Ivermectin as a potential therapeutic strategy for glioma.

Ivermectin (IVM), a semi-synthetic macrolide parasiticide, has demonstrated considerable effectiveness in combating internal and external parasites, particularly nematodes and arthropods. Its remarkable ability to control parasites has earned it significant recognition, culminating in Satoshi Omura and William C. Campbell's receipt of the 2015 Nobel Prize in Physiology or Medicine for their contributions to the development of IVM. In recent years, investigations have revealed that IVM possesses antitumor properties. It can suppress the growth of various cancer cells, including glioma, through a multitude of mechanisms such as selective targeting of tumor-specific proteins, inducing programmed cell death, and modulation of tumor-related signaling pathways. Hence, IVM holds tremendous potential as a novel anticancer drug. This review seeks to provide an overview of the underlying mechanisms that enable IVM's capacity to suppress glioma. Furthermore, it aims to elucidate the challenges and prospects associated with utilizing IVM as a new anticancer agent.

AKR1C1 connects autophagy and oxidative stress by interacting with SQSTM1 in a catalytic-independent manner.

Targeting autophagy might be a promising anticancer strategy; however, the dual roles of autophagy in cancer development and malignancy remain unclear. NSCLC (non-small cell lung cancer) cells harbour high levels of SQSTM1 (sequestosome 1), the autophagy receptor that is critical for the dual roles of autophagy. Therefore, mechanistic insights into SQSTM1 modulation may point towards better approaches to treat NSCLC. Herein, we used multiple autophagy flux models and autophagy readouts to show that aldo-keto reductase family 1 member C1 (AKR1C1), which is highly expressed in NSCLC, promotes autophagy by directly binding to SQSTM1 in a catalytic-independent manner. This interaction may be strengthened by reactive oxygen species (ROS), important autophagy inducers. Further mechanistic research demonstrated that AKR1C1 interacts with SQSTM1 to augment SQSTM1 oligomerization, contributing to the SQSTM1 affinity for binding cargo. Collectively, our data reveal a catalytic-independent role of AKR1C1 for interacting with SQSTM1 and promoting autophagy. All these findings not only reveal a novel functional role of AKR1C1 in the autophagy process but also indicate that modulation of the AKR1C1-SQSTM1 interaction may be a new strategy for targeting autophagy.

Association Between MTHFR Gene Common Variants, Serum Homocysteine, and Risk of Early-Onset Coronary Artery Disease: A Case-Control Study.

The common variants of the methylenetetrahydrofolate reductase (MTHFR) gene are related to the activity of the MTHFR enzyme and the concentrations of blood homocysteine (Hcy). This study was designed to investigate the associations of MTHFR in Chinese populations with early-onset coronary artery disease (EOCAD). The two common variants of the MTHFR gene were genotyped in 875 EOCAD patients and 956 controls using PCR, followed by direct sequencing of the PCR product. Serum levels of Hcy were measured using an automatic biochemistry analyzer. A significant association between the MTHFR-677C/T variant and the risk of EOCAD was detected in CC versus TT (odds ratio (OR) 1.456, 95% confidence interval (CI) 1.120-1.892), dominant genetic model (OR 1.266, 95% CI 1.027-1.546), and recessive genetic model (OR 1.306, 95% CI 1.040-1.639). Hcy was most abundant in TT genotype (18.31 ± 7.22 µmol/L), least abundant in CC genotype (11.37 ± 5.23 µmol/L), and detectable at intermediate levels in heterozygotes (15.25 ± 6.58 µmol/L). Elevated serum Hcy levels were an independent risk factor for EOCAD (ORadjust 1.431, 95% CI 1.135-1.763). Our findings indicated that the T allele of -677C/T MTHFR variant predisposes to high levels of Hcy, and that the T allele is an important risk factor for EOCAD in the Chinese population.

Deficiency of Ttyh1 downstream to Notch signaling results in precocious differentiation of neural stem cells.

Mammalian neural stem cells (NSCs) are not only responsible for normal development of the central nervous system (CNS), but also participate in brain homeostasis and repair, thus hold promising clinical potentials in the treatment of neurodegenerative diseases and trauma. However the molecular networks regulating the stemness and differentiation of NSCs have not been fully understood. In this study, we show that Tweety-homolog 1 (Ttyh1), a five-pass transmembrane protein specifically expressed in mouse brain, is involved in maintaining stemness of murine NSCs. Blocking or activating Notch signal led to downregulation and upregulation of Ttyh1 in cultured NSCs, respectively, suggesting that Ttyh1 is under the control of Notch signaling. Knockdown of Ttyh1 in cultured NSCs resulted in a transient increase in the number and size of neurospheres, followed by a decrease of stemness as manifested by compromised neurosphere formation, downregulated stem cell markers, and increased neuronal differentiation. We generated Ttyh1 knockout mice by deleting its exon 4 using the CRISPR-Cas9 technology. Surprisingly, in contrast to a previous report, Ttyh1 knockout did not result in embryonic lethality. NSCs derived from Ttyh1 knockout mice phenocopied NSCs transfected with Ttyh1 siRNA. Immunofluorescence showed that loss of Ttyh1 leads to the increase of neurogenesis in adult mice. Taken together, these findings indicate that Ttyh1, which is likely downstream to Notch signaling, plays an important role in regulating NSCs.

