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关键词： ankylosing spondylitis   bone mineral density   TNF-alpha   DKK-1   SOST   BMP-6   IL-17  

摘要： Background: Ankylosing spondylitis (AS) is a chronic autoinflammatory rheumatic disease mainly affecting the sacroiliac joints and spine, causing altered bone remodeling. Pro-inflammatory cytokines such as TNF-alpha and IL-17 contribute to bone loss by modulating pathways including Wnt/beta-catenin, which is inhibited by proteins like Dickkopf-1 (DKK-1) and sclerostin (SOST). Bone morphogenetic protein-6 (BMP-6) promotes osteoblast differentiation and bone formation. This study evaluated the association between serum levels of DKK-1, SOST, BMP-6, and bone mineral density (BMD) in AS patients treated with anti-TNF agents and conventional synthetic DMARDs (csDMARDs). Methods: A cross-sectional study included 76 AS patients diagnosed by modified New York criteria and 30 healthy donors matched by age and sex. BMD at the lumbar spine and hips was assessed by DXA in all participants. Disease activity (BASDAI) and functional index (BASFI) were measured in AS patients. Serum levels of DKK-1, SOST, BMP-6, TNF-alpha, and IL-17 were quantified by ELISA in both groups. AS patients were divided into two treatment groups: combined anti-TNF alpha and csDMARD therapy (n = 38), and only csDMARDs (n = 38). Results: Bone mineral density showed no significant statistical differences between the spine (p = 0.930) and hips (p = 0.876) in AS patients compared to healthy controls. The activity (BASDAI) and functionality (BASFI) scores were similar in both treatment groups (p = 0.161 and p = 0.271, respectively). No significant differences were found in serum levels of DKK-1 (p = 0.815), SOST (p = 0.771), BMP-6 (p = 0.451), or IL-17 (p = 0.335) between combined anti-TNF alpha and csDMARD therapy versus monotherapy with csDMARD. Conclusions: The combination of anti-TNF bDMARD therapy and csDMARD therapy is not significantly associated with serum levels of DKK-1, SOST, BMP-6, and BMD compared to those treated with csDMARD monotherapy in patients with AS. This study provides novel and clinical

关键词： Angiogenesis   Aurora A   Hepatocellular carcinoma   Hypoxic microenvironment   Jiedu Fang  

摘要：

关键词： Il-6   RBP4   colorectal cancer   prognostic factor  

摘要： Background/Objectives: Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. Inflammation and metabolic dysregulation, particularly those related to obesity, have emerged as critical contributors to CRC progression. Interleukin-6 (IL-6) and retinol-binding protein 4 (RBP4), an adipokine involved in metabolic regulation, may be key mediators of these processes. This study aimed to evaluate the expression levels of IL-6 and RBP4 in CRC tissues and their associations with clinicopathological features and overall survival. Furthermore, in silico analyses were performed to explore the molecular networks and signaling pathways related to both biomarkers. Methods: Immunohistochemical staining of IL-6 and RBP4 was conducted in 118 CRC and matched adjacent normal tissues. Expression levels were assessed using the H-score system and correlated with clinical parameters. Survival analysis was performed using Kaplan-Meier curves. In silico analyses were based on RNA-seq data from TCGA and included pathway enrichment, gene co-expression, and protein-protein interaction networks. Results: IL-6 and RBP4 expression were significantly elevated in tumor tissue compared to adjacent normal mucosa. High IL-6 expression correlated with age and obesity measures, while RBP4 expression showed significant associations with pT stage, lymph node involvement, TNM stage, and obesity-related parameters. Kaplan-Meier analyses indicated shorter overall survival in patients with high IL-6 or RBP4 expression. In silico analysis confirmed upregulation of IL6 and RBP4 in CRC and highlighted immune-related pathways for IL-6 and developmental signaling for RBP4. Conclusions: Elevated expression of IL-6 and RBP4 in CRC tissue is associated with adverse clinical features and reduced survival, underscoring their potential role as prognostic biomarkers. These findings support the involvement of inflammation and metabolic dysfunction in CRC progression and suggest IL-6 and

关键词： Atezolizumab   diabetes   HLA   immune checkpoint inhibitor   prognosis  

摘要： To explore the clinical characteristics of diabetes mellitus (DM) induced by atezolizumab in cancer patients and provide evidence to guide the rational clinical application of atezolizumab. We conducted a retrospective study on diabetes induced by atezolizumab, analyzing it by retrieving the case reports in the database from 2016 to 8 April 2025. Overall, the median age of the 30 atezolizumab induced DM patients was 67 years (44-85 years), among which 19 patients (63.3%) were male. Atezolizumab induced DM occurred at a median of 147 days (15-600 days) after the treatment with atezolizumab. 12 patients (40.0%) had ICI-T1DM, 10 patients (33.3%) had ICI-FT1DM, 8 patients (26.7%) had ICI-DM. The HLA typing test information provided by 10 patients showed that these patients carried susceptible genes related to DM. After DM was induced by atezolizumab, insulin or a combination of insulin and oral hypoglycemic agents was used, achieving a good effect in blood glucose levels. 10 patients (33.3%) continued to use atezolizumab after glycemia improvement. Among the 30 patients, except for 4 patients who died due to tumor progression (3 cases) and liver injury (1 case), the rest all alive or not reported their survival status. In conclusion, when administering atezolizumab treatment for cancer patients, it is recommended to monitor blood glucose levels regularly. In case atezolizumab induced DM occurs, insulin should be administered to regulate blood glucose.

