Use of circulating tumor cells and microemboli to predict diagnosis and prognosis in diffuse glioma.

OBJECTIVE: Circulating tumor cell (CTC) detection is a promising noninvasive technique that can be used to diagnose cancer, monitor progression, and predict prognosis. In this study, the authors aimed to investigate the clinical utility of CTCs in the management of diffuse glioma. METHODS: Sixty-three patients with newly diagnosed diffuse glioma were included in this multicenter clinical cohort. The authors used a platform based on isolation by size of epithelial tumor cells (ISET) to detect and analyze CTCs and circulating tumor microemboli (CTMs) in the peripheral blood of patients both before and after surgery. Least absolute shrinkage and selector operation (LASSO) and Cox regression analyses were used to verify whether CTCs and CTMs are independent prognostic factors for diffuse glioma. RESULTS: CTC levels were closely related to the degree of malignancy, WHO grade, and pathological subtypes. Receiver operating characteristic curve analysis revealed that a high CTC level was a predictor for glioblastoma. The results also showed that CTMs originate from the parental tumor rather than from the circulation and are an independent prognostic factor for diffuse glioma. The postoperative CTC level is related to the peripheral immune system and patient survival. Cox regression analysis showed that postoperative CTC levels and CTM status are independent prognostic factors for diffuse glioma, and CTC- and CTM-based survival models had high accuracy in internal validation. CONCLUSIONS: The authors revealed a correlation between CTCs and clinical characteristics and demonstrated that CTCs and CTMs are independent predictors for the diagnosis and prognosis of diffuse glioma. Their CTC- and CTM-based survival models can enable clinicians to evaluate patients' response to surgery as well as their outcomes.

ADAMTS13 deficiency exacerbates neuroinflammation by targeting matrix metalloproteinase-9 in ischemic brain injury.

Our design aimed to explore the potential involvement of matrix metalloproteinase-9 (MMP-9) in the inflammatory response associated with acute ischemic stroke (AIS). We also aimed to preliminarily examine the potential impact of a disintegrin-like and metalloprotease with thrombospondin type I repeats-13 (ADAMTS13) on MMP-9 in AIS. We conducted oxygen-glucose deprivation models of microglia cells and mice models of AIS with middle cerebral artery occlusion (MCAO). We assessed the expression pattern of MMP-9 with western blotting (WB) and real-time quantitative PCR both in vivo and in vitro. MMP-9 downregulation was achieved by using ACE inhibitors such as trandolapril. For the MCAO model, we used ADAMTS13-deficient mice. We then evaluated the related neurological function scores, cerebral edema and infarct volume. The levels of inflammation-related proteins, such as COX2 and iNOS, were assessed using WB, and the expression of inflammatory cytokines was measured via enzyme-linked immuno sorbent assay in vivo. Our findings indicated that MMP-9 was up-regulated while ADAMTS13 was down-regulated in the MCAO model. Knockdown of MMP-9 reduced both inflammation and ischemic brain injury. ADAMTS13 prevented brain damage, improved neurological function and decreased the inflammation response in mice AIS models. Additionally, ADAMTS13 alleviated MMP-9-induced neuroinflammation in vivo. It showed that ADAMTS13 deficiency exacerbated ischemic brain injury through an MMP-9-dependent inflammatory mechanism. Therefore, the ADAMTS13-MMP-9 axis could have therapeutic potential for the treatment of AIS.

RND1 inhibits epithelial-mesenchymal transition and temozolomide resistance of glioblastoma via AKT/GSK3-ß pathway.

