Kankai Wang

Glioblastoma (GBM) remains difficult to control. Monoclonal antibodies (mAbs) have transformed the treatment of several extracranial cancers, but they have not consistently improved survival in GBM. This narrative review examines the main biological and translational barriers to antibody-based therapy. It also evaluates strategies to overcome them. We reviewed preclinical, translational, and clinical evidence on antibody delivery, target stability, the tumor microenvironment, target discovery, and emerging antibody formats. Heterogeneous blood–brain and blood–tumor barriers produce uneven intratumoral exposure, especially at infiltrative margins. Spatial and temporal heterogeneity promotes antigen loss and treatment escape. Lymphocyte dysfunction, myeloid dominance, and suppressive vascular and metabolic programs further limit immune activity. Receptor-mediated transcytosis and focused ultrasound may improve delivery. Single-cell and spatial profiling, surfaceome and endocytome proteomics, longitudinal sampling, and causal inference may improve target selection. Depending on their design, antibody–drug conjugates (ADCs) can deliver cytotoxic payloads, whereas bispecific constructs can enable immune redirection, dual-target recognition, or receptor-mediated transport. However, clinical benefit remains limited by construct design, target accessibility, regional exposure, toxicity, and inadequate biomarker selection. Successful translation requires modality-specific alignment of exposure at the relevant site of action, target requirements, immune dependence, molecular design, and safety. Biomarker-guided patient selection, spatial pharmacokinetic and pharmacodynamic validation, and early evidence of clinical benefit are also essential.

Intracerebral hemorrhage (ICH) is associated with substantial morbidity and mortality, and early hematoma expansion (HE), defined as an increase in hematoma volume on follow-up imaging, is a major determinant of early neurological deterioration and poor outcomes. Accurate, hyperacute prediction of HE is critical for guiding precise interventions, such as intensive blood pressure management and surgical evacuation. This narrative review examines the progression of prediction models from univariate predictors to systems incorporating artificial intelligence (AI), with particular attention to risk factors, model validation, and clinical translation. We further examine the validation status of current prediction models and the methodological and practical barriers to their clinical implementation. We review the progression from established independent predictors, such as the CT angiography (CTA) spot sign (SpS) and non-contrast CT (NCCT) island sign (IS), to multivariable clinical scoring systems, radiomics-based machine learning (ML) approaches, and deep learning (DL) models, while also discussing emerging generative architectures. Furthermore, major clinical trials evaluating strategies to limit HE are reviewed. Finally, the current challenges and future prospects of predictive models of HE are also elucidated.

Neurological diseases, often caused by irreversible loss of terminally differentiated neurons, present considerable challenges to treatment due to the limited regenerative capacity of these neurons. Although induced pluripotent stem cells hold promise for neuronal regeneration, their clinical application is constrained by risks, including tumorigenicity, incomplete neuronal maturation, and immune rejection. Recent advancements in direct neuronal reprogramming, which bypasses the intermediate pluripotent stage by directly converting non-neuronal cells into functional neurons, offer a compelling alternative for in situ neuronal replacement in neurodegenerative diseases. Key transcription factors, such as NeuroD1, Ascl1, Sox2, as well as CRISPR activation (CRISPRa) of NGN2 and ISL1, have been explored to convert glial cells into neurons. However, several challenges remain. This review discusses the current applications of direct neuronal reprogramming technology in several neurological diseases. We further highlight the potential contamination issues in adeno-associated virus (AAV) delivery systems and propose a code of conduct to avoid artifacts and pitfalls. Finally, we point out future directions for expanding direct reprogramming targets, integrating organoid-based disease modeling, and advancing reprogramming regulation techniques.

Glioblastoma (GBM) is the most common type of primary malignant brain tumor, characterized by a poor prognosis, high recurrence rate, and elevated mortality. In recent years, gene-targeted therapies leveraging small molecule compounds have gained momentum as a promising avenue for GBM intervention. Myoferlin (MYOF), a type II membrane protein of the Ferlin family, has emerged as a key regulator of membrane dynamics—governing processes such as vesicular trafficking, endocytosis, and membrane repair. In this study, we explore the previously uncharted role of MYOF in GBM progression and its potential as a diagnostic and therapeutic target. Our data reveal that silencing MYOF markedly suppresses glioma growth both in vitro and in vivo. Mechanistically, MYOF knockdown disrupts the nuclear translocation of phosphorylated STAT3 (P-STAT3), a critical oncogenic signaling event. Notably, we identified Entacapone (ENT), a small molecule capable of targeting MYOF, which significantly impedes glioma development across experimental models. These findings position MYOF as a novel molecular lever in GBM pathogenesis and highlight ENT as a potential therapeutic agent that exerts anti-glioma effects by blocking MYOF-mediated P-STAT3 nuclear import.

The central nervous system (CNS) maintains homeostasis and immune surveillance through a recently defined brain‐wide clearance network: the glymphatic–lymphatic axis. This system couples the intramural glymphatic pathway, responsible for convective fluid transport and parenchymal waste removal, with the meningeal lymphatic vessels (MLVs), which serve as the critical efferent route to the peripheral immune system. This review delineates the structural and functional foundations of each component, their regulatory dynamics, including the roles of sleep and aging, and their synergistic interplay in maintaining fluid balance, clearing metabolic waste, and facilitating neuroimmune communication. Mounting evidence identifies the dysfunction of this integrated axis as a common pathological mechanism across a spectrum of neurological disorders. We highlight its pivotal role in three key paradigms: acute injury (stroke), chronic proteinopathy (Alzheimer's disease, AD), and autoimmune dysregulation (multiple sclerosis, MS), where impaired clearance and maladaptive immune responses are central, recurring themes. The review critically evaluates emerging translational strategies aimed at therapeutically modulating this axis, including pharmacological targets (VEGF‐C, Piezo1 agonists), noninvasive neuromodulation (photo‐biomodulation, PBM), and surgical interventions (lymphaticovenous anastomosis, LVA). This synthesis positions the glymphatic–lymphatic axis as a fundamental physiological network and a pivotal target for novel interventions, outlining key future research directions in neurology.

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, is characterized by rapid recurrence and poor prognosis despite multimodal therapy.

Glioblastoma multiforme (GBM) remains one of the most aggressive primary brain tumors with limited therapeutic options. The efficacy of standard temozolomide chemotherapy is critically influenced by O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. While monoclonal antibody (mAb)-based biologics represent a promising therapeutic approach, current clinical trials have failed to demonstrate significant improvement in overall patient survival. In this study, systematic screening identified histamine H1 receptor (HRH1) as a potential therapeutic target. Genetic silencing of HRH1 significantly inhibited GBM cell proliferation, migration, and invasion both in vitro and in vivo. Pharmacological validation using the HRH1-specific antagonist terfenadine confirmed the anti-tumor effects of HRH1 targeting. Based on these findings, we developed an HRH1-targeting mAb that demonstrated potent anti-tumor activity in GBM xenograft models. Mechanistic investigations revealed that the therapeutic effect was mediated through protein kinase C (PKC)-dependent regulation of the RAF/MEK/ERK signaling pathway. In conclusion, we provided a new target, HRH1, for treating GBM and constructed an effective therapeutic mAb.