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关键词： Takayasu arteritis   baricitinib   JAK-STAT pathway   TNF-alpha   inhibitor-refractory   glucocorticoid-sparing therapy   clinical trial  

摘要： Objective This study aimed to assess the efficacy and safety of baricitinib in Takayasu arteritis (TAK) refractory to TNF-alpha inhibitors. Methods We conducted a multicentre, single-arm trial between February 2021 and August 2023. Patients with TAK unresponsive to at least 6 months of TNF-alpha inhibitors were treated with baricitinib 4 mg daily for up to 48 weeks, while continuing of immunosuppressants and glucocorticoids. Clinical features, inflammatory parameters, imaging changes and treatment data were collected during follow-up. The primary end point was the overall response (ORR) (complete response [CR] plus partial response [PR]) at 24 weeks. Results A total of 10 patients (nine female and one male) patients were enrolled, with median age of 29 years (26.0, 35.3) and a median disease duration of 56.5 months (31.8, 88.5). The ORR at 24 weeks was 80%, with six patients achieving CR and two achieving PR. Disease progression was noted in the remaining two patients. Disease activity, ESR and CRP at 24 weeks were significantly decreased compared with those at baseline. The median glucocorticoid dosage decreased from 20.0 mg/day (15.0, 26.3) at baseline (P < 0.001) to 6.3 mg/day (4.4, 10.6) at 24 weeks. No relapse was observed in the eight patients who achieved a response. The adverse effects (AEs) included upper respiratory tract infection (n = 2) and diarrhoea (n = 1), with no serious AEs reported. Conclusion Baricitinib is effective in patients with TAK resistant to conventional treatments and anti-TNF-alpha therapy and demonstrates a notable steroid-sparing effect. Trial registration ***;NCT06662721.

关键词： Immunotherapy   Cytokine   Gene therapy   Immune modulatory   Natural killer - NK  

摘要： Background Glioblastoma (GBM) is a rapidly growing, aggressive brain tumor with very poor prognosis without currently effective therapies. The immunosuppressive nature of the tumor microenvironment (TME) in GBM hinders the development of effective tumor-eradicating immunotherapies. This hostile TME can be modulated by administering immune-activating cytokines in combination with agents inducing tumor cell death. To achieve these objectives, we sought to harness the cancer-selective cell death-inducing properties of an enhanced "Superkine" version of melanoma differentiation associated gene-7/interleukin-24, IL-24S, and the immune-activating properties of IL-15 to modulate the TME of GBM to maximize therapeutic *** A fusion "Superkine" (FSK) comprised of IL-24S linked to IL-15 was generated, and antitumor effects were evaluated when transduced by a type 5 adenovirus (Ad.5) in a GBM immunocompetent mouse tumor model. To target the delivery of Ad.5 FSK systemically, we employed an innovative approach of focused ultrasound (FUS) paired with microbubbles (MBs), FUS-DMB (FUS plus double MB), to safely transport the FSK engineered Ad.5 construct into mouse brain to overcome limitations of systemic viral delivery and selectivity of the blood-brain *** The FSK stimulated higher tumor regression and enhanced survival in vivo than the individual "Superkine" or cytokine in GBM cancer models. Apoptosis of GBM cells was induced, as well as increased tumor infiltration of T cells, dendritic cells, macrophages and natural killer (NK) cells. The antitumor-inducing activity of FSK is a consequence of induction of cancer-specific growth suppression and induction of apoptosis (IL-24S) as well as diverse effects on immune cells (IL-15 and IL-24S). Antibody neutralization indicates that a primary immune mediator of anticancer activity of FSK is through recruitment and activation of NK cells. Global cytokine analyses indicated no changes in inflammatory cytokines

关键词： Green catalyst   green solvent   sustainable catalyst   sustainable solvent   green method   sustainable method   imidazoles  

摘要： In the current scenario, the use of nature-friendly methods in organic synthesis is regarded as invaluable and irreplaceable. Significant progress has been made in developing more sustainable and eco-friendly approaches for various organic syntheses and transformations. Within the scope of green synthesis, ILs have attracted a lot of interest since their special features fit for sustainable chemistry. Organic synthesis has increasingly utilized ILs as green catalysts and solvents for the development of countless heterocycles. Among these, imidazole is recognized as a highly valuable and preferred heterocyclic motif. It presents interesting chances for finding ideal structures in the synthesis of synthetic compounds with possible therapeutic uses and other major prospects. A diverse array of ILs has been successfully exploited toward the development of imidazoles. Therefore, this review article offers a thorough review of current studies on the function of ecologically safe ILs in producing a wide range of valuable imidazoles.

