Tumor treating fields in glioblastoma: long-term treatment and high compliance as favorable prognostic factors.

Introduction: Tumor treating fields (TTFields) have earned substantial attention in recent years as a novel therapeutic approach with the potential to improve the prognosis of glioblastoma (GBM) patients. However, the impact of TTFields remains a subject of ongoing debate. This study aimed to offer real-world evidence on TTFields therapy for GBM, and to investigate the clinical determinants affecting its efficacy. Methods: We have reported a retrospective analysis of 81 newly diagnosed Chinese GBM patients who received TTFields/Stupp treatment in the Second Affiliated Hospital of Zhejiang University. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier method. Cox regression models with time-dependent covariates were utilized to address non-proportional hazards and to assess the influence of clinical variables on PFS and OS. Results: The median PFS and OS following TTFields/STUPP treatment was 12.6 months (95% CI 11.0-14.1) and 21.3 months (95% CI 10.0-32.6) respectively. Long-term TTFields treatment (>2 months) exhibits significant improvements in PFS and OS compared to the short-term treatment group (≤2 months). Time-dependent covariate COX analysis revealed that longer TTFields treatment was correlated with enhanced PFS and OS for up to 12 and 13 months, respectively. Higher compliance to TTFields (≥ 0.8) significantly reduced the death risk (HR=0.297, 95%CI 0.108-0.819). Complete surgical resection and MGMT promoter methylation were associated with significantly lower risk of progression (HR=0.337, 95% CI 0.176-0.643; HR=0.156, 95% CI 0.065-0.378) and death (HR=0.276, 95% CI 0.105-0.727; HR=0.249, 95% CI 0.087-0.710). Conclusion: The TTFields/Stupp treatment may prolong median OS and PFS in GBM patients, with long-term TTFields treatment, higher TTFields compliance, complete surgical resection, and MGMT promoter methylation significantly improving prognosis.

The Roles of Circular RNAs in Ischemic Stroke through Modulating Neuroinflammation.

Ischemic stroke (IS) remains a serious threat to human health. Neuroinflammatory response is an important pathophysiological process after IS. Circular RNAs (circRNAs), a member of the non-coding RNA family, are highly expressed in the central nervous system and widely involved in regulating physiological and pathophysiological processes. This study reviews the current evidence on neuroinflammatory responses, the role of circRNAs in IS and their potential mechanisms in regulating inflammatory cells, and inflammatory factors affecting IS damage. This review lays a foundation for future clinical application of circRNAs as novel biomarkers and therapeutic targets.

Mechanisms by Which Electroacupuncture Alleviates Neurovascular Unit Injury after Ischemic Stroke: A Potential Therapeutic Strategy for Ischemic Brain Injury after Stroke.

Stroke is the most common cerebrovascular disease and one of the leading causes of death and disability worldwide. The current conventional treatment for stroke involves increasing cerebral blood flow and reducing neuronal damage; however, there are no particularly effective therapeutic strategies for rehabilitation after neuronal damage. Therefore, there is an urgent need to identify a novel alternative therapy for stroke. Acupuncture has been applied in China for 3000 years and has been widely utilized in the treatment of cerebrovascular diseases. Accumulating evidence has revealed that acupuncture holds promise as a potential therapeutic strategy for stroke. In our present review, we focused on elucidating the possible mechanisms of acupuncture in the treatment of ischemic stroke, including nerve regeneration after brain injury, inhibition of inflammation, increased cerebral blood flow, and subsequent rehabilitation.

The L27 Domain of MPP7 enhances TAZ-YY1 Cooperation to Renew Muscle Stem Cells.