GBM is one of the most malignant tumor in central nervous system. The resistance to temozolomide (TMZ) is inevitable in GBM and the characterization of TMZ resistance seriously hinders clinical treatment. It is worthwhile exploring the underlying mechanism of aggressive invasion and TMZ resistance in GBM treatment. Bioinformatic analysis was used to analyze the association between RND1 and a series of EMT-related genes. Colony formation assay and cell viability assay were used to assess the growth of U87 and U251 cells. The cell invasion status was evaluated based on transwell and wound-healing assays. Western blot was used to detect the protein expression in GBM cells. Treatment targeted RND1 combined with TMZ therapy was conducted in nude mice to evaluate the potential application of RND1 as a clinical target for GBM. The overexpression of RND1 suppressed the progression and migration of U87 and U251 cells. RND1 knockdown facilitated the growth and invasion of GBM cells. RND1 regulated the EMT of GBM cells via inhibiting the phosphorylation of AKT and GSK3-ß. The promoted effects of RND1 on TMZ sensitivity was identified both in vitro and in vivo. This research demonstrated that the overexpression of RND1 suppressed the migration and EMT status by downregulating AKT/GSK3-ß pathway in GBM. RND1 enhanced the TMZ sensitivity of GBM cells both in vitro and in vivo. Our findings may contribute to the targeted therapy for GBM and the understanding of mechanisms of TMZ resistance in GBM.

Netrin-1 Alleviates Early Brain Injury by Regulating Ferroptosis via the PPARγ/Nrf2/GPX4 Signaling Pathway Following Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a type of stroke with high morbidity and mortality. Netrin-1 (NTN-1) can alleviate early brain injury (EBI) following SAH by enhancing peroxisome proliferator-activated receptor gamma (PPARγ), which is an important transcriptional factor modulating lipid metabolism. Ferroptosis is a newly discovered type of cell death related to lipid metabolism. However, the specific function of ferroptosis in NTN-1-mediated neuroprotection following SAH is still unclear. This study aimed to evaluate the neuroprotective effects and the possible molecular basis of NTN-1 in SAH-induced EBI by modulating neuronal ferroptosis using the filament perforations model of SAH in mice and the hemin-stimulated neuron injury model in HT22 cells. NTN-1 or a vehicle was administered 2 h following SAH. We examined neuronal death, brain water content, neurological score, and mortality. NTN-1 treatment led to elevated survival probability, greater survival of neurons, and increased neurological score, indicating that NTN-1-inhibited ferroptosis ameliorated neuron death in vivo/in vitro in response to SAH. Furthermore, NTN-1 treatment enhanced the expression of PPARγ, nuclear factor erythroid 2-related factor 2 (Nrf2), and glutathione peroxidase 4 (GPX4), which are essential regulators of ferroptosis in EBI after SAH. The findings show that NTN-1 improves neurological outcomes in mice and protects neurons from death caused by neuronal ferroptosis. Furthermore, the mechanism underlying NTN-1 neuroprotection is correlated with the inhibition of ferroptosis, attenuating cell death via the PPARγ/Nrf2/GPX4 pathway and coenzyme Q10-ferroptosis suppressor protein 1 (CoQ10-FSP1) pathway.

Neutral polysaccharide from Gastrodia elata alleviates cerebral ischemia-reperfusion injury by inhibiting ferroptosis-mediated neuroinflammation via the NRF2/HO-1 signaling pathway.

AIMS: The crosstalk between ferroptosis and neuroinflammation considerably impacts the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). Neutral polysaccharide from Gastrodia elata (NPGE) has shown significant effects against oxidative stress and inflammation. This study investigated the potential effects of NPGE on CIRI neuropathology. METHODS: The effects of NPGE were studied in a mouse model of ischemic stroke (IS) and in oxygen-glucose deprivation/reperfusion (OGD/R)-induced HT22 cells. RESULTS: NPGE treatment decreased neurological deficits, reduced infarct volume, and alleviated cerebral edema in IS mice, and promoted the survival of OGD/R-induced HT22 cells. Mechanistically, NPGE treatment alleviated neuronal ferroptosis by upregulating GPX4 levels, lowering reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+ excessive hoarding, and meliorating GSH levels and SOD activity. Additionally, it inhibited neuroinflammation by down-regulating the level of IL-1ß, IL-6, TNF-α, NLRP3, and HMGB1. Meanwhile, NPGE treatment alleviated ferroptosis and inflammation in erastin-stimulated HT22 cells. Furthermore, NPGE up-regulated the expression of NRF2 and HO-1 and promoted the translocation of NRF2 into the nucleus. Using the NRF2 inhibitor brusatol, we verified that NRF2/HO-1 signaling mediated the anti-ferroptotic and anti-inflammatory properties of NPGE. CONCLUSION: Collectively, our results demonstrate the protective effects of NPGE and highlight its therapeutic potential as a drug component for CIRI treatment.