关键词： Tumors  

摘要： Advancing targeted cancer immunotherapy is pivotal for overcoming distant metastasis and tumor relapse. The recent study in Nature Cancer by Sanlorenzo et al. demonstrates a breakthrough strategy combining systemic type I interferon with topical Toll-like receptor 7/8 agonists, where oral imiquimod primes plasmacytoid dendritic cells (DCs) to produce type I interferon, thereby sensitizing conventional DCs in tumors to local Toll-like receptor 7 activation. This approach triggers c-Jun-dependent IL-12 production and CCL2-mediated plasmacytoid DC recruitment, enabling localized and systemic tumor suppression. Importantly, the therapy synergizes with PD-1 blockade to prevent recurrence, representing a significant advance in DC-targeted cancer immunotherapy.

关键词： CTRP-1   Periodontal disease   Gingival crevicular fluid   Non-surgical periodontal therapy   Biomarkers  

摘要： Objectives This study investigated the gingival crevicular fluid (GCF) levels of complement-C1q tumor necrosis factor related protein-1 (CTRP-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin-10 (IL-10) following non-surgical periodontal therapy (NSPT) in systemically healthy individuals with periodontal health (H), generalized gingivitis (G), and stage III grade B periodontitis (P). Moreover, this study aimed to investigate their diagnostic potential in distinguishing different periodontal diseases. Materials and methods 73 systemically healthy non-smoking individuals were divided into H (n = 25), G (n = 23) and P (n = 25) groups. Clinical periodontal parameters were recorded, and GCF samples were collected at baseline in all groups, and 3rd month after NSPT in the G and P groups. GCF levels of CTRP-1, TNF-alpha, and IL-10 were analyzed using ELISA. The area under the curve (AUC) was assessed using the receiver operating characteristic curve analysis. Results CTRP-1 levels were significantly elevated in the G and P group compared to the H group (p < 0.001), while there was no significant difference between the G and P groups (p = 0.095). TNF-alpha and IL-10 levels were significantly higher in the P group compared to the other groups (p < 0.001). GCF CTRP-1 demonstrated an excellent diagnostic performance to discriminate periodontitis and gingivitis from periodontal health (AUC value of 0.998 and 0.974 with 100% and 91.3% sensitivity). Conclusion CTRP-1 could serve as a potential biomarker for periodontal diseases. CTRP-1 demonstrated excellent diagnostic performance in distinguishing stage III grade B periodontitis and gingivitis from periodontal health.

关键词： HLA   histcompatibility   physical crossmatch   virtual crossmatch  

摘要： Donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) are a significant barrier to solid organ transplant and can lead to poor outcomes in the posttransplant setting. The physical crossmatch (PXM), including the complement-dependent cytotoxicity crossmatch and the flow cytometry crossmatch, has substantially reduced the incidence of hyperacute rejection and, for years, has been the gold standard for compatibility assessment before transplant. However, the advent of solid-phase anti-HLA antibody testing and molecular HLA typing has allowed the introduction and rise of the virtual crossmatch (VXM). With a high negative predictive value, the VXM has proven to be more sensitive than the PXM in detecting DSA. Recent regulations by the Centers for Medicare & Medicaid Services now recognize the VXM as a suitable alternative to the PXM in the pretransplant compatibility assessment. As the VXM gains acceptance, it is imperative that we understand its complexities, such as its definition, application, advantages, and disadvantages. In this review, we examine the principles underlying the VXM, including both generally accepted concepts and areas under debate. Furthermore, we highlight current applications and discuss opportunities for future improvement.

