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关键词： Arthritis   Polymorphism, Genetic   Spondyloarthritis   Sulfasalazine   Tumor Necrosis Factor Inhibitors  

摘要： Objectives Factors associated with peripheral arthritis and enthesitis, especially Achilles tendonitis and plantar fasciitis, were examined in a longitudinal cohort of 1075 patients with ankylosing spondylitis (AS) (also known as radiographic axial spondyloarthritis). Methods Patients were derived from the Prospective Study of Outcomes in Ankylosing Spondylitis cohort. Disease activity and functional indices, as well as physical examination and medications used, were measured at every study visit. Univariable and multivariable analyses of the association of peripheral arthritis and enthesitis with clinical, sociodemographic factors were performed. Human leucocyte antigen (HLA)-B alleles were analysed by single-stranded conformational polymorphism analysis. Results Those with peripheral arthritis on examination were more likely to have psoriasis (p=0.001, OR=1.68;CI, 1.11, 2.54), greater functional impairment (p<0.001 OR=1.72;CI, 1.31, 2.27), higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels (p<0.001), greater tumour necrosis factor (TNF) inhibitor (p<0.001, OR=1.50;CI, 1.14, 1.97) and use methotrexate/ sulfasalazine (p<0.001, OR=2.25, CI [1.57, 3.23]). Patients with enthesitis were less likely to be male (p<0.001, OR=0.57;CI, 0.43, 0.75) and have peripheral arthritis (p<0.001, OR=2.35;CI, 1.47, 3.75), greater functional impairment (p<0.001, OR=1.91;CI, 1.43, 2.55) and higher ESR/CRP levels (p<0.001). Patients with plantar fasciitis and/or Achilles’ tendonitis on examination were less likely to male (p<0.001 OR=0.57;CI, 0.43, 0.75), to have significant functional impairment (p<0.001), to be using TNF inhibitors (p<0.001, OR=1.48;CI 1.13, 1.93) and to be using either sulfasalazine or methotrexate (p<0.001, OR=1.86, CI, 1.30, 2.67). HLA-B*15 (p=0.03, OR=1.84;CI, 1.05, 3.21) and HLA-B*37 (p=0.04, OR=3.00;CI, 1.03, 8.74) were marginally increased in frequency in those with peripheral arthritis on examination compared with those without. Conc

摘要： Agonistic anti-CD40 with anti-PD-1 can elicit objective responses in a small number of patients with pancreatic ductal adenocarcinoma (PDA). Better understanding of their individual effects on the PDA tumor microenvironment will help inform new strategies to further improve outcomes. Herein, we map tumor-specific CD8+ T-cell differentiation following agonistic anti-CD40 and/or anti-PDL1 in PDA. Rare Tcf1+Slamf6+ CD8+ T cells (TSTEM) are shown to seed memory precursors that transition into a continuum of exhausted and effector T cells. In tumors, anti-PDL1 drove the clonal expansion of Gzmk+ progenitor exhausted (CD8+ T cells, whereas anti-CD40 promoted CD4+ T-cell clonal expansion and accumulation of CD8+ TTSTEM. Cloning the most frequent intratumoral T-cell receptors (TCRs) revealed identical neoepitope specificity, yet the top TCRs from anti-PDL1  anti-CD40 cohorts lacked tetramer binding suggesting lower affinity. Anti-CD40 + anti-PDL1 markedly drove the clonal hyperexpansion of a unique exhausted T-cell (TEX) subset in spleen. TEX were enriched for IL2R, and provision of IL-15 complex (IL-15C) mitigated systemic and intratumoral T-cell exhaustion when combined with anti-CD40 + anti-PDL1, resulting in enhanced antitumor effects, prolongation of animal survival, and resistance to orthotopic tumor rechallenge. Mechanistically, while anti-CD40 + anti-PDL1 mitigated Tox, IL-15C + anti-CD40 + anti-PDL1 increased T-bet thereby conferring a higher T-bet:Tox ratio in tumor-specific CD8+ T cells. Collectively, agonistic anti-CD40 and anti-PDL1 drove systemic and intratumoral CD8+ T-cell clonal expansion and acquisition of exhaustion features. Provision of IL-15C altered the trajectory of T-cell differentiation induced by immunotherapy, resulting in PDA eradication and long-lived antitumor memory T cells.