Self-Assembled nanoparticles of natural bioactive molecules enhance the delivery and efficacy of paclitaxel in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant tumor in the central nervous system. Paclitaxel (PTX) is a well-established and highly effective anti-cancer drug for peripheral solid tumors. However, the application of PTX in GBM is hindered by several limitations, including poor water solubility, restricted entry across the blood-brain barrier (BBB), and enhanced excretion by efflux transporters. P-glycoprotein (P-gp) is a crucial efflux transporter that is abundantly present in cerebral vascular endothelial cells and GBM cells. It plays a significant role in the exocytosis of PTX within tumor tissues. METHODS: Recently, we have developed a novel technique for creating self-assembled nanoparticles utilizing a range of natural bioactive molecules. These nanoparticles can encapsulate insoluble drugs and effectively cross the BBB. In additional, we revealed that certain nanoparticles have the potential to act as P-gp inhibitors, thereby reducing the excretion of PTX. In this study, we conducted a screening of bioactive molecular nanoparticles to identify those that effectively inhibit the function of P-gp transporters. RESULTS: Among the candidates, we identified ursolic acid nanoparticles (UA NPs) as the P-gp inhibitors. Furthermore, we prepared co-assembled UA NPs embedded with paclitaxel, referred to as UA-PTX NPs. Our results demonstrate that UA-PTX NPs can enhance the blood concentration of PTX, facilitate its entry into the BBB, and inhibit the function of P-gp, resulting in a decrease in the excretion of PTX. This discovery effectively addressed the above three issues associated with the use of PTX in glioma treatment. CONCLUSIONS: UA-PTX NPs demonstrate strong anti-tumor effects and show great potential for treating GBM.

Treatment of brainstem and fourth ventricle lesions by the full neuroendoscopic telovelar approach.

OBJECTIVE: To explore the surgical techniques, advantages, and disadvantages of neuroendoscopic telovelar approach in the treatment of brainstem and fourth ventricle lesions. METHODS: The clinical data of 5 patients treated by neuroendoscopic telovelar approach from March 2020 to March 2022 were analyzed retrospectively. RESULTS: Among the 5 patients, there were 3 cavernous hemangiomas in pontine arm and 2 tumors in brainstem and fourth ventricle. All patients could successfully complete the operation, and 4 patients recovered well, other 1 patient discharged automatically for serious complications of other systems after the operation. CONCLUSION: The telovelar approach has gained popularity as a safe and effective strategy for lesions in fourth ventricular and brainstem. However, without removing the posterior arch of the atlas, it is difficult to enter the upper part of the fourth ventricle under a microscope. Transcranial neuroendoscopy can effectively compensate for the shortcomings of microscopy, whether used as an auxiliary measure for microsurgery or alone with proficient endoscopic techniques, it will provide greater application in minimally invasive surgery for fourth ventricle and brainstem lesions. By utilizing the excellent degree of freedom of transcranial neuroendoscopy, there is no need to open the posterior arch of the atlas, making the surgery more minimally invasive. However, the sample size of this study is small, and it was completed under the very mature neuroendoscopic technology of our team. Its general safety and practicality still require extensive clinical research validation.

Advantages of computed tomography-based navigation in clipping distal anterior cerebral artery aneurysms: a retrospective cohort study.

