MicroRNA-451 Regulates Angiogenesis in Intracerebral Hemorrhage by Targeting Macrophage Migration Inhibitory Factor.

Intracerebral hemorrhage (ICH) is a subtype of stroke with the highest fatality and disability rate. Up to now, commonly used first-line therapies have limited value in improving prognosis. Angiogenesis is essential to neurological recovery after ICH. Recent studies have shown that microRNA-451(miR-451) plays an important role in angiogenesis by regulating the function of vascular endothelial cells. We found miR-451 was significantly decreased in the peripheral blood of ICH patients in the acute stage. Based on the clinical findings, we conducted this study to investigate the potential regulatory effect of miR-451 on angiogenesis after ICH. The expression of miR-451 in ICH mouse model and in a hemin toxicity model of human brain microvascular endothelial cells (hBMECs) was decreased the same as in ICH patients. MiR-451 negatively regulated the proliferation, migration, and tube formation of hBMECs in vitro. MiR-451 negatively regulated the microvessel density in the perihematoma tissue and affected neural functional recovery of ICH mouse model. Knockdown of miR-451 could recovered tight junction and protect the integrity of blood-brain barrier after ICH. Based on bioinformatic programs, macrophage migration inhibitory factor (MIF) was predicted to be the target gene and identified to be regulated by miR-451 inhibiting the protein translation. And p-AKT and p-ERK were verified to be downstream of MIF in angiogenesis. These results all suggest that miR-451 will be a potential target for regulating angiogenesis in ICH.

Reversal and resumption of anticoagulants in patients with anticoagulant-associated intracerebral hemorrhage.

The use of anticoagulants has become more frequent due to the progressive aging population and increased thromboembolic events. Consequently, the proportion of anticoagulant-associated intracerebral hemorrhage (AAICH) in stroke patients is gradually increasing. Compared with intracerebral hemorrhage (ICH) patients without coagulopathy, patients with AAICH may have larger hematomas, worse prognoses, and higher mortality. Given the need for anticoagulant reversal and resumption, the management of AAICH differs from that of conventional medical or surgical treatments for ICH, and it is more specific. Understanding the pharmacology of anticoagulants and identifying agents that can reverse their effects in the early stages are crucial for treating life-threatening AAICH. When patients transition beyond the acute phase and their vital signs stabilize, it is important to consider resuming anticoagulants at the right time to prevent the occurrence of further thromboembolism. However, the timing and strategy for reversing and resuming anticoagulants are still in a dilemma. Herein, we summarize the important clinical studies, reviews, and related guidelines published in the past few years that focus on the reversal and resumption of anticoagulants in AAICH patients to help implement decisive diagnosis and treatment strategies in the clinical setting.

Evolving Therapeutic Landscape of Intracerebral Hemorrhage: Emerging Cutting-Edge Advancements in Surgical Robots, Regenerative Medicine, and Neurorehabilitation Techniques.

Intracerebral hemorrhage (ICH) is the most serious form of stroke and has limited available therapeutic options. As knowledge on ICH rapidly develops, cutting-edge techniques in the fields of surgical robots, regenerative medicine, and neurorehabilitation may revolutionize ICH treatment. However, these new advances still must be translated into clinical practice. In this review, we examined several emerging therapeutic strategies and their major challenges in managing ICH, with a particular focus on innovative therapies involving robot-assisted minimally invasive surgery, stem cell transplantation, in situ neuronal reprogramming, and brain-computer interfaces. Despite the limited expansion of the drug armamentarium for ICH over the past few decades, the judicious selection of more efficacious therapeutic modalities and the exploration of multimodal combination therapies represent opportunities to improve patient prognoses after ICH.

The Role of ICP Monitoring in Minimally Invasive Surgery for the Management of Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is the second major stroke type, with high incidence, high disability rate, and high mortality. At present, there is no effective and reliable treatment for ICH. As a result, most patients have a poor prognosis. Minimally invasive surgery (MIS) is the fastest treatment method to remove hematoma, which is characterized by less trauma and easy operation. Some studies have confirmed the safety of MIS, but there are still no reports showing that it can significantly improve the functional outcome of ICH patients. Intracranial pressure (ICP) monitoring is considered to be an important part of successful treatment in traumatic brain diseases. By monitoring ICP in real time, keeping stable ICP could help patients with craniocerebral injury get a good prognosis. In the course of MIS treatment of ICH patients, keeping ICP stable may also promote patient recovery. In this review, we will take ICP monitoring as the starting point for an in-depth discussion.