关键词： HLA   HLA-B*51:428   next-generation sequencing   novel allele  

摘要： HLA-B*51:428 differs from B*51:01:01 by one nucleotide substitution in codon 260 in exon 4.

关键词： 前列腺癌   前列腺特异性膜抗原   PET显像   镓-68   镥-177   诊疗一体化  

摘要： 转移性去势抵抗前列腺癌 （metastatic castration-resistant prostate cancer， mCRPC） 属于前列腺癌晚期阶段， 一线治疗手段疗效不佳， 已成为男性健康的重大威胁。前列腺特异性膜抗原 （prostate-specific membrane antigen， PSMA） 靶向治疗核药 [177Lu]Lu-PSMA-617已于2022年获得FDA批准用于mCRPC治疗， 临床患者获益显著。本研究基于PSMA-617的分子结构， 开发了基于螯合体p-SCN-Bn-DOTA的放射性配体PSMA-SCN， 并系统评估其前列腺癌诊疗性能。分子对接与细胞竞争抑制结果均表明， p-SCN-Bn-DOTA的引入提升了PSMA-SCN与靶蛋白PSMA的亲和力。MicroPET成像结果显示 [68Ga]Ga-PSMA-SCN在两种荷瘤小鼠模型的肿瘤摄取值 [（46.27 ± 0.45） 和 （31.15 ± 0.21）%ID·g-1] 均高于 [68Ga]Ga-PSMA-617 [（16.8 ± 0.98） 和 （13.38 ± 1.44）%ID·g-1]， 且非靶器官清除速率快。这是由于p-SCN-Bn-DOTA的引入提高了PSMA-SCN与靶向蛋白的亲和力， 同时药物代谢没有受到明显影响。[177Lu]Lu-PSMA-SCN的肿瘤生长抑制率高于 [177Lu]Lu-PSMA-617， 并表现出良好的安全性。综上所述， PSMA靶向分子PSMA-SCN的理论分析和生物评价证实了其在前列腺癌的诊断与治疗中的潜在价值。研究使用的实验动物与实验过程遵循中国医学科学院药物研究所实验动物伦理规范， 伦理证书编号: 00002217。

关键词： circadian rhythm   dry eye disease   IL-17   melatonin   ocular surface inflammation   ocular surface microbiota  

摘要： The association between modern lifestyle factors and dry eye disease (DED) pathogenesis has garnered increasing scientific attention. Emerging evidence implicates circadian disruption-a prevalent consequence of contemporary living patterns-as a significant yet not fully clarified pathogenic factor in DED development. To address this knowledge gap, we developed a circadian disruption mouse model using chronic jet lag exposure. Mice subjected to chronic jet lag exhibited conjunctival clock gene dysregulation and upregulated pro-inflammatory mediators, such as TNF-alpha, IL-6, and IL-17. Transcriptomic profiling demonstrated marked activation of IL-17-mediated inflammatory pathways within the conjunctival tissue. Therapeutic IL-17 neutralization substantially attenuated ocular surface inflammation, improved corneal epithelial integrity, and decreased apoptotic cell density in circadian disruption-induced dry eye mouse model. Moreover, REV-ERB alpha agonism potently suppressed IL-17 transcription, whereas BMAL1 deficiency exacerbated IL-17-driven inflammatory responses through REV-ERB alpha downregulation. Chronic jet lag additionally induced ocular surface microbiota dysbiosis, characterized by Firmicutes overproliferation. Melatonin administration effectively suppressed conjunctival IL-17 expression through BMAL1-REV-ERB alpha pathway activation while reducing the relative abundance of Firmicutes to restore ocular surface microbiota balance. Our study reveals that circadian disruption induces ocular surface inflammation through the BMAL1-REV-ERB alpha-IL-17 signaling axis and exacerbates dysbiosis of the ocular surface microbiota. Melatonin mitigates these pathological alterations via dual-directional modulation of circadian-immune signaling crosstalk and restoration of microbiota balance. Importantly, this study establishes melatonin as a multifaceted therapeutic agent for combating lifestyle-associated DED, while elucidating the underlying mechanisms governing circa