Background: The occurrence rate of distal anterior cerebral artery (DACA) aneurysms is relatively low, primarily due to their deep-seated location, which makes surgical clamping challenging. The objective of this study was to investigate the efficacy and safety of computed tomography (CT) navigation-assisted clipping of DACA aneurysms compared to traditional clipping without navigation. Methods: A retrospective cohort study involving retrospective data collection was performed. The retrospective analysis was conducted on 139 patients with ruptured DACA aneurysms who underwent clipping. From January 2013 to November 2021, 164 patients were retrieved at the Department of Neurosurgery, Renmin Hospital of Wuhan University. The inclusion criteria were patients diagnosed with DACA aneurysms via CT angiography (CTA) or digital subtraction angiography (DSA), those with complete clinical data, and those who underwent craniotomy for aneurysm clipping. Meanwhile, the exclusion criteria were as follows: aneurysm recurrence, traumatic brain injury or surgery history, blood disorders or recent anticoagulant use, and severe organ dysfunction. Data on gender, age, Hunt-Hess grade, Fisher grade, modified Rankin Scale (mRS) score, aneurysm location, hospitalization time, aneurysm found time (the duration from incision to aneurysm discovery), and intraoperative bleeding volume were collected from medical records and neurosurgical databases. Patients were followed up in the clinic or by telephone in May 2022. All patients were divided into a navigation group or a traditional group for statistical analysis. Results: No statistically significant differences were observed in age, sex, Fisher grade, Hunt-Hess grade, hospitalization time, or aneurysm site between the navigation group and traditional group (P>0.05). Intraoperative blood loss was lower in the navigation group than in the traditional group {370 [280-460] vs. 430 [310-610] mL, P=0.045}. Patients in the traditional group had a shorter aneurysm found time than did those in the navigation group {49 [42-53] vs. 79 [63-84] min, P<0.001}. There was no significant difference in the mRS score at hospital discharge (P=0.336) or follow-up (P=0.157) between the two groups. Conclusions: CT neuronavigation-assisted microsurgery for clipping DACA aneurysms may improve surgical accuracy, shorten the time to locate aneurysms, and reduce intraoperative blood loss. Although no significant difference in prognosis was observed, this technique shows promise as a safe and effective alternative to traditional clipping without navigation.

Post-operative rebleeding in patients with spontaneous supratentorial intracerebral hemorrhage: factors and clinical outcomes.

OBJECTIVE: To explore factors affecting postoperative rebleeding in patients with spontaneous supratentorial intracerebral hemorrhage (SSICH). METHODS: We retrospectively analyzed data from 724 patients with SSICH treated at Renmin Hospital of Wuhan University from December 2018 to October 2021. Finally, 294 people were eligible to be included in this study. Hematoma locations were classified as basal ganglia, thalamus, subcortex, or intraventricular. Surgery was categorized as neuroendoscopic surgery, burr hole (stereotactic drilling and drainage), or open craniotomy. Postoperative rebleeding was recorded. The incidence, risk factors, and prognosis of postoperative rebleeding were evaluated. RESULTS: All procedures were successfully completed. Postoperative rebleeding occurred in 57 patients (19.83%, 57/294). Univariate logistic regression analysis identified these risk factors for rebleeding: admission Glasgow Coma Scale (GCS) score, irregular hematoma morphology by preoperative Computed Tomography (CT), postoperative hypertension, hematoma location, surgical method (P<0.05), and preoperative hematoma volume (P<0.1). Multivariate logistic regression analysis confirmed admission GCS score, irregular hematoma morphology by preoperative CT, postoperative hypertension, hematoma location, and surgical method as significant risk factors (P<0.05). Burr hole surgery and basal ganglia hematomas were associated with increased odds of rebleeding, and the mortality rates in patients with rebleeding versus no rebleeding were 7.02% versus 0.84%. CONCLUSIONS: Neuroendoscopic surgery, craniotomy, and burr hole are all effective for treating SSICH, but burr hole surgery was an important risk factor for rebleeding and an adverse outcome. Admission GCS score, irregular hematoma morphology, blood pressure control, hematoma location, and surgical method are affected the risk of postoperative rebleeding. 3D Slicer-assisted neuroendoscopic surgery may be the most effective treatment for many patients with SSICH.

Transcriptome-Wide Analysis of Neutrophil-Related Circ_22232 in Neuroinflammation from Ischemic Stroke Mice.