The Emerging Role of Microglial Hv1 as a Target for Immunomodulation in Myelin Repair.

In the central nervous system (CNS), the myelin sheath ensures efficient interconnection between neurons and contributes to the regulation of the proper function of neuronal networks. The maintenance of myelin and the well-organized subtle process of myelin plasticity requires cooperation among myelin-forming cells, glial cells, and neural networks. The process of cooperation is fragile, and the balance is highly susceptible to disruption by microenvironment influences. Reactive microglia play a critical and complicated role in the demyelination and remyelination process. Recent studies have shown that the voltage-gated proton channel Hv1 is selectively expressed in microglia in CNS, which regulates intracellular pH and is involved in the production of reactive oxygen species, underlying multifaceted roles in maintaining microglia function. This paper begins by examining the molecular mechanisms of demyelination and emphasizes the crucial role of the microenvironment in demyelination. It focuses specifically on the role of Hv1 in myelin repair and its therapeutic potential in CNS demyelinating diseases.

Surgical Robotics for Intracerebral Hemorrhage Treatment: State of the Art and Future Directions.

Intracerebral hemorrhage (ICH) is a stroke subtype with high mortality and disability, and there are no proven medical treatments that can improve the functional outcome of ICH patients. Robot-assisted neurosurgery is a significant advancement in the development of minimally invasive surgery for ICH. This review encompasses the latest advances and future directions of surgical robots for ICH. First, three robotic systems for neurosurgery applied to ICH are illustrated. Second, the key technologies of robot-assisted surgery for ICH are introduced in aspects of stereotactic technique and navigation, the puncture instrument, and hematoma evacuation. Finally, the limitations of current surgical robots are summarized, and the possible development direction is discussed, which is named "multisensor fusion and intelligent aspiration control of minimally invasive surgical robot for ICH". It is expected that the new generation of surgical robots for ICH will facilitate quantitative, precise, individualized, standardized treatment strategies for ICH.

Directional induction of neural stem cells, a new therapy for neurodegenerative diseases and ischemic stroke.

Due to the limited capacity of the adult mammalian brain to self-repair and regenerate, neurological diseases, especially neurodegenerative disorders and stroke, characterized by irreversible cellular damage are often considered as refractory diseases. Neural stem cells (NSCs) play a unique role in the treatment of neurological diseases for their abilities to self-renew and form different neural lineage cells, such as neurons and glial cells. With the increasing understanding of neurodevelopment and advances in stem cell technology, NSCs can be obtained from different sources and directed to differentiate into a specific neural lineage cell phenotype purposefully, making it possible to replace specific cells lost in some neurological diseases, which provides new approaches to treat neurodegenerative diseases as well as stroke. In this review, we outline the advances in generating several neuronal lineage subtypes from different sources of NSCs. We further summarize the therapeutic effects and possible therapeutic mechanisms of these fated specific NSCs in neurological disease models, with special emphasis on Parkinson's disease and ischemic stroke. Finally, from the perspective of clinical translation, we compare the strengths and weaknesses of different sources of NSCs and different methods of directed differentiation, and propose future research directions for directed differentiation of NSCs in regenerative medicine.

Effects of Dl-3-n-butylphthalide on cognitive functions and blood-brain barrier in chronic cerebral hypoperfusion rats.

Vascular cognitive impairment (VCI) has been one of the major types of cognitive impairment. Blood-brain barrier damage plays an essential part in the pathogenesis of VCI. At present, the treatment of VCI is mainly focused on prevention, with no drug clinically approved for the treatment of VCI. This study aimed to investigate the effects of DL-3-n-butylphthalide (NBP) on VCI rats. A modified bilateral common carotid artery occlusion (mBCCAO) model was applied to mimic VCI. The feasibility of the mBCCAO model was verified by laser Doppler, 13N-Ammonia-Positron Emission Computed Tomography (PET), and Morris Water Maze. Subsequently, the Morris water maze experiment, Evans blue staining, and western blot of tight junction protein were performed to evaluate the effect of different doses of NBP (40 mg/kg, 80 mg/kg) on the improvement of cognitive impairment and BBB disruption induced by mBCCAO. Immunofluorescence was employed to examine the changes in pericyte coverage in the mBCCAO model and the effect of NBP on pericyte coverage was preliminarily explored. mBCCAO surgery led to obvious cognitive impairment and the decrease of whole cerebral blood flow, among which the blood flow in the cortex, hippocampus and thalamus brain regions decreased more significantly. High-dose NBP (80 mg/kg) improved long-term cognitive function in mBCCAO rats, alleviated Evans blue leakage and reduced the loss of tight junction proteins (ZO-1, Claudin-5) in the early course of the disease, thereby exerting a protective effect on the blood-brain barrier. No significant changes in pericyte coverage were observed after mBCCAO. High-dose NBP improved cognitive function in mBCCAO rats. High-dose NBP protected the integrity of BBB by upregulating TJ protein expression, rather than regulating pericyte coverage ratio. NBP could be a potential drug for the treatment of VCI.