关键词： 华蟾酥毒基   单克隆抗体   间接竞争酶联免疫吸附试验   定量   腹痛水  

摘要： 目的：制备可特异性识别华蟾酥毒基（CBG）的单克隆抗体，建立特异、快速定量检测CBG的方法，并用于对腹痛水中CBG的含量检测。方法：将CBG和载体蛋白偶联，合成人工抗原，免疫BALB/c小鼠后，利用杂交瘤技术制备单克隆抗体，建立间接竞争酶联免疫吸附试验（ic ELISA），并检测不同批次腹痛水中CBG的含量。结果：实验成功筛选出2株抗CBG单克隆抗体：C1和C6，效价分别为1∶90 000和1∶810 000。利用C6抗体建立icELISA，灵敏度IC50为15.92 ng·mL-1，线性范围(IC20～IC80)为2.45～103.42 ng·mL-1，检测限IC10为1.32 ng·mL-1。交叉反应结果显示，抗CBG单克隆抗体与脂蟾毒配基和蟾毒灵的交叉反应率分别为9.37%和0.03%，与脱氧胆酸和雄酮的交叉反应率均小于0.01%。回收试验显示批内和批间回收率分别为92%～115%和92%～106%，精密度试验显示批内和批间浓度测定值的RSD均小于10%。使用建立的icELISA检测5批次腹痛水中CBG的含量为5.06～6.07μg·mL-1，与HPLC结果一致。结论：本研究制备了CBG特异性的单克隆抗体，用其建立了ic ELISA检测方法，使用该方法对5批次腹痛水中CBG含量的检测显示其批间一致性较好。

关键词： Bacterial extracellular vesicles   italic>Deinococcus radiodurans   Deinoxanthin   Dendritic cell maturation   Tolerogenic dendritic cells   Immune modulation   IL-10  

摘要： Extracellular vesicles (EVs) derived from bacteria are emerging as potent bioactive carriers that affect host immunity. Deinococcus radiodurans, an extremophilic bacterium with strong antioxidant capacity, produces EVs enriched in deinoxanthin (DX), a carotenoid with a reactive oxygen species-scavenging activity. Here, we assessed the antioxidant activity of D. radiodurans-derived EVs (R1-EVs) in biochemical assays and their immunomodulatory effects on dendritic cells (DCs). R1-EVs exhibited significantly higher antioxidant activity than EVs from a DX-deficient mutant strain (Delta crtI-EVs), consistent with DX enrichment. Bone marrow-derived DCs treated with R1-EVs in the presence of lipopolysaccharide displayed reduced expression of surface maturation markers and pro-inflammatory cytokines, while interleukin-10 (IL-10) production and antigen uptake were preserved, indicating a tolerogenic phenotype. This tolerogenic program led to decreased proliferation and cytokine production in allogeneic CD4+ and CD8+ T cells. Mechanistically, R1-EVs inhibited mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappa B) signaling pathways, key regulators of the DC activation. Importantly, IL-10 neutralization reversed these effects, restoring DC and T cell activation. Notably, Delta crtI-EVs showed weaker antioxidant and immunoregulatory activities. Together, our findings identify R1-EVs as dual-functions, DX- and IL-10-dependent nanoplatform that integrates antioxidant and tolerogenic properties, with potential applications in inflammatory and autoimmune disease control.

关键词： melanoma   neoantigens   human leukocyte antigen (HLA)   Major Histocompatibility Complex (MHC)   cancer   immunotherapy  

摘要： Human Leukocyte Antigen (HLA) Class II (HLA-II) molecules bind peptides of phagocytosed non-self proteins and present them on the cell surface to circulating CD4+ T lymphocytes. A successful binding of the presented peptide with the T cell receptor (TCR) activates the CD4+ T cell, leading to the production of antibodies against the peptide (and the protein of its origin) by the B cell and augmentation of the cytotoxic and memory functions of CD8+ T cells. The first and essential step in this process is the successful formation of a stable peptide-HLA-II complex (pHLA-II), which is achieved when the peptide binds with high affinity to the HLA-II molecule. Such highly antigenic non-self peptides occur in melanoma-associated proteins and could be used as antitumor agents when bound to a matching HLA-II molecule. The objective of this study was to identify such peptides from 15 melanoma-associated proteins. We determined in silico the predicted binding affinity (IC50) of all pHLA-II pairs between 192 common HLA-II molecules and all possible linear 15-amino acid (15-mer) peptides (epitopes) of 15 known melanoma-associated antigens (N = 3466 epitopes) for a total of 192 x 3466 = 665,472 determinations. From this set, we identified epitopes with strong antigenicity (predicted best binding affinity [PBBA] IC50 < 50 nM). Of a total of 665,472 pHLA-II tested, 5941 (0.89%) showed strong PBBA, stemming from 117 HLA-II alleles and 679 distinct epitopes. This set of 5941 pHLA-II pairs with predicted high antigenicity possesses the requisite information for devising multipeptide vaccines with those epitopes alone or in combination with the corresponding HLA-II molecules. The results obtained have a major implication for cancer therapy, namely that the administration of subsets of the 679 high antigenicity epitopes above, alone or in combination with their associated HLA-II molecules, would be successful in engaging CD4+ T helper lymphocytes to augment the cytotoxic action and memo