Stem cells regenerate differentiated cells to maintain and repair tissues and organs. They also replenish themselves, i.e. self-renewal, for the regenerative process to last a lifetime. How stem cells renew is of critical biological and medical significance. Here we use the skeletal muscle stem cell (MuSC) to study this process. Using a combination of genetic, molecular, and biochemical approaches, we show that MPP7, AMOT, and TAZ/YAP form a complex that activates a common set of target genes. Among these targets, Carm1 can direct MuSC renewal. In the absence of MPP7, TAZ can support regenerative progenitors and activate Carm1 expression, but not to a level needed for self-renewal. Facilitated by the actin polymerization-responsive AMOT, TAZ recruits the L27 domain of MPP7 to up-regulate Carm1 to the level necessary to drive MuSC renewal. The promoter of Carm1, and those of other common downstream genes, also contain binding site(s) for YY1. We further demonstrate that the L27 domain of MPP7 enhances the interaction between TAZ and YY1 to activate Carm1. Our results define a renewal transcriptional program embedded within the progenitor program, by selectively up-regulating key gene(s) within the latter, through the combination of protein interactions and in a manner dependent on the promoter context.

Redox homeostasis dysregulation in noise-induced hearing loss: oxidative stress and antioxidant treatment.

Noise exposure is an important cause of acquired hearing loss. Studies have found that noise exposure causes dysregulated redox homeostasis in cochlear tissue, which has been recognized as a signature feature of hearing loss. Oxidative stress plays a pivotal role in many diseases via very complex and diverse mechanisms and targets. Reactive oxygen species are products of oxidative stress that exert toxic effects on a variety of physiological activities and are considered significant in noise-induced hearing loss (NIHL). Endogenous cellular antioxidants can directly or indirectly counteract oxidative stress and regulate intracellular redox homeostasis, and exogenous antioxidants can complement and enhance this effect. Therefore, antioxidant therapy is considered a promising direction for NIHL treatment. However, drug experiments have been limited to animal models of NIHL, and these experiments and related observations are difficult to translate in humans; therefore, the mechanisms and true effects of these drugs need to be further analyzed. This review outlines the effects of oxidative stress in NIHL and discusses the main mechanisms and strategies of antioxidant treatment for NIHL.

The L27 Domain of MPP7 enhances TAZ-YY1 Cooperation to Renew Muscle Stem Cells.

Stem cells regenerate differentiated cells to maintain and repair tissues and organs. They also replenish themselves, i.e. self-renewal, for the regenerative process to last a lifetime. How stem cells renew is of critical biological and medical significance. Here we use the skeletal muscle stem cell (MuSC) to study this process. Using a combination of genetic, molecular, and biochemical approaches, we show that MPP7, AMOT, and TAZ/YAP form a complex that activates a common set of target genes. Among these targets, Carm1 can direct MuSC renewal. In the absence of MPP7, TAZ can support regenerative progenitors and activate Carm1 expression, but not to a level needed for self-renewal. Facilitated by the actin polymerization-responsive AMOT, TAZ recruits the L27 domain of MPP7 to up-regulate Carm1 to the level necessary to drive MuSC renewal. The promoter of Carm1, and those of other common downstream genes, also contain binding site(s) for YY1. We further demonstrate that the L27 domain of MPP7 enhances the interaction between TAZ and YY1 to activate Carm1. Our results define a renewal transcriptional program embedded within the progenitor program, by selectively up-regulating key gene(s) within the latter, through the combination of protein interactions and in a manner dependent on the promoter context.

Corrigendum: Prognostic models for survival and consciousness in patients with primary brainstem hemorrhage.

[This corrects the article DOI: 10.3389/fneur.2023.1126585.].

Disruption of Dopamine Homeostasis Associated with Alteration of Proteins in Synaptic Vesicles: A Putative Central Mechanism of Parkinson's Disease Pathogenesis.