Dihydromyricetin attenuates intracerebral hemorrhage by reversing the effect of LCN2 via the system Xc- pathway.

BACKGROUND: The limited understanding of the pathological mechanisms of intracerebral hemorrhage (ICH) and the absence of successful therapies lead to poor prognoses for patients with ICH. Dihydromyricetin (DMY) has many physiological functions, such as regulating lipid and glucose metabolism and modulating tumorigenesis. Moreover, DMY has been proven to be an effective treatment of neuroprotection. However, no reports to date have been made regarding the impact of DMY on ICH. PURPOSE: This investigation aimed to identify the role of DMY on ICH in mice and the underlying mechanisms. METHODS/RESULTS: This study demonstrated that DMY treatment effectively reduced hematoma size and cell apoptosis of brain tissue, and improved neurobehavioral outcomes in mice with ICH. Transcriptional and network pharmacological analyses revealed that lipocalin-2 (LCN2) was a potential target of DMY in ICH. After ICH, LCN2 mRNA and protein expression in brain tissue increased and DMY could inhibit the expression of LCN2. The rescue experiment with the implementation of LCN2 overexpression verified these observations. Furthermore, after DMY treatment, there was a significant decrease in cyclooxygenase 2 (COX2), phospho-extracellular regulated protein kinase (P-ERK), iron deposition, and the number of abnormal mitochondria, which were reversed by the overexpression of LCN2. Proteomics analysis suggests that SLC3A2 may be the downstream target of LCN2, promoting ferroptosis. Finally, LCN2 was shown to bind to SLC3A2 and regulate the downstream glutathione (GSH) synthesis and Glutathione Peroxidase 4 (GPX4) expression and glutathione (GSH) synthesis, as determined by molecular docking and co-immunoprecipitation analysis. CONCLUSION: Our study confirmed for the first time that DMY might offer a favorable treatment for ICH through its action on LCN2. The possible mechanism for this could be that DMY reverses the inhibitory effect of LCN2 on the system Xc-, lessening ferroptosis in brain tissue. The findings of this study offer a greater understanding of how DMY affects ICH at a molecular level and could be conducive to developing therapeutic targets for ICH.

From static to dynamic: live observation of the support system after ischemic stroke by two photon-excited fluorescence laser-scanning microscopy.

Ischemic stroke is one of the most common causes of mortality and disability worldwide. However, treatment efficacy and the progress of research remain unsatisfactory. As the critical support system and essential components in neurovascular units, glial cells and blood vessels (including the blood-brain barrier) together maintain an optimal microenvironment for neuronal function. They provide nutrients, regulate neuronal excitability, and prevent harmful substances from entering brain tissue. The highly dynamic networks of this support system play an essential role in ischemic stroke through processes including brain homeostasis, supporting neuronal function, and reacting to injuries. However, most studies have focused on postmortem animals, which inevitably lack critical information about the dynamic changes that occur after ischemic stroke. Therefore, a high-precision technique for research in living animals is urgently needed. Two-photon fluorescence laser-scanning microscopy is a powerful imaging technique that can facilitate live imaging at high spatiotemporal resolutions. Two-photon fluorescence laser-scanning microscopy can provide images of the whole-cortex vascular 3D structure, information on multicellular component interactions, and provide images of structure and function in the cranial window. This technique shifts the existing research paradigm from static to dynamic, from flat to stereoscopic, and from single-cell function to multicellular intercommunication, thus providing direct and reliable evidence to identify the pathophysiological mechanisms following ischemic stroke in an intact brain. In this review, we discuss exciting findings from research on the support system after ischemic stroke using two-photon fluorescence laser-scanning microscopy, highlighting the importance of dynamic observations of cellular behavior and interactions in the networks of the brain's support systems. We show the excellent application prospects and advantages of two-photon fluorescence laser-scanning microscopy and predict future research developments and directions in the study of ischemic stroke.

