autophagic Degradation.

Epithelial-to-mesenchymal transition (EMT) and angiogenesis have emerged as two pivotal events in cancer progression. Paeoniflorin has been widely studied in experimental models and clinical trials for cancer treatment because of its anti-cancer property. However, the underlying mechanisms of paeoniflorin in EMT and angiogenesis in glioblastoma was not fully elucidated. The present study aimed to investigate whether paeoniflorin inhibits EMT and angiogenesis, which involving c-Met suppression, while exploring the potential ways of c-Met degradation. In our study, we found that paeoniflorin inhibited EMT via downregulating c-Met signaling in glioblastoma cells. Furthermore, overexpressing c-Met in glioblastoma cells abolished the effects of paeoniflorin on EMT. Moreover, paeoniflorin showed anti-angiogenic effects by suppressing cell proliferation, migration, invasion and tube formation through downregulating c-Met in human umbilical vein endothelial cells (HUVECs). And c-Met overexpression in HUVECs offset the effects of paeoniflorin on angiogenesis. Additionally, paeoniflorin induced autophagy activation involving mTOR/P70S6K/S6 signaling and promoted c-Met autophagic degradation, a process dependent on K63-linked c-Met polyubiquitination. Finally, paeoniflorin suppressed mesenchymal makers (snail, vimentin, N-cadherin) and inhibited angiogenesis via the identical mechanism in an orthotopic xenograft mouse model. The in vitro and in vivo experiments showed that paeoniflorin treatment inhibited EMT, angiogenesis and activated autophagy. What's more, for the first time, we identified c-Met may be a potential target of paeoniflorin and demonstrated paeoniflorin downregulated c-Met via K63-linked c-Met polyubiquitination-dependent autophagic degradation. Collectively, these findings indicated that paeoniflorin inhibits EMT and angiogenesis via K63-linked c-Met polyubiquitination-dependent autophagic degradation in human glioblastoma.

Prediction of Cancer-Specific Survival of Brainstem Glioma in Children Based on Risk Stratification Model.

Objective: To develop and authenticate a risk stratification framework and nomogram for ascertaining cancer-specific survival (CSS) among the pediatric brainstem gliomas. Methods: For patients less than 12 years, according to Surveillance, Epidemiology, and End Results (SEER), information from 1998 to 2016 is found in their databases. The survival outcomes, treatments, and demographic clinicopathologic conditions are scrutinized per the database validation, and training cohorts are divided and validated using multivariate Cox regression analysis. A nomogram was designed, and predominantly, the risk stratification conceptualization engaged selected tenets according to the multivariate analysis. The model's authenticity was substantiated through C-index measure and calibration curves. Results: There are 806 pediatric concerns of histologically concluded brainstem glioma in the research. According to multivariate analysis, age, grade, radiotherapy, and race (with P value < 0.05) depicted independent prognostic variations of the pediatric gliomas. The nomogram's C-index was approximately 0.75 and an accompanied predictive capability for CSS. Conclusion: The nomogram constructed in this glioma's context is the primary predictor of using risk stratification. A combination of nomograms with the risk stratification mechanism assists clinicians in monitoring high-risk individuals and engage targeted accessory treatment.