Multimodal treatments combined with gamma knife surgery for primary atypical teratoid/rhabdoid tumor of the central nervous system: a single-institute experience of 18 patients.

OBJECTIVES: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly malignant tumor of the central nervous system with poor prognosis. Nowadays, multimodal management, including surgery, chemotherapy (CMT), and radiation therapy (RT), is advocated. However, AT/RT treatment with gamma knife surgery (GKS) was rarely reported. The aim of this study was to assess the efficacy and safety of GKS for the treatment of AT/RT. PATIENTS AND METHODS: Medical records of AT/RT patients who underwent surgery from 2007 to 2014 at the West China Hospital were retrospectively reviewed and statistically analyzed. RESULTS: Eighteen patients (12 males and 6 females) were presented with AT/RTs. Median age during presentation was 20.5 months (range, 4-179 months). Twelve patients were < 3 years and six patients were > 3 years. Tumor location was supratentorial in seven patients, infratentorial in ten patients, and center area of the brain in one patient. Treatments performed were as follows: surgery alone in two patients, surgery+RT in two patients, surgery+CMT in five patients, surgery+CMT+RT in two patients, and surgery+CMT+RT+GKS in seven patients. The 2-year overall survival (OS) rate and event-free survival (EFS) rate for all 18 consecutive patients were 33.3 and 27.8%, respectively. Cox regression analyses showed that multimodal management combined with GKS was an independent positive prognostic factor for OS. CONCLUSIONS: Although AT/RTs are lethal cancer types, the OS of the disease was improved by using multimodal therapeutic strategies, including surgery, CMT, and RT, combined with GKS.

Upper thoracic intradural-extramedullary cavernous malformation presenting as subarachnoid hemorrhage without spinal dysfunction: a case report and review of the literature.

A 45-year-old man had subarachnoid hemorrhage (SAH) which was confirmed by lumbar puncture, since it was negative on head computed tomography. The result of neurological examination was normal. Following pan-cerebral angiography and cranial magnetic resonance imaging (MRI) failed to find out the cause of bleeding. The whole spinal MRI revealed an intradural-extramedullary mass lesion at the upper thoracic level which was consistent with cavernous malformation after surgery. When patients presented with SAH of no spinal symptoms, the diagnosis of an intradural-extramedullary cavernous malformation is challenging. A whole spinal workup should be considered in a patient with spontaneous SAH when bleeding from intracranial origin is carefully excluded.

[Microsurgical management of adult brainstem gliomas under the DTI and intraoperative nuclei mapping: a retrospective analysis of 19 cases].

OBJECTIVE: To explore the role of DTI-Tractography and intraoperative nuclei mapping in microsurgery of adult brainstem gliomas. METHODS: Nineteen patients with adult brainstem gliomas were recruited for this study in our hospital from 2010 to 2012. The role of DTI-Tractography and intraoperative nuclei mapping in the microsurgery was retrospectively reviewed. RESULTS: Two patients underwent almost total resection, while 11 patents underwent subtotal resection and 6 patients underwent partial resection. Neurological functions improved or remained stable in 14 patients (73.7%) after surgery; whereas, 5 patients (26.3%) experienced deteriorated or transitory new symptoms. Follow-up visits found that 17 patients (89.5%)had improved or stable neurological functions. CONCLUSION: DTI-Tractography and intraoperative nuclei mapping provides great support to the choice of surgical approach and the determination of degree of resection. It helps achieve maximal safe resection of adult brainstem gliomas.

Subject Separation Network for Reducing Calibration Time of MI-Based BCI.