A Nomogram Model for Predicting Prognosis in Spontaneous Intracerebral Hemorrhage Patients.

OBJECTIVES: Intracranial hemorrhage is the second most common stroke subtype following ischemic stroke and usually induces high mortality and disability. Here, we conducted a retrospective study to establish a nomogram clinical prediction model. METHODS: First, the baseline data of patients who presented to our hospital in 2015-2021 were collected and compared (789 patients for the training cohort and 378 patients for the validation cohort). Second, univariate and binary logistic analyses were performed to screen out alternative indicators. Finally, a clinical prediction model by nomogram was established that included such indicators to estimate the prognosis of intracranial hemorrhage patients. RESULTS: Univariate logistic analysis was used to screen several possible impact factors, including hypertension, hematoma volume, Glasgow Coma Scale (GCS) score, intracranial hemorrhage (ICH) score, irregular shape, uneven density, intraventricular hemorrhage (IVH) relation, fibrinogen, D-dimer, low density lipoprotein (LDL), high-density lipoprotein (HDL), creatinine, total protein, hemoglobin (HB), white blood cell (WBC), neutrophil blood cell (NBC), lymphocyte blood cell (LBC), the neutrophil lymphocyte ratio (NLR), surgery, deep venous thrombosis (DVT) or pulmonary embolism (PE) rate, hospital day, and hypertension control. Further binary logistic analysis revealed that ICH score (p = 0.036), GCS score (p = 0.000), irregular shape (p = 0.000), uneven density (p = 0.002), IVH relation (p = 0.014), surgery (p = 0.000) were independent indicators to construct a nomogram clinical prediction model. The C statistic was 0.840. CONCLUSIONS: ICH score, GCS score, irregular shape, uneven density, IVH relation, surgery are easily available indicators to assist neurologists in formulating the most appropriate therapy for every intracranial hemorrhage patient. Further large prospective clinical trials are needed to obtain more integrated and reliable conclusions.

Effect of antiplatelet therapy on the incidence, prognosis, and rebleeding of intracerebral hemorrhage.

OBJECTIVE: Antiplatelet medications are increasingly being used for primary and secondary prevention of ischemic attacks owing to the increasing prevalence of ischemic stroke occurrences. Currently, many patients receive antiplatelet therapy (APT) to prevent thromboembolic events. However, long-term use of APT might also lead to an increased occurrence of intracerebral hemorrhage (ICH) and affect the prognosis of patients with ICH. Furthermore, some research suggest that restarting APT for patients who have previously experienced ICH may result in rebleeding events. The precise relationship between APT and ICH remains unknown. METHODS: We searched PubMed for the most recent related literature and summarized the findings from various studies. The search terms included "antiplatelet," "intracerebral hemorrhage," "cerebral microbleeds," "hematoma expansion," "recurrent," and "reinitiate." Clinical studies involving human subjects were ultimately included and interpreted in this review, and animal studies were not discussed. RESULTS: When individuals are administered APT, the risk of thrombotic events should be weighted against the risk of bleeding. In general, for some patients' concomitant with risk factors of thrombotic events, the advantages of antiplatelet medication may outweigh the inherent risk of rebleeding. However, the use of antiplatelet medications for other patients with a higher risk of bleeding should be carefully evaluated and closely monitored. In the future, a quantifiable system for assessing thrombotic risk and bleeding risk will be necessary. After evaluation, the appropriate time to restart APT for ICH patients should be determined to prevent underlying ischemic stroke events. According to the present study results and expert experience, most patients now restart APT at around 1 week following the onset of ICH. Nevertheless, the precise time to restart APT should be chosen on a case-by-case basis as per the patient's risk of embolic events and recurrent bleeding. More compelling evidence-based medicine evidence is needed in the future. CONCLUSION: This review thoroughly discusses the relationship between APT and the development of ICH, the impact of APT on the course and prognosis of ICH patients, and the factors influencing the decision to restart APT after ICH. However, different studies' conclusions are inconsistent due to the differences in quality control. To support future clinical decisions, more large-scale randomized controlled trials are required.

