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关键词： neuroblastoma   chimeric antigen receptor   CAR   ROR1   natural killer cells   oncolytic herpes simplex virus   interleukin-21   IL-21  

摘要： Children with recurrent/metastatic neuroblastoma (NB) have a dismal survival (<25%). Novel therapies are desperately needed. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is highly expressed on NB. C021 is a selective oncolytic herpes simplex virus modified to overexpress human interleukin-21 (hIL-21), a cytokine that enhances natural killer (NK) cell cytotoxicity. In the current study, we successfully engineered ex-vivo-expanded NK cells to express a chimeric antigen receptor (CAR) against ROR1 using mRNA electroporation and investigated the efficacy of anti-ROR1-CAR-NK cells combined with C021 in targeting ROR1(+) NB. We found that C021-infected NB cells secreted hIL-21 in vitro and in vivo. Compared to the non-cytokine-secreting parental virus C134, C021 significantly enhanced the in vitro cytotoxicity (p < 0.05) of anti-ROR1-CAR-NK cells with increased interferon (IFN)-gamma (p < 0.05), granzyme B (p < 0.05), and perforin (p < 0.05) secretion against NB cells. Furthermore, the combination of C021 and anti-ROR1-CAR-NK cells significantly extended the survival of human NB xenografted NSG mice compared to controls (mock NK, ROR1-CAR-NK, C134, C021, C134+ROR1-CAR-NK, and C021+mock NK). Our results suggest that cytokine-secreting oncolytic virus in combination with CAR-NK cells is a novel, effective immunotherapeutic approach for high-risk NB.

关键词： glioblastoma   AhR   flavonoid  

摘要： Background: Glioblastoma (GBM) is a highly aggressive brain tumor characterized by rapid cell proliferation, invasive behavior, and chemoresistance. The aryl hydrocarbon receptor (AhR) is implicated in chemoresistance and immune evasion, making it a promising therapeutic target. Natural compounds such as flavonoids have gained attention for their anti-inflammatory, antioxidant, and anticancer properties. Among them, naringenin, a citrus-derived flavonoid, exerts antiproliferative, pro-apoptotic, and immunomodulatory effects. Objectives: This study investigated the antiglioma effects of the flavonoid naringenin on the viability, growth, and migration of glioma cells and its potential role as an AhR modulator. Methods: Human (U87) and rat (C6) glioma cell lines were exposed to naringenin (10-300 mu M) alone or in combination with the AhR agonist indole-3-carbinol (50 mu M) for 24 to 48 h. Cell viability, scratch wound, and cell migration assays were performed. The expression of inflammatory markers was also analyzed by RT-qPCR. Results: Naringenin exerted dose- and time-dependent inhibition of cell viability and migration. The treatment decreased the gene expression of interleukin-6 (IL-6) and chemokine (CCL2), alongside increased tumor necrosis factor-alpha (TNF-alpha) expression, an effect reversed by the AhR agonist. Conclusions: These findings highlight naringenin's potential as an antiglioma agent and its role in AhR signaling.

关键词： Endometriosis   SCM-198   IFN-gamma T+ cells   CCR5(+)T cells   CCL5  

摘要： Endometriosis is a common gynecological disease that causes severe pain and infertility. However, the available treatments for EMS are limited. SCM-198, a synthetic form of leonurine, possesses various abilities, including anti-inflammatory, immunomodulatory, antioxidant, anti-fibrotic, and anti-proliferative effects. Previous studies have shown that SCM-198 can inhibit the growth of ectopic lesions, but the specific mechanism remains unknown. The results of our studies indicate that SCM-198 significantly suppresses the endometriotic growth of EMS mice. Enrichment analysis of RNA-seq indicates that SCM-198 is involved in T cell differentiation, activation, cytokine production, stimulation of chemotaxis, and migration. Flow cytometry reveals that SCM-198 reverses the decreased proportions of IFN-gamma T+ cells and CCR5 + T cells in ectopic lesions. RNA-seq analysis shows that SCM-198 enhances the expression of CCL5 in the ectopic lesions, and western blot is conducted to verify this conclusion both in vivo and in vitro. These findings demonstrate that SCM-198 reverses the decreased proportions of IFN-gamma + T cells and CCR5 + T cells, alleviating the growth of mouse ectopic lesions, and the changes in CCR5 + T cells are likely due to the reduced expression of CCL5.