Motor imagery brain-computer interface (MI-based BCIs) have demonstrated great potential in various applications. However, to well generalize classifiers to new subjects, a time-consuming calibration process is necessary due to high inter-subject variabilities of EEG signals. This process is costly and tedious, hindering the further expansion of MI-based BCIs outside of the laboratory. To reduce the calibration time of MI-based BCIs, we propose a novel domain adaptation framework that adapts multiple source subjects' labeled data to the unseen trials of target subjects. Firstly, we train one Subject Separation Network(SSN) for each of the source subjects in the dataset. Based on adversarial domain adaptation, a shared encoder is constructed to learn similar representations for both domains. Secondly, to model the factors that cause subject variabilities and eliminate the correlated noise existing in common feature space, private feature spaces orthogonal to the shared counterpart are learned for each subject. We use a shared decoder to validate that the model is actually learning from task-relevant neurophysiological information. At last, an ensemble classifier is built by the integration of the SSNs using the information extracted from each subject's task-relevant characteristics. To quantify the efficacy of the framework, we analyze the accuracy-calibration cost trade-off in MI-based BCIs, and theoretically guarantee a generalization bound on the target error. Visualizations of the transformed features illustrate the effectiveness of domain adaptation. The experimental results on the BCI Competition IV-IIa dataset prove the effectiveness of the proposed framework compared with multiple classification methods. We infer from our results that users could learn to control MI-based BCIs without a heavy calibration process. Our study further shows how to design and train Neural Networks to decode task-related information from different subjects and highlights the potential of deep learning methods for inter-subject EEG decoding.

Exosome-mediated inhibition of microRNA-449a promotes the amplification of mouse retinal progenitor cells and enhances their transplantation in retinal degeneration mouse models.

Inherited and age-related retinal degenerations are the commonest causes of blindness without effective treatments. Retinal progenitor cells (RPCs), which have the multipotency to differentiate into various retinal cell types, are regarded as a promising source of cell transplantation therapy for retinal degenerative diseases. However, the self-limited expansion of RPCs causes difficulty in cell source supply and restrict its clinical treatment. In this work, we found that inhibition of microRNA-449a (miR-449a) in RPCs can promote proliferation and inhibit apoptosis of RPCs, partially through upregulating Notch signaling. Further optimization of transduction miR-449a inhibitor into RPCs by endothelial cell-derived exosomes can promote the survival of RPCs transplanted in vivo and reduce cell apoptosis in retinal degeneration mouse models. In summary, these studies have shown that exosome-miR-449a inhibitor can effectively promote the expansion of RPCs in vitro and enhance transplanted RPCs survival in vivo, which might provide a novel intervention strategy for retinal degenerations in the future.

Surgical Treatment of Pineal Region Tumors: An 18 year-Experience at a Single Institution.

BACKGROUND: The pineal tumor was once considered as a restricted area for surgery. Such cases are rare, with many different opinions on surgical treatment. This study aimed to review our experience of tumor treatment in the pineal region and explore the optimal treatment strategy. METHODS: The clinical data of 72 patients with pineal tumors from January 1997 to May 2015 (18 years) were retrospectively analyzed. Preoperative preparation, pathology type, tumor resection rate, surgical approach, and follow-up outcomes were used as the indicators to evaluate the treatment efficacy. RESULTS: The Krause approach was used in 46 cases, the Poppen approach in 10 cases, and the transcallosal-lateral ventricle-choroid fissure approach in 16 cases. The postoperative pathological results were as follows: 24 cases of germinoma, 11 of teratoma, 15 of glioma, 6 of meningioma, 11 of Pineocytoma, 2 of cholesteatoma, 2 of cavernous hemangioma, and 1 of choriocarcinoma. Further, the study included 64 cases of total surgical resections, 8 of subtotal resections, and 2 deaths. The follow-up period was from 7 months to 10 years. Further, 51 (70.8%) patients were followed up. The multivariate regression model showed that the surgical method and the pathological type contributed significantly to predicting outcomes. CONCLUSIONS: The type of pathology, extent of excision, and surgical approach had a significant impact on the prognosis of patients. The transcallosal-lateral ventricle-choroid fissure approach for large and medium-sized pineal tumors near the posterior part of the third ventricle had good efficacy.

Coordination-Driven Self-Assembly of Biomedicine to Enhance Photodynamic Therapy by Inhibiting Proteasome and Bcl-2.