Ischemic stroke (IS) often leads to high rates of disability and mortality worldwide with secondary damage due to neuroinflammation. Identification of potential therapeutic targets via the novel circular RNAs (circRNAs) would advance the field and provide a better treatment option for neuroinflammation after IS. Gene Ontology Term Enrichment (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were applied to identify differentially expressed genes/miRNAs/circRNAs in the genome-wide RNA-seq profiles of ischemic mice. Meanwhile, relevant circRNAs were screened by differential expression analysis and coexpression RNA regulation network analysis. To explore the function of circ_22232 (Specc1l), we generated circ_22232 knockdown mice and applied middle cerebral artery occlusion (MCAO) to study IS. Cytokine levels were detected by enzyme-linked immunosorbent assay. Morphological changes were observed with immunohistochemical staining and hematoxylin-eosin staining. The circ_22232/miR-847-3p/Bmp1 axis was found to be highly correlated with neutrophil-associated neuroinflammation in cerebral tissue of mice. Immunohistochemical showed a progressive increase in the proportion of neutrophils after IS. In in vivo experiments, the circ_22232 knockdown alleviated cerebral injury by reducing the activation of neutrophils and inflammatory cytokine production. This suggests that circ_22232 is associated with inflammation, which may serve as a potential therapeutic target for IS.

Deep learning-assisted identification and quantification of aneurysmal subarachnoid hemorrhage in non-contrast CT scans: Development and external validation of Hybrid 2D/3D UNet.

Accurate stroke assessment and consequent favorable clinical outcomes rely on the early identification and quantification of aneurysmal subarachnoid hemorrhage (aSAH) in non-contrast computed tomography (NCCT) images. However, hemorrhagic lesions can be complex and difficult to distinguish manually. To solve these problems, here we propose a novel Hybrid 2D/3D UNet deep-learning framework for automatic aSAH identification and quantification in NCCT images. We evaluated 1824 consecutive patients admitted with aSAH to four hospitals in China between June 2018 and May 2022. Accuracy and precision, Dice scores and intersection over union (IoU), and interclass correlation coefficients (ICC) were calculated to assess model performance, segmentation performance, and correlations between automatic and manual segmentation, respectively. A total of 1355 patients with aSAH were enrolled: 931, 101, 179, and 144 in four datasets, of whom 326 were scanned with Siemens, 640 with Philips, and 389 with GE Medical Systems scanners. Our proposed deep-learning method accurately identified (accuracies 0.993-0.999) and segmented (Dice scores 0.550-0.897) hemorrhage in both the internal and external datasets, even combinations of hemorrhage subtypes. We further developed a convenient AI-assisted platform based on our algorithm to assist clinical workflows, whose performance was comparable to manual measurements by experienced neurosurgeons (ICCs 0.815-0.957) but with greater efficiency and reduced cost. While this tool has not yet been prospectively tested in clinical practice, our innovative hybrid network algorithm and platform can accurately identify and quantify aSAH, paving the way for fast and cheap NCCT interpretation and a reliable AI-based approach to expedite clinical decision-making for aSAH patients.

Claudin-3 facilitates the progression and mediates the tumorigenic effects of TGF-ß in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a significantly malignant and lethal brain tumor with an average survival time of less than 12 months. Several researches had shown that Claudin-3 (CLDN3) is overexpressed in various cancers and might be important in their growth and spread. In this study, we used qRT-PCR, western blotting, immunohistochemistry, and immunofluorescence staining assays to investigate the expression levels of various proteins. To explore the proliferation abilities of GBM cells, we conducted the CCK-8 and EdU-DNA formation assays. Wound healing and transwell assays were used to investigate the capacities of invasion and migration of GBM cells. Additionally, we constructed an intracranial xenograft model of GBM to study the in vivo role of CLDN3. Our study devoted to investigate the function of CLDN3 in the pathogenesis and progression of GBM. Our study revealed that CLDN3 was upregulated in GBM and could stimulate tumor cell growth and epithelial-mesenchymal transition (EMT) in both laboratory and animal models. We also discovered that CLDN3 expression could be triggered by transforming growth factor-ß (TGF-ß) and reduced by specific inhibitors of the TGF-ß signaling pathway, such as ITD-1. Further analysis revealed that increased CLDN3 levels enhanced TGF-ß-induced growth and EMT in GBM cells, while reducing CLDN3 levels weakened these effects. Our study demonstrated the function of CLDN3 in facilitating GBM growth and metastasis and indicated its involvement in the tumorigenic effects of TGF-ß. Developing specific inhibitors of CLDN3 might, therefore, represent a promising new approach for treating this devastating disease.