关键词： Essential hypertension   Interleukin-33   interleukin-1receptor associated protein   Genetic polymorphisms   rs16865597  

摘要： BackgroundThe IL-33/ST2 pathway plays a crucial role in the development of essential hypertension (EH). This study aimed to investigate the relationship between EH and genetic variations in this pathway in the Chinese Han *** total of 1,151 EH patients and 1,135 healthy controls were included in the study. Sixteen single nucleotide polymorphisms (SNPs) in the interleukin-33 (IL-33) and interleukin-1receptor associated protein (IL-1RAcP) genes were genotyped using the Sequenom MassArray and TaqMan assays. Genotype and allele frequencies were compared between the EH patients and controls using logistic regression *** rs16865597 SNP in the IL-1RAcP gene was found to be associated with the risk of EH. Specifically, the presence of the C allele of rs16865597 was negatively correlated with EH susceptibility in both the additive model (P = 0.014, OR = 0.75, 95% CI = 0.59-0.94) and the recessive model (P = 0.011, OR = 0.72, 95% CI = 0.56-0.93). Additionally, rs16865597 was linked to a reduced risk of EH in specific subgroups, including males (OR add = 0.73, 95% CI = 0.56-0.94, P = 0.015), nonsmokers (OR add = 0.72, 95% CI = 0.54-0.96, P = 0.023), nondrinkers (OR add = 0.70, 95% CI = 0.53-0.93, P = 0.013), and individuals with low BMI (OR add = 0.69, 95% CI = 0.51-0.92, P = 0.013). Moreover, the C genotype of rs16865597 was strongly associated with higher interleukin-10 levels in *** rs16865597 SNP is significantly associated with a reduced risk of EH in the Chinese Han population, potentially due to its role in immune regulation.

关键词： prostate cancer   cardiac glycosides   Lanatoside C   tumor necrosis factor   interleukin-17  

摘要： Prostate cancer remains a leading cause of cancer-related morbidity and mortality among men globally, with limited therapeutic options for advanced and metastatic disease. The therapeutic potential of natural compounds has attracted increasing attention in cancer treatment. Lanatoside C (Lan C), a cardiac glycoside derived from Digitalis lanata, has demonstrated promising anticancer activity across various cancer types. However, its role and mechanisms in prostate cancer remain underexplored. In this study, evidence shows that Lan C significantly inhibits the proliferation of prostate cancer cells, as demonstrated by reduced cell viability, suppressed colony formation, and G2/M cell cycle arrest. Additionally, Lan C promotes apoptosis and inhibits the migration and invasion of prostate cancer cells. Mechanistically, transcriptomic analysis identified differentially expressed genes, which were further validated at both the mRNA and protein levels. Our findings suggest that Lan C exerts its effects by modulating the TNF/IL-17 signaling pathway, influencing the tumor microenvironment and regulating key processes involved in tumor progression, immune response, and apoptosis.

关键词： HLA-DRA   HLA-DQA1   IL-6   Glatiramer acetate   MS  

摘要： Multiple sclerosis (MS) is among the most common autoimmune disorders and is characterized by inflammation and degeneration affecting the central nervous system. Glatiramer acetate (GA) is an immunomodulatory drug utilized for treating relapsing-remitting MS. However, a considerable number of patients do not exhibit an appropriate response to this drug. This condition is known as GA resistance. This study aimed to investigate the relationship between nucleotide variations in the HLA-DRA, HLA-DQA1 and IL-6 genes and GA resistance. Additionally, the relationship of environmental factors with MS was investigated. One hundred thirty-nine MS patients were enrolled in this study. Patients were divided into two groups: non-responders (n = 58) and responders (n = 81). After DNA was isolated from peripheral blood, the rs3135388 and rs3135391 variations in HLA-DRA, the rs9272346 variation in HLA-DQA1, and the rs1800795 and rs1900796 variations in IL-6 were analyzed by Real-Time Polymerase Chain Reaction (RT-PCR). At the end of the study, it was found that the number of females was approximately 3 times greater in responders and 4 times greater in non-responders than in males. When nucleotide variations and allele distributions were compared between the groups, no significant relationships were found. Similarly, no significant relationship was found between risk factors and nucleotide variations. However, in non-responders, the expanded disability status scale and lesion load were found to be significantly high. In conclusion, by increasing the number of patients, more meaningful results can be achieved in future studies. Elucidating the pharmacogenetic characteristics (the drug-gene relationship) of MS patients using GA could lead to the development of personalized treatment strategies.