Homocysteine impedes neurite outgrowth recovery after intracerebral haemorrhage by downregulating pCAMK2A.

Hyperhomocysteinemia (HHcy) is independently associated with poorer long-term prognosis in patients with intracerebral haemorrhage (ICH); however, the effect and mechanisms of HHcy on ICH are still unclear. Here, we evaluated neurite outgrowth and neurological functional recovery using simulated models of ICH with HHcy in vitro and in vivo. We found that the neurite outgrowth velocity and motor functional recovery in the ICH plus HHcy group were significantly slower than that in the control group, indicating that homocysteine (Hcy) significantly impedes the neurite outgrowth recovery after ICH. Furthermore, phosphoproteomic data and signalome analysis of perihematomal brain tissues suggested that calmodulin-dependent protein kinases 2 (CAMK2A) kinase substrate pairs were significantly downregulated in ICH with HHcy compared with autologous blood injection only, both western blot and immunofluorescence staining confirmed this finding. Additionally, upregulation of pCAMK2A significantly increased neurite outgrowth recovery in ICH with HHcy. Collectively, we clarify the mechanism of HHcy-hindered neurite outgrowth recovery, and pCAMK2A may serve as a therapeutic strategy for promoting neurological recovery after ICH.

Two-photon microscopy: application advantages and latest progress for in vivo imaging of neurons and blood vessels after ischemic stroke.

Two-photon microscopy (TPM) plays an important role in the study of the changes of the two important components of neurovascular units (NVU) - neurons and blood vessels after ischemic stroke (IS). IS refers to sudden neurological dysfunction caused by focal cerebral ischemia, which is one of the leading causes of death and disability worldwide. TPM is a new and rapidly developing high-resolution real-time imaging technique used in vivo that has attracted increasing attention from scientists in the neuroscience field. Neurons and blood vessels are important components of neurovascular units, and they undergo great changes after IS to respond to and compensate for ischemic injury. Here, we introduce the characteristics and pre-imaging preparations of TPM, and review the common methods and latest progress of TPM in the neuronal and vascular research for injury and recovery of IS in recent years. With the review, we clearly recognized that the most important advantage of TPM in the study of ischemic stroke is the ability to perform chronic longitudinal imaging of different tissues at a high resolution in vivo. Finally, we discuss the limitations of TPM and the technological advances in recent years.

Network and experimental pharmacology on mechanism of Si-Wu-tang improving ovarian function in a mouse model of premature ovarian failure induced by cyclophosphamide.

ETHNOPHARMACOLOGICAL RELEVANCE: Si-Wu-Tang (SWT) has become a common basic prescription for supplementing blood and regulating menstruation, and enjoys the reputation of "the first prescription in gynecology". It is often reported in the treatment of premature ovarian failure (POF). However, knowledge of its specific mechanism is still limited. AIM OF THE STUDY: This study aimed to identify the potential effects and underlying mechanisms of SWT on POF. MATERIALS AND METHODS: After confirming the therapeutic effect of SWT on POF mice induced by cyclophosphamide, we further clarified the promoting effect of SWT on ovarian follicle development by detecting the expression of key factors related to follicle development in the ovary in different ways.Then, network pharmacology and gene expression profiling of POF from the GEO database were used to clarify the underlying mechanisms. Molecular biology and molecular docking analysis were applied for final mechanism verification. RESULTS: Our results showed that SWT increased body weight, ovarian index, reversed disordered serum hormone levels, and menstrual cycle in POF mice. After SWT treatment, the number of follicles at all levels in mice with POF also recovered. Using molecular biology techniques, it was proven that SWT can improve follicle development and angiogenesis in the microenvironment. The network pharmacology and gene expression profiling from the GEO database indicated that the PI3K/Akt signaling pathway may be the reason why SWT improves ovarian function in mice with POF. Subsequently, further Western blot and immunoprecipitation indicated that SWT indeed inhibited the PI3K/Akt signaling pathway in mice with POF. In addition, this conclusion was further confirmed by molecular docking experiments. CONCLUSIONS: SWT can improve ovarian function in POF mice induced by cyclophosphamide, and its mechanism is related to the inhibition of the PI3K/Akt signaling pathway.

Comparative study on acute management of intracerebral haematoma using local thrombolysis in moyamoya and non-moyamoya patients: a single institution experience.