摘要： Although cytotoxic CD8+ T lymphocytes (CTLs) are essential for anti-tumour immunity, they are frequently dysfunctional in tumours1. Cytokines that sustain CTL activity are attractive for cancer immunotherapy, but avoiding inflammatory toxicity remains a challenge for their clinical use2. Here we show that expression of a CTL signature is strongly associated with IL27 expression in human and mouse tumours. In mice, IL-27 acts directly on tumour-specific CTLs to promote their persistence and effector function in the tumour microenvironment. Moreover, treatment with inducible IL-27 overexpression or a half-life-extended IL-27 protein in vivo is well tolerated, induces regression of established tumours, drives an enhanced cytotoxic program in anti-tumour CTLs and synergizes with PD-L1 blockade. In patients with cancer who were treated with anti-PD-1/PD-L1 therapy, high expression of IL-27 correlates with a favourable clinical response, and IL-27 supports human CTL function during chronic antigen stimulation ex vivo. Our data demonstrate that endogenous IL-27 is essential for anti-tumour immunity and that IL-27 receptor agonism can safely improve anti-tumour T cell responses alone or in combination with PD-L1 blockade.

关键词： 再生障碍性贫血   造血干细胞移植   淋巴细胞亚群   免疫重建  

摘要： 目的：分析研究造血干细胞移植治疗对再生障碍性贫血患者淋巴细胞亚群及血细胞计数的影响。方法：选取2019年2月至2022年4月通过造血干细胞移植治疗的获得性再生障碍性贫血患者84例。分别检测治疗前、治疗后1个月、治疗后3个月、治疗后6个月外周血淋巴细胞亚群以及血细胞变化，包括CD19+B细胞、CD3+T细胞、CD3+CD4+辅助T细胞、CD3+CD8+抑制T细胞、CD3-CD16+CD56-NK细胞、CD3+CD16+CD56-NKT细胞百分比、CD4+/CD8+T细胞比值、淋巴细胞占白细胞百分比、白细胞计数、红细胞计数及血小板计数等11项。结果：患者治疗前外周血CD3+、CD3+CD8+、CD3+CD16+CD56+、淋巴细胞占白细胞百分比均高于正常值，CD4/CD8、白细胞计数、红细胞计数、血小板计数均低于正常值。治疗前后CD19+、CD3+CD4+、CD3-CD16+CD56-均维持正常水平。CD4+/CD8+、血小板计数在治疗后6个月内仍低于正常值。其余均在3个月左右恢复至正常水平。结论：再生障碍性贫血可以导致患者免疫系统存在不同程度的紊乱，且全身血细胞减少。造血干细胞移植可以较好的治疗再生障碍性贫血，患者淋巴细胞亚群以及血细胞在3个月左右恢复正常水平。

关键词： Polychondritis   Relapsing   Spondylitis   Ankylosing   Treatment Adherence and Compliance  

摘要： Objective: Diagnostic/therapeutic accidents Background: Relapsing polychondritis is a rare autoimmune disease of unknown etiology. There are no defined protocols for treatment, and its management depends on the physician's knowledge and empirical experience. Various reports often highlight the insufficient efficacy of conventional disease-modifying anti-rheumatic drugs, and report controversial results associated with the use of different biologic agents. Case Report: The patient was a 32-year-old woman, previously diagnosed with ankylosing spondylitis. Four years after the initial diagnosis and following her second delivery, the patient presented with a refractory and aggressive relapsing polychondritis, which posed a significant challenge for treatment. Two months prior to the onset of the chondritis, the patient exhibited high disease activity of ankylosing spondylitis, with ASDAS-CRP 3.5 and BASDAI 6.0. After treatment failure using a combination of an anti-TNFa inhibitor and methotrexate, we achieved remission of both co-existing autoimmune diseases using an IL-17 inhibitor (secukinumab). Conclusions: Further investigations are needed to better understand the pathogenesis of this rare condition. The existence of various reports on the controversial effects of treatment with different biologic agents, including IL-17 antagonists, raises several questions, including whether the onset of relapsing polychondritis is a side effect of the use of biologics or if it is an autoimmune disease that occurs independently of the treatment. This is the first time that the use of an anti-IL-17 agent is reported to have successfully suppressed an aggressive, progressive form of this disease, without any symptom-free period before the initiation of secukinumab.