关键词： 益肾活血方   Toll样受体4/核转录因子-κB信号通路   多发性骨髓瘤   小鼠   炎症反应  

摘要： 目的　探讨益肾活血方通过调控Toll样受体4/核转录因子-κB（TLR4/NF-κB）信号通路对多发性骨髓瘤小鼠炎症反应的影响。方法　常规培养人源多发性骨髓瘤细胞系（RPM18226细胞）。采用随机数字表法将60只小鼠分为对照组、模型组、阳性对照组，及益肾活血方低、中、高剂量组，每组10只。除对照组，其余各组给予RPM18226细胞接种制备多发性骨髓瘤小鼠模型。益肾活血方低、中、高剂量组分别给予益肾活血方5、10、15 g/（kg·d）灌胃，阳性对照组给予罗格列酮5 mg/（kg·d）灌胃，模型组给予等体积生理盐水灌胃，1次/d，连续给药30 d。比较各组腹水量和肿瘤体积，苏木素-伊红（HE）染色观察肿瘤组织病理变化，酶联免疫吸附试验（ELISA）检测血清炎症因子［白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）］，噻唑蓝溴化四氮唑（MTT）法检测脾脏组织B淋巴细胞、T淋巴细胞增殖，Western blotting法检测肿瘤组织中TLR4、NF-кB p65、p-NF-кB p65、IL-1β蛋白表达，实时荧光定量聚合酶链反应（qRT-PCR）检测肿瘤组织中TLR4、NF-кB、IL-1β mRNA表达。结果　与对照组比较，模型组小鼠腹水量和肿瘤体积升高（P<0.05）；与模型组比较，益肾活血方各剂量组和阳性对照组腹水量、肿瘤体积低（P<0.05）；与益肾活血方低剂量组比较，益肾活血方中、高剂量组和阳性对照组腹水量、肿瘤体积低（P<0.05）；与益肾活血方中剂量组比较，益肾活血方高剂量组和阳性对照组腹水量、肿瘤体积低（P<0.05）。益肾活血方各剂量组和阳性对照组瘤体细胞逐渐减少，液化和坏死现象也逐渐消失。与对照组比较，模型组小鼠血清IL-6、TNF-α水平高，B淋巴细胞、T淋巴细胞增殖率低（P<0.05）；与模型组比较，益肾活血方各剂量组和阳性对照组血清IL-6、TNF-α水平低，B淋巴细胞、T淋巴细胞增殖率高（P<0.05）；与益肾活血方低剂量组比较，益肾活血方中、高剂量组和阳性对照组血清IL-6、TNF-α水平低，B淋巴细胞、T淋巴细胞增殖率高（P<0.05）；与益肾活血方中剂量组比较，益肾活血方高剂量组和阳性对照组血清IL-6、TNF-α水平低，B淋巴细胞、T淋巴细胞增殖率高（P<0.05）。与对照组比较，模型组肿瘤组织中TLR4、p-NF-кB p65、IL-1β蛋白表达高（P<0.05）；与模型组比较，益肾活血方各剂量组和阳性对照组肿瘤组织中TLR4、p-NF-кB p65、IL-1β蛋白表达低（P<0.05）；与益肾活血方低剂量组比较，益肾活血方中、高剂量组和阳性对照组肿瘤组织中TLR4、p-NF-кB p65、IL-1β蛋白表达低（P<0.05）；与益肾活血方中剂量组比较，益肾活血方高剂量组和阳性对照组肿瘤组织中TLR4、p-NF-кB p65、IL-1β蛋白表达低（P<0.05）。与对照组比较，模型组肿瘤组织中TLR4、NF-кB p65、IL-1β mRNA表达高（P<0.05）；与模型组比较，益肾活血方各剂量组和阳性对照组肿瘤组织中TLR4、NF-кB p65、IL-1β mRNA表达低（P<0.05）；与益肾活血方低剂量组比较，益肾活血方中、高剂量组和阳性对照组肿瘤组织中肿瘤组织中TLR4、NF-кB p65、IL-1β mRNA表达低（P<0.05）；与益肾活血方中剂量组比较，益肾活血方高剂量组和阳性对照组肿瘤组织中TLR4、NF-кB p65、IL-1β mRNA表达低（P<0.05）。结论　益肾活血方可有效改善多发性骨髓瘤小鼠炎症反应及细胞免疫功能，其机制可能与抑制TLR4/NF-κB信号通路有关。

关键词： antigen presentation   colorectal cancer   MHC   biomarkers   survival  

摘要： The immune system is alerted for virally infected cells in the body by the antigen presentation pathway, which is in turn mediated by the major histocompatibility complex (MHC) class I and II molecules. Cancer cells overcome immune evasion as a major hallmark by downregulation of the antigen presentation pathway. Therefore, the present study aimed to explore the effect of genetic variants in genes involved in MHC class I and II pathways in patients treated with first-line chemotherapy in combination with targeted antibodies in metastatic colorectal cancer (mCRC) patients. Genomic DNA from the blood samples of 775 patients enrolled in three independent, randomized, first-line trials, namely TRIBE (FOLFIRI-bevacizumab, N = 215), FIRE-3 (FOLFIRI-bevacizumab, N = 107;FOLFIRI-cetuximab, N = 129), and MAVERICC (FOLFIRI-bevacizumab, N = 163;FOLFOX6-bevacizumab, N = 161), was genotyped through OncoArray, a custom array manufactured by Illumina including approximately 530K SNP markers. The impact on the outcome of 40 selected SNPs in 22 genes of MHC class I and II pathways was analyzed. We identified several SNPs in multiple genes associated with targeted treatment benefits across different treatment arms in our study population (p < 0.05). Treatment-SNP interaction analyses confirmed a significant treatment interaction with the targeted agents (bevacizumab vs. cetuximab) and the chemotherapy backbone (FOLFIRI vs. FOLFOX) in certain selected SNPs. Our results highlight a potential role for MHC SNPs as prognostic and predictive biomarkers for first-line treatment in mCRC, with differential effects based on the biologic agent and chemotherapy backbone. These biomarkers, when further validated, may contribute to personalized treatment strategies for mCRC patients.

关键词： acute-on-chronic liver failure   COVID-19   SARS-CoV-2   mortality   prognosis   IL-6