Tumor cells resist oxidative damage and apoptosis by activating defense mechanisms. Herein, a self-delivery biomedicine (designated as BSC) is developed by the self-assembly of Bortezomib (BTZ), Sabutoclax (Sab) and Chlorin e6 (Ce6). Interestingly, BTZ can be coordinated with Sab to promote the assembly of uniform ternary biomedicine through non-covalent intermolecular interactions. Moreover, BTZ as a proteasome inhibitor can prevent tumor cells from scavenging damaged proteins to reduce their oxidative resistance. Sab can downregulate B-cell lymphoma 2 (Bcl-2) to decrease the antiapoptotic protein. Both the proteasome and Bcl-2 inhibitions contribute to increasing cell apoptosis and amplifying photodynamic therapy (PDT) efficacy of Ce6. Encouragingly, carrier-free BSC receives all biological activities of these assembly elements, including photodynamic performance as well as inhibitory capabilities of proteasome and Bcl-2. Besides, BSC has a preferable cellular uptake ability and tumor retention property, which increase the drug delivery efficiency and bioavailability. In vitro and in vivo research demonstrate the superior PDT efficiency of BSC by proteasome and Bcl-2 inhibitions. Of special note, the coordination-driven self-assembly of BSC is pH-responsive, which can be disassembled for controlled drug release upon tumor acidic microenvironment. This study will expand the applicability of self-delivery nanomedicine with sophisticated mechanisms for tumor treatment.

Atypical meningioma of sylvian fissure with a 20-year history: a rare case report.

Atypical meningiomas of sylvian fissure are extremely rare. We reported a case of sylvian fissure atypical meningioma with a 20-year history. The tumor was excised subtotally, thereafter a postoperative radiation therapy was done. The patient had a favorable outcome during the two-year follow-up. The possible pathogenesis of this case was hypothesized and analyzed in this article.

Intracranial extraaxial ependymoma in children: a rare case report and review of the literature.

Intracranial extraaxial ependymomas (IEAEs) are extremely rare. We present a pediatric patient with IEAE misdiagnosed as a meningioma preoperatively, successfully treated surgically with a favorite outcome. The literature about IEAEs was briefly reviewed. Thereafter we discuss the clinical characteristics of the disease.

Neural Research on Depth Perception and Stereoscopic Visual Fatigue in Virtual Reality.

Virtual reality (VR) technology provides highly immersive depth perception experiences; nevertheless, stereoscopic visual fatigue (SVF) has become an important factor currently hindering the development of VR applications. However, there is scant research on the underlying neural mechanism of SVF, especially those induced by VR displays, which need further research. In this paper, a Go/NoGo paradigm based on disparity variations is proposed to induce SVF associated with depth perception, and the underlying neural mechanism of SVF in a VR environment was investigated. The effects of disparity variations as well as SVF on the temporal characteristics of visual evoked potentials (VEPs) were explored. Point-by-point permutation statistical with repeated measures ANOVA results revealed that the amplitudes and latencies of the posterior VEP component P2 were modulated by disparities, and posterior P2 amplitudes were modulated differently by SVF in different depth perception situations. Cortical source localization analysis was performed to explore the original cortex areas related to certain fatigue levels and disparities, and the results showed that posterior P2 generated from the precuneus could represent depth perception in binocular vision, and therefore could be performed to distinguish SVF induced by disparity variations. Our findings could help to extend an understanding of the neural mechanisms underlying depth perception and SVF as well as providing beneficial information for improving the visual experience in VR applications.

Investigate the Neuro Mechanisms of Stereoscopic Visual Fatigue.

Stereoscopic visual fatigue (SVF) due to prolonged immersion in the virtual environment can lead to negative user experience, thus hindering the development of virtual reality (VR) industry. Previous studies have focused on investigating the evaluation indicators associated with SVF, while few studies have been conducted to reveal the underlying neural mechanism, especially in VR applications. In this paper, a modified Go/NoGo paradigm was adopted to induce SVF in VR environment with Go trials for maintaining participants' attention and NoGo trials for investigating the neural effects under SVF. Random dot stereograms (RDSs) with 11 disparities were presented to evoke the depth-related visual evoked potentials (DVEPs) during 64-channel EEG recordings. EEG datasets collected from 15 participants in NoGo trials were selected to conduct individual processing and group analysis, in which the characteristics of the DVEPs components for various fatigue degrees were compared and independent components were clustered to explore the original cortex areas related to SVF. Point-by-point permutation statistics revealed that DVEPs sample points from 230 ms to 280 ms (component P2) in most brain areas changed significantly when SVF increased. Additionally, independent component analysis (ICA) identified that component P2 which originated from posterior cingulate cortex and precuneus, was associated statistically with SVF. We believe that SVF is rather a conscious status concerning the changes of self-awareness or self-location awareness than the performance reduction of retinal image processing. Moreover, we suggest that indicators representing higher conscious state may be a better indicator for SVF evaluation in VR environments.

Exosome-mediated delivery of RBP-J decoy oligodeoxynucleotides ameliorates hepatic fibrosis in mice.