关键词： IL-36RN   gene mutation   treatment   pediatric   pustular psoriasis  

摘要： Pediatric pustular psoriasis (PPP) is an autoimmune skin disease that seriously affects the physical and mental health of children. The IL-36RN (Interleukin-36 Receptor Antagonist) gene plays a key role in the pathogenesis of PPP. This review comprehensively elaborates on the research progress of IL-36RN in the context of the pathogenesis and treatment of PPP, covering the basic structure, function, mutation sites and types, and inheritance patterns of the gene and its role in the pathogenesis of PPP. In addition, we discussed the frequency of IL-36RN mutations in patients with different types of PPP and the treatment methods for these patients, aiming to provide a valuable reference for further research and treatment of this disease.

关键词： microglia   hypoxia   mitochondria   inflammatory pathways   anti-TNF alpha   anti-IL-1 beta   proteomics   apoptosis  

摘要： The disruption of microglial homeostasis and cytokine release are critical for neuroinflammation post-injury and strongly implicated in retinal neurodegenerative diseases like glaucoma. This study examines microglial responses to chemical hypoxia induced by cobalt chloride (CoCl2) in BV-2 murine microglial cells, focusing on signaling pathways and proteomic alterations. We assessed the protective effects of monoclonal antibodies against TNF alpha and IL-1 beta. CoCl2 exposure led to decreased cell viability, reduced mitochondrial membrane potential, increased lactate dehydrogenase release, elevated reactive oxygen species generation, and activation of inflammatory pathways, including nitric oxide synthase (iNOS), STAT1, and NF-kappa B/NLRP3. These responses were significantly mitigated by treatment with anti-TNF alpha and anti-IL-1 beta, suggesting their dual role in reducing microglial damage and inhibiting inflammatory reactivity. Additionally, these treatments reduced apoptosis by modulating ATF4 and the p38 MAPK/caspase-3 pathways. Label-free quantitative mass spectrometry-based proteomics and Gene Ontology revealed that CoCl2 exposure led to the upregulation of proteins primarily involved in endoplasmic reticulum and catabolic processes, while downregulated proteins are associated with biosynthesis. Anti-TNF alpha and anti-IL-1 beta treatments partially restored the proteomic profile toward normalcy, with network analysis identifying heat shock protein family A member 8 (HSPA8) as a central mediator in recovery. These findings offer insights into the pathogenesis of hypoxic microglial impairment and suggest potential therapeutic targets.

关键词： diabetic wound   fecal microbiota transplant   IL-17A   mTOR   HIF1 alpha  

摘要： IMPORTANCE Glycogen storage disease type Ib (GSDIb) is a rare metabolic disorder characterized by impaired glucose-6-phosphate transporter function with limited descriptions. OBJECTIVE To describe the genetic and clinical features of Chinese patients with GSDIb. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study retrieved the medical records of 113 Chinese patients with GSDIb treated at a single institution in Shanghai from November 1, 2000, to June 30, 2024. MAIN OUTCOMES AND MEASURES Biochemical parameters and clinical features (infections, inflammatory bowel disease [IBD], kidney and cardiovascular issues, growth and puberty) at baseline and the last follow-up, all-cause mortality, and mental and social development were assessed. RESULTS A total of 113 patients (96 children [85%];67 males [59%]) had GSDIb genetically diagnosed at a median age of 1.4 (range, 0.0-35.5) years. Thirty-eight novel SLC37A4 variants were identified. Hypoglycemia and metabolic derangements were the primary concerns in patients aged years or younger (45%). Short stature (75%), infections (75%), and recurrent epistaxis (31%) became more prevalent in patients aged 2.1 to 5.0 years. The frequency of respiratory tract infection decreased after a median age of 7.0 (IQR, 3.5-10.5) years. Forty-four patients (46%) developed IBD at a median age of 6.0 (IQR, 3.0-12.0) years, 14% of whom developed IBD-associated arthritis at a median age of 10.5 (IQR, 5.8-19.6) years. The mean (SD) difference between the z scores of actual height and target height (Delta height z scores) at the final visit (-2.11 [1.76]) did not significantly increase even after uncooked cornstarch treatment. The mean (SD) Delta height z scores of the patients with IBD (-2.99 [1.70]) were significantly lower than those without IBD (mean [SD], -1.36 [1.44]) (P < .001). Ten patients (9%) died due to complications of GSDIb, including metabolic derangements, sepsis, and/or severe pneumonia (n = 8), IBD (n = 1), and pulmo