Vestigial dopaminergic cells in PD have selectivity for a sub-class of hypersensitive neurons with the nigrostriatal dopamine (DA) tract. DA is modulated in pre-synaptic nerve terminals to remain stable. To be specific, proteins at DA release sites that have a function of synthesizing and packing DA in cytoplasm, modulating release and reingestion, and changing excitability of neurons, display regional discrepancies that uncover relevancy of the observed sensitivity to neurodegenerative changes. Although the reasons of a majority of PD cases are still indistinct, heredity and environment are known to us to make significant influences. For decades, genetic analysis of PD patients with heredity in family have promoted our comprehension of pathogenesis to a great extent, which reveals correlative mechanisms including oxidative stress, abnormal protein homeostasis and mitochondrial dysfunction. In this review, we review the constitution of presynaptic vesicle related to DA homeostasis and describe the genetic and environmental evidence of presynaptic dysfunction that increase risky possibility of PD concerning intracellular vesicle transmission and their functional outcomes. We summarize alterations in synaptic vesicular proteins with great involvement in the reasons of some DA neurons highly vulnerable to neurodegenerative changes. We generalize different potential targets and therapeutic strategies for different pathogenic mechanisms, providing a reference for further studies of PD treatment in the future. But it remains to be further researched on this recently discovered and converging mechanism of vesicular dynamics and PD, which will provide a more profound comprehension and put up with new therapeutic tactics for PD patients.

Temporal dynamics of microglia-astrocyte interaction in neuroprotective glial scar formation after intracerebral hemorrhage.

The role of glial scar after intracerebral hemorrhage (ICH) remains unclear. This study aimed to investigate whether microglia-astrocyte interaction affects glial scar formation and explore the specific function of glial scar. We used a pharmacologic approach to induce microglial depletion during different ICH stages and examine how ablating microglia affects astrocytic scar formation. Spatial transcriptomics (ST) analysis was performed to explore the potential ligand-receptor pair in the modulation of microglia-astrocyte interaction and to verify the functional changes of astrocytic scars at different periods. During the early stage, sustained microglial depletion induced disorganized astrocytic scar, enhanced neutrophil infiltration, and impaired tissue repair. ST analysis indicated that microglia-derived insulin like growth factor 1 (IGF1) modulated astrocytic scar formation via mechanistic target of rapamycin (mTOR) signaling activation. Moreover, repopulating microglia (RM) more strongly activated mTOR signaling, facilitating a more protective scar formation. The combination of IGF1 and osteopontin (OPN) was necessary and sufficient for RM function, rather than IGF1 or OPN alone. At the chronic stage of ICH, the overall net effect of astrocytic scar changed from protective to destructive and delayed microglial depletion could partly reverse this. The vital insight gleaned from our data is that sustained microglial depletion may not be a reasonable treatment strategy for early-stage ICH. Inversely, early-stage IGF1/OPN treatment combined with late-stage PLX3397 treatment is a promising therapeutic strategy. This prompts us to consider the complex temporal dynamics and overall net effect of microglia and astrocytes, and develop elaborate treatment strategies at precise time points after ICH.

Microglia Autophagy Mediated by TMEM166 Promotes Ischemic Stroke Secondary to Carotid Artery Stenosis.

Ischemic stroke can be a serious complication of selective carotid endarterectomy (CEA) in patients with carotid artery stenosis (CAS). The underlying risk factors and mechanisms of these postoperative strokes are not completely understood. Our previous study showed that TMEM166-induced neuronal autophagy is involved in the development of secondary brain injury following cerebral ischemia-reperfusion injury in rats. This current study aimed to investigate the role of TMEM166 in ischemic stroke following CEA. In the clinical part of this study, the quantitative analysis demonstrated circulating TMEM166, interleukin 6 (IL-6), and C-reactive protein (CRP) levels were significantly elevated in patients who suffered an ischemic stroke after CEA compared to those who did not. Furthermore, non-survivors exhibited higher levels of these proteins than survivors. In the preclinical part of this study, a middle cerebral artery occlusion (MCAO) model was implemented following CAS simulation in TMEM166-/- mice. We found TMEM166 expression was positively correlated with the degree of ischemic brain injury. Ad5-TMEM166 transfection aggravated ischemic brain injury by inducing microglial autophagy activation and release of inflammatory cytokines. Accordingly, TMEM166 deficiency reduced brain inflammation and inhibited excessive microglial autophagy through the mammalian target of rapamycin (mTOR) pathway. These findings suggest that TMEM166 may play a key role in the development of ischemic injury after CEA and may serve as a biomarker for risk assessment of postoperative ischemic stroke.