PURPOSE: Spontaneous intracerebral haemorrhage (ICH) is the main presentation in adults with moyamoya disease (MMD), an unusual clinical entity with a poor prognosis. However, optimal management in the acute stage of ICH in patients with MMD remains a challenge. Since minimally invasive surgery (MIS) plus local thrombolysis has emerged as a promising strategy for ICH, we aimed to describe our experience of performing this procedure in this special population in the acute phase, while focusing on its efficacy and safety. MATERIALS AND METHODS: The medical data of patients with ICH treated with MIS and local thrombolysis between November 2013 and December 2017 were retrospectively reviewed at our institution. MMD was identified based on the angiographic images. The primary outcome was postoperative intracranial rebleeding. The secondary outcomes were 30-day mortality and 6-month outcome graded using the modified Rankin scale (mRS). Logistic regression was applied to explore independent risk factors for the above outcomes. RESULTS: A cohort of consecutive 337 ICH patients was analysed, of whom 14 (4.15%) were diagnosed with MMD. In total, 36 (11.46%) patients experienced postoperative intracranial rehaemorrhage, of which one patient had MMD. No significant difference was found between the patients with and without MMD regarding postoperative rebleeding (9.09% vs. 11.55%, p = 1.000). Additionally, the 30-day mortality of patients with MMD was 21.42% (3/14), which was not significantly different from that of non-MMD patients (10.83%; p = 0.201). Moreover, 53.8% of patients had poor outcomes at the 6-month follow-up among MMD patients, similar to 43.9% of patients without MMD (p = 0.573). The coexistence of MMD failed to show a significant association with postoperative intracranial rebleeding (p = 0.348), 30-day mortality (p = 0.211), or poor outcome at the 6-month follow-up (p = 0.450). CONCLUSION: Our findings suggest that coexistent MMD is not associated with an increased risk of postoperative rebleeding or poor outcome after local thrombolysis for ICH.

Piezo1 Mediates Inflammation in Balloon-inflated Rat Brain and its Bidirectional Mechanosensitivity.

BACKGROUND: Brain injury after intracerebral hemorrhage is extremely complicated, and the exact mechanism remains puzzling. Piezo1, a novel mammalian mechanosensitive ion channel, has been identified to play important roles in several pathologic and physiologic procedures that involve cellular mechanotransduction. However, the role of Piezo1 in hematoma compression after intracerebral hemorrhage is still unclear. MATERIALS AND METHODS: In the present study, we established a balloon-inflated brain model based on an adult male rat mimicking the pure mechanical compression of a hematoma. Then the behavioral assessment (Garcia Scale) was taken to observe the syndrome after "hematoma". Western blotting and immunofluorescence were applied to detect Piezo1 expression around lesions in rat brains. ELISA was used for quantitative analysis of inflammation factors. A statistical significance was confirmed as P value<0.05. RESULTS: Balloon compression lesions were detected in the basal ganglia region of the brain, resulting in abnormal behaviors and a significant increase in the expression of Piezo1 and proinflammatory cytokines. GsMTx4, an antagonist of Piezo1, reversed these effects. Additionally, the balloon deflation time affected behavioral function and the levels of Piezo1 and proinflammatory cytokines. CONCLUSION: These results establish the first in vivo evidence for the role of Piezo1 in blood-brain neuroinflammation after hematoma compression. Piezo1 showed "bidirectional mechanosensitivity" and therefore is a potential therapeutic target for the treatment of intracerebral hemorrhage.

Integrative genomic analysis facilitates precision strategies for glioblastoma treatment.

Glioblastoma (GBM) is the most common form of malignant primary brain tumor with a dismal prognosis. Currently, the standard treatments for GBM rarely achieve satisfactory results, which means that current treatments are not individualized and precise enough. In this study, a multiomics-based GBM classification was established and three subclasses (GPA, GPB, and GPC) were identified, which have different molecular features both in bulk samples and at single-cell resolution. A robust GBM poor prognostic signature (GPS) score model was then developed using machine learning method, manifesting an excellent ability to predict the survival of GBM. NVP-BEZ235, GDC-0980, dasatinib and XL765 were ultimately identified to have subclass-specific efficacy targeting patients with a high risk of poor prognosis. Furthermore, the GBM classification and GPS score model could be considered as potential biomarkers for immunotherapy response. In summary, an integrative genomic analysis was conducted to advance individual-based therapies in GBM.