New trends in brain tumor immunity with the opportunities of lymph nodes targeted drug delivery.

Lymph nodes targeted drug delivery is an attractive approach to improve cancer immunotherapy outcomes. Currently, the depth of understanding of afferent and efferent arms in brain immunity reveals the potential clinical applications of lymph node targeted drug delivery in brain tumors, e.g., glioblastoma. In this work, we systematically reviewed the microenvironment of glioblastoma and its structure as a basis for potential immunotherapy, including the glial-lymphatic pathway for substance exchange, the lymphatic drainage pathway from meningeal lymphatic vessels to deep cervical lymph nodes that communicate intra- and extracranial immunity, and the interaction between the blood-brain barrier and effector T cells. Furthermore, the carriers designed for lymph nodes targeted drug delivery were comprehensively summarized. The challenges and opportunities in developing a lymph nodes targeted delivery strategy for glioblastoma using nanotechnology are included at the end.

Essential genes Ptgs2, Tlr4, and Ccr2 regulate neuro-inflammation during the acute phase of cerebral ischemic in mice.

Ischemic stroke (IS) is associated with changes in gene expression patterns in the ischemic penumbra and extensive neurovascular inflammation. However, the key molecules related to the inflammatory response in the acute phase of IS remain unclear. To address this knowledge gap, conducted a study using Gene Set Enrichment Analysis (GSEA) on two gene expression profiles, GSE58720 and GSE202659, downloaded from the GEO database. We screened differentially expressed genes (DEGs) using GEO2R and analyzed 170 differentially expressed intersection genes for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) analysis. We also used Metascape, DAVID, STRING, Cytoscape, and TargetScan to identify candidate miRNAs and genes. The targeted genes and miRNA molecule were clarified using the mice middle cerebral artery occlusion-reperfusion (MCAO/R) model. Our findings revealed that 170 genes were correlated with cytokine production and inflammatory cell activation, as determined by GO and KEGG analyses. Cluster analysis identified 11 hub genes highly associated with neuroinflammation: Ccl7, Tnf, Ccl4, Timp1, Ccl3, Ccr1, Sele, Ccr2, Tlr4, Ptgs2, and Il6. TargetScan results suggested that Ptgs2, Tlr4, and Ccr2 might be regulated by miR-202-3p. In the MCAO/R model, the level of miR-202-3p decreased, while the levels of Ptgs2, Tlr4, and Ccr2 increased compared to the sham group. Knockdown of miR-202-3p exacerbated ischemic reperfusion injury (IRI) through neuroinflammation both in vivo and in vitro. Our study also demonstrated that mRNA and protein levels of Ptgs2, Tlr4, and Ccr2 increased in the MCAO/R model with miR-202-3p knockdown. These findings suggest that differentially expressed genes, including Ptgs2, Tlr4, and Ccr2 may play crucial roles in the neuroinflammation of IS, and their expression may be negatively regulated by miR-202-3p. Our study provides new insights into the regulation of neuroinflammation in IS.

3D slicer combined with neuroendoscope in treatment of a distal segment aneurysm of the anterior choroidal artery complicated intraventricular hemorrhage: A case report and literature review.