Role of Circular RNAs in Atherosclerosis through Regulation of Inflammation, Cell Proliferation, Migration, and Apoptosis: Focus on Atherosclerotic Cerebrovascular Disease.

Atherosclerosis (AS) is a disease dangerous to human health and the main pathological cause of ischemic cardiovascular diseases. Although its pathogenesis is not fully understood, numerous basic and clinical studies have shown that AS is a chronic inflammatory disease existing in all stages of atherogenesis. It may be a common link or pathway in the pathogenesis of multiple atherogenic factors. Inflammation is associated with AS complications, such as plaque rupture and ischemic cerebral infarction. In addition to inflammation, apoptosis plays an important role in AS. Apoptosis is a type of programmed cell death, and different apoptotic cells have different or even opposite roles in the process of AS. Unlike linear RNA, circular RNA (circRNA) a covalently closed circular non-coding RNA, is stable and can sponge miRNA, which can affect the stages of AS by regulating downstream pathways. Ultimately, circRNAs play very important roles in AS by regulating inflammation, apoptosis, and some other mechanisms. The study of circular RNAs can provide new ideas for the prediction, prevention, and treatment of AS.

Regulatory T Cells Secrete IL10 to Suppress Neuroinflammation in Early Stage after Subarachnoid Hemorrhage.

Objective: Accumulating evidence supports neuroprotective effects of regulatory T cells (Tregs) in response to brain injury. However, the precise mechanisms underlying the beneficial effects of Tregs on suppressing neuroinflammation after subarachnoid hemorrhage (SAH) remain unclear. Methods: We performed flow cytometry to detect the infiltration of Tregs into the brain at different time points after SAH. Behavioral tests, including Adhesive and Rotarod, were performed to assess neurological deficits in mice after SAH. Bulk RNA sequencing was used to investigate the transcriptomic change of Tregs infiltrating into the brain after SAH. qPCR was performed to verify the variation of inflammatory cytokines expression in the brain after Tregs exogenous infusion. FoxP3-DTR mice and Il10 gene KO mice were used to explore the mechanism of Tregs inhibiting neuron apoptosis after infiltrating the brain following SAH onset. Results: Peripheral Tregs infiltrated into the brain one day after SAH and gradually accumulated in the hemorrhagic hemisphere. An exogenous infusion of Tregs significantly improved the neurological function of mice after SAH, while poor recovery of neurological function was observed in Tregs depletion mice. Transcriptome sequencing data suggested that the immunosuppressive function of brain-infiltrated Tregs was significantly upregulated. qPCR showed that the expression of pro-inflammatory cytokines decreased in the brain of SAH mice after exogenous Tregs infusion. Bioinformatic analysis revealed that IL-10 and other cytokines secreted by brain-infiltrated Tregs were upregulated after SAH. Moreover, exogenous infusion of Il10 gene KO Tregs did not totally improve neurological function in SAH mice. Conclusions: Tregs infiltrated into the brain in the early stage after SAH and exerted neuroprotective effect by secreting IL-10 to suppress neuroinflammation and reduce neuron apoptosis.

Oxidative stress in pituitary neuroendocrine tumors: Affecting the tumor microenvironment and becoming a new target for pituitary neuroendocrine tumor therapy.

Pituitary adenomas (PAs), or pituitary neuroendocrine tumors (PitNETs), are commonly found in the anterior pituitary gland. Although the majority of PitNETs are benign and stable, several tumors have malignant characteristics. The tumor microenvironment (TME) plays an important role in the process of tumorigenesis and is composed of several types of cells. Various cells in the TME are significantly affected by oxidative stress. It has been reported that immunotherapeutic strategies have good effects in several cancers. However, the clinical potential of immunotherapies in PitNETs has not yet been fully discussed. Oxidative stress can regulate PitNET cells and immune cells in the TME, thus affecting the immune status of the TME of PitNETs. Therefore, modulation of oxidative stress-regulated immune cells using a combination of several agents and the immune system to suppress PitNETs is a promising therapeutic direction. In this review, we systematically analyzed the oxidative stress process within PitNET cells and various immune cells to elucidate the potential value of immunotherapy.

