Guangdong 999 Brain Hospital

ABSTRACTChimeric antigen receptor T (CAR‐T) cells have been used to treat patients with glioblastoma (GBM) in clinical trial settings by targeting GBM‐associated antigens. However, the efficacy of these CAR‐T cells remains limited mainly due to the heterogeneous expression of tumor antigen and their anergy in the tumor microenvironment (TME). Cytokine‐inducible SH2‐containing protein (CIS, encoded by the gene CISH) is a potent intracellular checkpoint inducing T‐cell anergy. Here, we identified fibroblast activation protein alpha (FAPα) as a highly attractive target for CAR‐T cell therapy against GBM based on its dual expression pattern (on tumor cells and perivascular cells) in GBM. A panel of nanobodies specific for FAPα was isolated, and FAPα‐targeting CAR‐T cells were developed using the isolated nanobody to verify their specific cytotoxicity to GBM cells. Furthermore, a non‐viral circular single‐stranded DNA (cssDNA)‐based CRISPR/Cas9‐targeted genome‐editing (cssDNA/CRISPR/Cas9) technology was used to integrate CAR cassettes at the CISH locus to generate CISH‐knockout (CISH‐KO) CAR‐T cells. The resulting CISH‐KO‐CAR‐T cells exhibited robust proliferation and potent anti‐GBM activity in vitro and in vivo. Thus, our results provide novel engineered CAR‐T cells with enhanced efficacy against GBM.

Background Glenohumeral subluxation (GHS) is a common complication following stroke, with an incidence rate of up to 73% in the acute phase, significantly impairing upper limb functional recovery and activities of daily living. Conventional support devices, such as the Harris hemiplegic sling and Bobath sling, have limitations including tendency to slip and displacement, resulting in incomplete reduction. To address these challenges, our research team has developed a novel 3D-printed elbow-forearm support orthotic device. Methods This study employs a single-center, prospective, assessor-blinded randomized controlled trial design. We plan to recruit 60 post-stroke patients with GHS, who will be randomly allocated to either the intervention group (elbow-forearm support orthosis) or the control group (conventional shoulder sling). The intervention period is 4 weeks with 6 h of daily wear, followed by an 8-week follow-up period (total observation period of 12 weeks). The primary outcome measures are vertical distance (VD) and horizontal distance (HD) from the inferior margin of the acromion to the center of the humeral head. Secondary outcome measures include the Modified Ashworth Scale, Visual Analog Scale for pain, Fugl-Meyer Assessment for upper extremity motor function, and Modified Barthel Index. Statistical analysis will be performed using mixed-effects linear models. Discussion The elbow-forearm support orthosis improves GHS through mechanisms including biomechanical support and neuromuscular modulation. This study employs standardized radiographic measurements, multidimensional assessment systems, and rigorous randomization design, which may provide high-quality evidence-based medicine for the treatment of post-stroke GHS. Study limitations include single-center design and limited sample size, necessitating multicenter large-scale studies for validation. Clinical trial registration https://www.chictr.org.cn/ , identifier ChiCTR1800018730.

Chronic post-surgical pain (CPSP) in rats is characterized by persistent mechanical allodynia and spinal neuronal hypersensitivity. Astrocyte-derived L-lactate, a key modulator of neuronal excitability and synaptic plasticity, was herein investigated for its role in CPSP development following skin/muscle incision and retraction (SMIR). SMIR triggered long-lasting mechanical allodynia, concomitantly with astrocyte activation and elevated L-lactate levels in the spinal dorsal horn. Blockage of glycogenolysis by 4-dideoxy-1,4-imino-D-arabinitol (DAB), inhibition of carbonic anhydrase (CA) by acetazolamide or inhibition of soluble adenylyl cyclase (sAC) by bithionol prevented SMIR-induced mechanical allodynia and reduced spinal dorsal horn L-lactate levels, implicating a critical role of astrocyte-derived lactate in CPSP development and maintenance. Chemogenetic inhibition of spinal astrocyte suppressed mechanical allodynia and decreased L-lactate accumulation in the dorsal horn. Notably, exogenous L-lactate enhanced the firing rate of spinal lamina Ⅰ-II neurons but failed to alter excitatory synaptic transmission, suggesting a selective role for L-lactate in modulating spinal neuronal intrinsic excitability. Mechanistically, SMIR elevated plasma glucocorticoid levels, while adrenalectomy (ADX) abolished both SMIR- induced mechanical allodynia and spinal lactate elevation. Collectively, these findings indicate that glucocorticoid receptor signaling drives astrocytic L-lactate release in spinal dorsal horn following SMIR, which promotes spinal neuronal hyperexcitability and contributes to CPSP pathogenesis.

BackgroundFew interventions have been proven to improve dynamic cerebral autoregulation (dCA). GB34 is a common acupoint for motor function treatment in the clinic. However, the effects of acupuncture on dCA have never been reported and whether acupuncture at GB34 can improve dCA is unknown.MethodsA self-controlled interventional study was conducted. Each participant randomly received two acupuncture interventions, including active acupuncture and sham acupuncture. Transcranial Doppler and servo-controlled finger photoplethysmography were used to record continuous cerebral blood flow velocity in the bilateral middle cerebral arteries and continuous blood pressure to assess dCA with transfer function analysis during acupuncture intervention.ResultsTwenty healthy volunteers were enrolled. The left and right phase values in the low-frequency band after acupuncture treatment were significantly higher than baseline levels. Meanwhile, a reduction in heart rate was observed after acupuncture treatment. In contrast, no real-time changes were observed in any parameters after sham acupuncture intervention.ConclusionThe results suggested that treatment with acupuncture at GB34 increased dCA in young healthy volunteers. The increased dCA may contribute to the beneficial effects of acupuncture on cerebrovascular function.Clinical Trial Registrationhttps://www.chictr.org.cn/showproj.html?proj=121012, identifier ChiCTR2100042762.

Background: Schizophrenia primarily depends on pharmacotherapy, which has demonstrated limited efficacy in enhancing cognitive impairments. High-definition transcranial direct current stimulation (HD-tDCS) and computerized cognitive remediation therapy (CCRT) hold potential for improving cognitive impairments. This study aims to investigate the effects of combining HD-tDCS with CCRT on cognition and to explore the mechanisms of this approach in schizophrenia. Study Design: This is the protocol of a randomized controlled trial. Methods: Schizophrenia patients will be randomly assigned to one of 4 groups: HD-tDCS + CCRT group (Group 1), HD-tDCS group (Group 2), CCRT group (Group 3), and a control group (Group 4). The central electrode will be personalized using magnetic resonance imaging (MRI)-guided localization in the medial prefrontal cortex (mPFC). CCRT includes 6 therapeutic modules and 10 distinct tasks. Both HD-tDCS and CCRT will be administered once daily, 5 days per week, for 4 consecutive weeks, culminating in a total of 20 sessions. Assessments will occur at baseline (T0), after 10 sessions (T1), after 20 sessions (T2), and after 6 months of follow-up (T3). The primary outcome measure is the change in cognition. We will employ multimodal MRI, serum concentrations of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) to explore the underlying mechanisms. Expected Results: An involvement of mPFC and synaptic plasticity in response to HD-tDCS and CCRT is hypothesized. Conclusion: The study will provide empirical evidence for the effectiveness of combined therapy at an individual level, explore its mechanisms, and may ultimately result in personalized medicine. Clinical Trial Registration: ChiCTR2500102731, https://www.chictr.org.cn/hvshowprojectEN.html?id=276964&v=1.0.