Rationale: Macrophages play multi-dimensional roles in hepatic fibrosis. Studies have implicated Notch signaling mediated by the transcription factor RBP-J in macrophage activation and plasticity. Additionally, we have previously shown that myeloid-specific disruption of RBP-J can ameliorate hepatic fibrosis in mice. Accordingly, we next asked whether blocking Notch signaling in macrophages could serve as a therapeutic strategy to treat hepatic fibrosis. In this study, we used a combination of transcription factor decoy oligodeoxynucleotides (ODNs) and exosomes to test this possibility. Methods: Hairpin-type decoy oligodeoxynucleotides (ODNs) were designed for the transcription factor RBP-J. The effects of RBP-J decoy ODNs on Notch signaling were evaluated by western blot, quantitative RT-PCR, luciferase reporter assays, and electrophoretic mobility shift assays. ODNs were loaded into HEK293T-derived exosomes by electroporation. A hepatic fibrosis mouse model was established by the intraperitoneal injection of carbon tetrachloride or bile duct ligation. Mice with hepatic fibrosis were administered exosomes loaded with RBP-J decoy ODNs via tail vein injection. The in vivo distribution of exosomes was analyzed by fluorescence labeling and imaging. Liver histology was examined using hematoxylin and eosin, Sirius red, and Masson staining, as well as immunohistochemical staining for Col1α1 and αSMA. Results: We found that RBP-J decoy ODNs could be efficiently loaded into exosomes and inhibit the activation of Notch signaling. Furthermore, exosomes administered via the tail vein were found to be primarily taken up by hepatic macrophages in mice with liver fibrosis. Importantly, RBP-J decoy ODNs delivered by exosomes could efficiently inhibit Notch signaling in macrophages and ameliorate hepatic fibrosis in mice. Conclusions: Combined, our data showed that the infusion of exosomes loaded with RBP-J decoy ODNs represents a promising therapeutic strategy for the treatment of hepatic fibrosis.

Transmembrane Protein Ttyh1 Maintains the Quiescence of Neural Stem Cells Through Ca2+/NFATc3 Signaling.

The quiescence, activation, and subsequent neurogenesis of neural stem cells (NSCs) play essential roles in the physiological homeostasis and pathological repair of the central nervous system. Previous studies indicate that transmembrane protein Ttyh1 is required for the stemness of NSCs, whereas the exact functions in vivo and precise mechanisms are still waiting to be elucidated. By constructing Ttyh1-promoter driven reporter mice, we determined the specific expression of Ttyh1 in quiescent NSCs and niche astrocytes. Further evaluations on Ttyh1 knockout mice revealed that Ttyh1 ablation leads to activated neurogenesis and enhanced spatial learning and memory in adult mice (6-8 weeks). Correspondingly, Ttyh1 deficiency results in accelerated exhaustion of NSC pool and impaired neurogenesis in aged mice (12 months). By RNA-sequencing, bioinformatics and molecular biological analysis, we found that Ttyh1 is involved in the regulation of calcium signaling in NSCs, and transcription factor NFATc3 is a critical effector in quiescence versus cell cycle entry regulated by Ttyh1. Our research uncovered new endogenous mechanisms that regulate quiescence versus activation of NSCs, therefore provide novel targets for the intervention to activate quiescent NSCs to participate in injury repair during pathology and aging.

Temozolomide Treatment Induces HMGB1 to Promote the Formation of Glioma Stem Cells via the TLR2/NEAT1/Wnt Pathway in Glioblastoma.

Formation of glioma stem cells (GSCs) is considered as one of the main reasons of temozolomide (TMZ) resistance in glioma patients. Recent studies have shown that tumor microenvironment-derived signals could promote GSCs formation. But the critical molecule and underlying mechanism for GSCs formation after TMZ treatment is not entirely identified. Our study showed that TMZ treatment promoted GSCs formation by glioma cells; TMZ treatment of biopsy-derived glioblastoma multiforme cells upregulated HMGB1; HMGB1 altered gene expression profile of glioma cells with respect to mRNA, lncRNA and miRNA. Furthermore, our results showed that TMZ-induced HMGB1 increased the formation of GSCs and when HMGB1 was downregulated, TMZ-mediated GSCs formation was attenuated. Finally, we showed that the effect of HMGB1 on glioma cells was mediated by TLR2, which activated Wnt/ß-catenin signaling to promote GSCs. Mechanistically, we found that HMGB1 upregulated NEAT1, which was responsible for Wnt/ß-catenin activation. In conclusion, TMZ treatment upregulates HMGB1, which promotes the formation of GSCs via the TLR2/NEAT1/Wnt pathway. Blocking HMGB1-mediated GSCs formation could serve as a potential therapeutic target for preventing TMZ resistance in GBM patients.