关键词： Microenvironment   Molecular biology   Epigenetics   Immunology  

摘要： Immune checkpoint blockade (ICB) has revolutionized metastatic melanoma care, yet many patients remain unresponsive. The tumor microenvironment (TME), shaped by metabolic stress, influences tumor antigenicity and ICB sensitivity. Here, we show that prolonged metabolic stress enhances melanoma antigen presentation via epigenetic mechanisms. Glucose-deprived melanoma cells, mimicking the nutrient-deprived TME, exhibit increased major histocompatibility complex class I (MHC-I) expression and heightened T cell-mediated killing. Proteomic and chromatin analyses reveal that metabolic stress reduces histone methyltransferase enhancer of zeste homolog 2 (EZH2), leading to H3K27me3 loss at MHC-I regulatory genes. Chromatin immunoprecipitation (ChIP) sequencing and ChIP-PCR reveal H3K27me3 loss at genes specific to MHC-I presentation. Prolonged metabolic stress transcriptionally reduces EZH2 and H3K27me3 at these promoters, elevating MHC-I antigenicity and CD8+ T cell killing. These findings suggest EZH2 abundance and mutation status as potential prognostic indicators for ICB responsiveness in metastatic melanoma and support EZH2 inhibition as an immunotherapy adjuvant.

关键词： 胆结石   胆囊炎   腹腔镜  

摘要： 探讨腹腔镜治疗对胆结石并发胆囊炎患者临床疗效。方法 选择2021年8月至2024年8月收治胆结石并发胆囊炎患者40例进行研究,随机分组,对照组行小切口胆囊手术,观察组行腹腔镜胆囊切除术,比较临床疗效。结果 观察组治疗后氧化应激指标、炎性因子指标、并发症发生率均优于对照组(P<0.05)。结论 腹腔镜手术可发挥显著疗效,可临床应用。

关键词： 复发性流产   寿胎丸   血管内皮生长因子   可溶性血管内皮生长因子受体-1   白细胞介素17  

摘要： 目的：研究寿胎丸加味辅助治疗复发性流产患者效果及对血清血管内皮生长因子（vascular endothelial growth factor，VEGF）、可溶性血管内皮生长因子受体-1（soluble fms-like tyrosine kianse-1，sFLT-1）、白细胞介素17(interleukin-17， IL-17)的影响。方法：选取2023年1月～2024年3月医院治疗的复发性流产患者96例，按照随机数字表法均分为两组，各48例患者。对照组采用常规西药治疗，观察组在对照组基础上增加寿胎丸加味辅助治疗，用药至孕12周。比较两组患者的疗效，中医证候积分变化，血清VEGF、sFLT-1、IL-17水平，不良反应发生情况。结果：观察组治愈率87.50%、对照组70.83%，观察组高于对照组（P＜0.05）。治疗后，两组患者神疲肢软、肢体寒冷、头晕耳鸣、夜尿频繁积分均显著降低，观察组低于对照组（P＜0.05）。治疗后，两组患者血清VEGF水平明显降低，sFLT-1、IL-17水平明显升高，观察组患者血清VEGF水平高于对照组，sFLT-1、IL-17水平低于对照组，差异有统计学意义（P＜0.05）。两组均无严重不良反应发生。结论：寿胎丸加味辅助治疗复发性流产患者效果满意，能够有效调控血清内炎症因子与血管内皮相关因子，促进患者的症状缓解，保证妊娠安全。

摘要： Neoadjuvant immunotherapy is a first-line treatment for recurrent and metastatic head and neck squamous cell carcinoma. However, only a fraction of advanced HNSCC patients benefit from immunotherapy. Identifying accurate and accessible biomarkers is essential for optimal patient selection. Herein, we integrated single-cell RNA-sequencing and T cell receptor-sequencing to comprehensively characterize the tumor immune microenvironment (TIME) of HNSCC biopsies prior to a phase II neoadjuvant immunotherapy clinical trial. Tumor-specific MHC-II (tsMHC-II) was identified as a superior predictor of response to neoadjuvant immunotherapy in HNSCC compared to PD-L1. Mechanistically, tsMHC-II ignited a hot TIME and enhanced the effect of PD-1 blockade by recruiting T cells through the induction of chemokines, particularly CCL5. Moreover, tsMHC-II triggered a Th1 response and activated CD4+ and CD8+ T cell expansion, suppressing HNSCC growth in a CD4+ T-cell-dependent manner. Simultaneously, tsMHC-II facilitated an increase in PD-1+CD4+ T cells and a modest elevation in tumor PD-L1, thereby enhancing sensitivity to anti-PD-1 therapy. This study highlights that tsMHC-II, by generating an inflamed TIME, is crucial in enhancing the effectiveness of neoadjuvant immunotherapy in HNSCC.