Introduction: Pure ventricular hemorrhage is often secondary to Moyamoya disease, rarely caused by rupture of ventricular aneurysm. The surgical treatment of the latter is very challenging. 3D Slicer reconstruction technology can accurately locate small intracranial lesions and combined with minimally invasive surgery with transcranial neuroendoscope is a new attempt to treat the above diseases. Case presentation: We report a case of pure intraventricular hemorrhage secondary to rupture of a distal segment aneurysm of the anterior choroidal artery. Brain computed tomography (CT) before admission showed pure ventricular hemorrhage, and brain CT angiography (CTA) before operation showed a distal segment aneurysm of the anterior choroidal artery. We used 3D Slicer reconstruction and precise location of the focus before the operation and used the minimally invasive surgery technique with transcranial neuroendoscope to completely remove the hematoma in the ventricle, and found the responsible aneurysm located in the ventricle. Conclusion: Pure intraventricular hemorrhage requires vigilance against the distal segment aneurysm of the anterior choroidal artery. At present, conventional microscopic craniotomy and intravascular interventional therapy have limitations, and 3D Slicer reconstruction and precise positioning technology combined with transcranial neuroendoscope minimally invasive surgery may be a good choice.

Effect of Spontaneous Subarachnoid Hemorrhage on Cerebrospinal Fluid Indicators.

The cerebrospinal fluid (CSF) analysis in ruptured aneurysms can be greatly affected by subarachnoid hemorrhage (SAH), making the diagnosis of intracranial infection more difficult after surgery. This study aimed to identify the reference value range of CSF in the pathological state following spontaneous SAH. A retrospective analysis of demographic and CSF data of all spontaneous SAH patients treated between January 2018 and January 2023 was conducted. A total of 101 valid CSF specimen data were collected for analysis. Our results indicate that in 95% of patients after spontaneous SAH, the leukocyte count in CSF was less than 880 × 106/L. Additionally, the proportion of neutrophils, lymphocytes, and monocytes did not exceed 75%, 75%, and 15%, respectively, in 95% of the population. Furthermore, in 95% of the specimens, the concentration of chloride, glucose, and protein was >115 mmol/L, >2.2 mmol/L, and <2.3 g/L, respectively. Compared to the normal reference values, the CSF indexes after spontaneous SAH showed significant changes, especially in the leukocyte count, chloride concentration, and glucose concentration. Using "white blood cell count < 880/mm3, glucose > 2.2 mmol/L, chloride > 115" as the reference values for SAH pathological status is more meaningful for reference purposes.

Combination of multi-modal MRI radiomics and liquid biopsy technique for preoperatively non-invasive diagnosis of glioma based on deep learning: protocol for a double-center, ambispective, diagnostical observational study.

Background: 2021 World Health Organization (WHO) Central Nervous System (CNS) tumor classification increasingly emphasizes the important role of molecular markers in glioma diagnoses. Preoperatively non-invasive "integrated diagnosis" will bring great benefits to the treatment and prognosis of these patients with special tumor locations that cannot receive craniotomy or needle biopsy. Magnetic resonance imaging (MRI) radiomics and liquid biopsy (LB) have great potential for non-invasive diagnosis of molecular markers and grading since they are both easy to perform. This study aims to build a novel multi-task deep learning (DL) radiomic model to achieve preoperative non-invasive "integrated diagnosis" of glioma based on the 2021 WHO-CNS classification and explore whether the DL model with LB parameters can improve the performance of glioma diagnosis. Methods: This is a double-center, ambispective, diagnostical observational study. One public database named the 2019 Brain Tumor Segmentation challenge dataset (BraTS) and two original datasets, including the Second Affiliated Hospital of Nanchang University, and Renmin Hospital of Wuhan University, will be used to develop the multi-task DL radiomic model. As one of the LB techniques, circulating tumor cell (CTC) parameters will be additionally applied in the DL radiomic model for assisting the "integrated diagnosis" of glioma. The segmentation model will be evaluated with the Dice index, and the performance of the DL model for WHO grading and all molecular subtype will be evaluated with the indicators of accuracy, precision, and recall. Discussion: Simply relying on radiomics features to find the correlation with the molecular subtypes of gliomas can no longer meet the need for "precisely integrated prediction." CTC features are a promising biomarker that may provide new directions in the exploration of "precision integrated prediction" based on the radiomics, and this is the first original study that combination of radiomics and LB technology for glioma diagnosis. We firmly believe that this innovative work will surely lay a good foundation for the "precisely integrated prediction" of glioma and point out further directions for future research. Clinical trail registration: This study was registered on ClinicalTrails.gov on 09/10/2022 with Identifier NCT05536024.