Clinical Potential of Immunotherapies in Subarachnoid Hemorrhage Treatment: Mechanistic Dissection of Innate and Adaptive Immune Responses.

Subarachnoid hemorrhage (SAH), classified as a medical emergency, is a devastating and severe subtype of stroke. SAH induces an immune response, which further triggers brain injury; however, the underlying mechanisms need to be further elucidated. The current research is predominantly focused on the production of specific subtypes of immune cells, especially innate immune cells, post-SAH onset. Increasing evidence suggests the critical role of immune responses in SAH pathophysiology; however, studies on the role and clinical significance of adaptive immunity post-SAH are limited. In this present study, we briefly review the mechanistic dissection of innate and adaptive immune responses post-SAH. Additionally, we summarized the experimental studies and clinical trials of immunotherapies for SAH treatment, which may form the basis for the development of improved therapeutic approaches for the clinical management of SAH in the future.

URB2 as an important marker for glioma prognosis and immunotherapy.

Introduction: Glioma is the most common primary brain tumor and primary malignant tumor of the brain in clinical practice. Conventional treatment has not significantly altered the prognosis of patients with glioma. As research into immunotherapy continues, glioma immunotherapy has shown great potential. Methods: The clinical data were acquired from the Chinese Glioma Genome Atlas (CGGA) database and validated by the Gene Expression Omnibus (GEO) database, The Cancer Genome Atlas (TCGA) dataset, Clinical Proteomic Tumor Analysis Consortium (CPTAP) database, and Western blot (WB) analysis. By Cox regression analyses, we examined the association between different variables and overall survival (OS) and its potential as an independent prognostic factor. By constructing a nomogram that incorporates both clinicopathological variables and the expression of URB2, we provide a model for the prediction of prognosis. Moreover, we explored the relationship between immunity and URB2 and elucidated its underlying mechanism of action. Results: Our study shows that URB2 likely plays an oncogenic role in glioma and confirms that URB2 is a prognostic independent risk factor for glioma. Furthermore, we revealed a close relationship between immunity and URB2, which suggests a new approach for the immunotherapy of glioma. Conclusion: URB2 can be used for prognosis prediction and immunotherapy of glioma.

Prognostic models for survival and consciousness in patients with primary brainstem hemorrhage.

Objectives: Primary brainstem hemorrhage (PBSH) is one of the most catastrophic spontaneous intracerebral hemorrhage diseases, with a mortality rate of 70-80%. We explored the predictive factors for survival and consciousness in patients with PBSH (ClinicalTrials.gov ID: NCT04910490). Methods: We retrospectively reviewed 211 patients with PBSH admitted to our institution between January 2014 and October 2020. Clinical outcomes included the 30-day survival rate and the 90-day consciousness rate as evaluated by the National Institutes of Health Stroke Scale score. Multiple logistic regression analysis was performed. Results: The overall 30-day survival rate of 211 patients with PBSH was 70%. Several predictive factors including hematoma volume, hematoma location, activated partial thromboplastin time (APTT) upon admission, and therapeutic strategy were significantly related to 30-day survival. Compared with conservative treatment, stereotactic aspiration in our prediction model is strongly associated with improved 30-day survival (odds ratio, 6.67; 95% confidence interval, 3.13-14.29; P < 0.001). The prognosis prediction model of 90-day consciousness including factors such as mydriasis, APTT value, hematoma location, and hematoma volume upon admission has a good predictive effect (AUC, 0.835; 95% confidence interval, 0.78-0.89; P < 0.001). Conclusion: In patients with PBSH, conscious state upon admission, coagulation function, hematoma volume, hematoma location, and therapeutic strategy were significantly associated with prognosis. Stereotactic aspiration could significantly reduce the 30-day mortality rate.