Ursolic acid nanoparticles for glioblastoma therapy.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common and fatal primary tumor in the central nervous system (CNS). The effect of chemotherapy of GBM is limited due to the existence of blood-brain barrier (BBB). The aim of this study is to develop self-assembled nanoparticles (NPs) of ursolic acid (UA) for GBM treatment. METHODS: UA NPs were synthesized by solvent volatilization method. Western blot analysis fluorescent staining and flow cytometry were launched to explore the anti-glioblastoma mechanism of UA NPs. The antitumor effects of UA NPs were further confirmed in vivo using intracranial xenograft models. RESULTS: UA were successfully prepared. In vitro, UA NPs could significantly increase the protein levels of cleaved-caspase 3 and LC3-II to strongly eliminate glioblastoma cells through autophagy and apoptosis. In the intracranial xenograft models, UA NPs could further effectively enter the BBB, and greatly improve the survival time of the mice. CONCLUSIONS: We successfully synthesized UA NPs which could effectively enter the BBB and show strong anti-tumor effect which may have great potential in the treatment of human glioblastoma.

Fatostatin induces ferroptosis through inhibition of the AKT/mTORC1/GPX4 signaling pathway in glioblastoma.

Glioblastoma multiforme (GBM) is the most common and fatal primary malignant central nervous system tumor in adults. Although there are multiple treatments, the median survival of GBM patients is unsatisfactory, which has prompted us to continuously investigate new therapeutic strategies, including new drugs and drug delivery approaches. Ferroptosis, a kind of regulated cell death (RCD), has been shown to be dysregulated in various tumors, including GBM. Fatostatin, a specific inhibitor of sterol regulatory element binding proteins (SREBPs), is involved in lipid and cholesterol synthesis and has antitumor effects in a variety of tumors. However, the effect of fatostatin has not been explored in the field of ferroptosis or GBM. In our study, through transcriptome sequencing, in vivo experiments, and in vitro experiments, we found that fatostatin induces ferroptosis by inhibiting the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway. We also designed a p28-functionalized PLGA nanoparticle loaded with fatostatin, which could better cross the blood-brain barrier (BBB) and be targeted to GBM. Our research identified the unprecedented effects of fatostatin in GBM and presented a novel drug-targeted delivery vehicle capable of penetrating the BBB in GBM.

TUG1 aggravates intracerebral hemorrhage injury by inhibiting angiogenesis in an miR-26a-dependent manner.

Long non-coding RNA taurine-upregulated gene 1 (TUG1) plays pivotal roles in angiogenesis, an important mechanism of neural repair after intracerebral hemorrhage (ICH). However, the role of TUG1 in angiogenesis following ICH is not clear. Therefore, in this study, we investigated the role and the underlying mechanism of TUG1 in neurologic impairment and cerebral angiogenesis following ICH. The ICH rat model was established and then rats were injected with TUG1-expressing plasmid (pcDNA-TUG1) or miR-26a mimic, a critical regulator of VEGF-mediated angiogenesis. We confirmed the overexpression of TUG1 and miR-26a by qRT-PCR. The neurological deficits of ICH rats were evaluated by modified neurological severity scores. The expression of angiogenesis markers VEGF and CD31 were examined by immunohistochemistry and western blot. The interaction between TUG1 and miR-26a was determined by luciferase reporter assay. Our results showed that ICH caused a marked upregulation of TUG1 and a significant downregulation of miR-26a. TUG1 overexpression led to the deterioration of neurologic function and inhibited cerebral angiogenesis in ICH rats. In contrast, overexpression of miR-26a alleviated the neurologic damage and promoted cerebral angiogenesis in ICH rats, but these could be attenuated by TUG1 overexpression. Furthermore, TUG1 directly bound to miR-26a and inhibited its expression. Importantly, TUG1 overexpression inhibited the expression of VEGF by targeting miR-26a. In conclusion, our results indicated that TUG1 aggravated ICH-mediated injury by suppressing angiogenesis by downregulating miR-26a. This suggests a rationale for targeting TUG1/miR-26a in the therapy of ICH.