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关键词： ankylosing spondylitis   cancer   recurrence   risk   tumour necrosis factor inhibitors  

摘要： OBJECTIVE:To investigate the effect of tumour necrosis factor inhibitors (TNFi) on the risk of cancer recurrence in patients with ankylosing spondylitis (AS) and a history of cancer. METHODS:We conducted a nested case-control study using a cohort derived from a nationwide database. The cohort consisted of patients with AS and a history of cancer after AS diagnosis. We determined cases of cancer recurrence and selected controls at a ratio of 1:1, matched for age, sex, date of index cancer diagnosis, and follow-up time. Multivariable conditional logistic regression analysis was used to assess the effect of TNFi exposure on the risk of cancer recurrence. RESULTS:A total of 2,574 patients with AS and a history of cancer were included in the cohort. Among these, cancer recurred in 394 (15.3%) patients. The incidence rate of cancer recurrence was 4.87 (95% confidence interval [CI] 4.40-5.34)/100 person-years. From this cohort, 254 cases and age-, sex-, index date-, and follow-up time-matched 254 controls were included for the nested case-control study. The proportion of patients exposed to TNFi did not differ between the cases and controls (24.8% vs. 24.4%, p = 0.918). In the multivariable conditional logistic regression analysis, TNFi exposure was not associated with an increased risk of cancer recurrence (adjusted odds ratio 1.157, 95% CI 0.734-1.825, p = 0.531). CONCLUSION:TNFi exposure was not associated with an increased risk of cancer recurrence in patients with AS. Our findings suggest that TNFi may be used with caution in patients with AS and a history of cancer.

摘要： Accurate prediction of symptomatic radiation therapy-induced pneumonitis (RT-IP) remains an important clinical challenge. Currently, mean lung dose and volume of the lungs receiving a 20 Gy threshold of ≤20 Gy and ≤35%, respectively, are utilized to reduce the incidence of pneumonitis to 20%. However, its occurrence is not entirely predictable even at the recommended threshold levels. Hence, in this study, we aimed to evaluate several biological markers, specifically chromosome aberrations by peptide nucleic acid fluorescence in situ hybridization (PNA-FISH), γH2AX, serum IL-6, and IL-17, as potential predictors of symptomatic (grade ≥2) radiation therapy-induced pneumonitis. We prospectively enrolled patients with locally advanced lung cancer. Peripheral blood samples were collected from eleven patients before, during (2 Gy, 20 Gy, 60/66 Gy), and one month after chemoradiotherapy. We then compared these biomarkers between overreactors (grade ≥2 RT-IP) and non-overreactors (grade 0 to 1 RT-IP). Our findings show that chromosome aberration frequency, serum IL-6, and IL-17 after 20 Gy are higher in overreactors than in non-overreactors. Moreover, overreactors accumulated more complex aberrations, such as tricentrics, quadricentrics, and quintacentrics. While chromosome aberration frequency correlated with mean lung dose and IL-17, a pneumonitis marker, IL-6 correlated with the irradiated volume after 20 Gy. Receiver operating characteristic curve analysis further showed that chromosome aberration frequency and IL-6 have the highest specificity for predicting grade ≥2 RT-IP among the assays. In conclusion, we demonstrated the superior predictive capability of PNA-FISH-based chromosome aberration frequency and serum IL-6 for radiation therapy-induced pneumonitis in lung cancer patients. This supports the usefulness of these biomarkers for predicting radiation therapy-induced pneumonitis.

关键词： Omicron   核衣壳蛋白   多克隆抗体   γ干扰素(IFN-γ)   白细胞介素1β(IL-1β)  

摘要： 目的 旨在研究新型冠状病毒Omicron（BA.1、BA.2）N蛋白的免疫学功能，并评估不同新冠病毒突变株N蛋白的免疫原性差异。方法 运用序列比对确定Omicron（BA.1、BA.2）N蛋白相对新冠病毒原型株（Wuhan-Hu-1）的突变位点，以pET-28a-N-Wuhan-Hu-1质粒为模版经单点突变或同源重组构建pET-28a-BA.1/BA.2-N。利用原核系统分别表达上述三种N蛋白，经Ni-NTA亲和层析柱纯化后免疫小鼠。运用间接ELISA和Western blot法检测多克隆抗体的效价和反应性以及免疫小鼠脾脏细胞中白细胞介素1β（IL-1β）和γ干扰素（IFN-γ）的表达水平。结果 成功利用构建的原核表达质粒在*** BL21(DE3)中表达了Wuhan-Hu-1 N、BA.1 N和BA.2 N蛋白，表达条件为37 ℃，4 h。间接ELISA试验测得三种N蛋白制备的多克隆抗体效价均为1:51200。三种N蛋白均可使IFN-γ和IL-1β两种细胞因子表达升高，但是Omicron N蛋白较Wuhan-Hu-1 N蛋白激活两种细胞因子的效果更为明显。结论 研究获得了三种新冠病毒N蛋白及多克隆抗体，并证实了N蛋白发生氨基酸位点的突变会对其免疫原性产生影响。这为开发针对不同新冠变异株N蛋白的快速诊断方法提供了依据。

关键词： 竹荪多糖   小脑浦肯野细胞   NLRP3炎症小体   细胞焦亡   乙醇暴露  

摘要： 目的：探究竹荪多糖（DIP）通过抑制NLRP3/GSDMD/IL-1β信号通路缓解慢性乙醇暴露对小鼠小脑浦肯野细胞（PC）的损伤。方法：构建小鼠慢性乙醇暴露模型，按照随机数字表法分成5组（n=8）：（1）对照组（Control， Con），（2）Con+DIPH，（3）20%乙醇组（Ethanol， EtOH），（4）20% EtOH+DIPL，（5）20% EtOH+DIPH。利用步态试验和转棒试验检测小鼠的运动协调和平衡能力，ELISA实验检测白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）的表达水平。苏木精-伊红（H&E）染色观察PC的形态，尼氏染色观察PC尼氏小体的分布及形态，钙结合蛋白（Calbindin）染色观察PC的形态、分布和数量，Tunel染色观察PC凋亡情况。利用胶质纤维酸性蛋白（GFAP）染色和离子钙结合衔接分子-1（Iba-1）染色观察胶质细胞增殖状态，2'，3'-环核苷酸 3'-磷酸二酯酶染色可用于反映髓鞘的完整性，甘氨酸银染用于观察PC轴突的改变，透射电镜（TEM）观察PC表面的形态、突触的数量、细胞膜、细胞核以及线粒体的损伤情况，免疫印记法检测小脑组织内NLRP3炎症通路相关蛋白表达水平，高尔基染色观察PC树突棘的改变。结果：与Con组相比，EtOH组小鼠的运动协调性和平衡力显著降低（P<0.01）。H&E、尼氏、Calbindin染色结果显示，EtOH组小鼠PC数量显著减少（P<0.01），GFAP及Iba-1阳性细胞数量明显增多（P<0.01， P<0.01）且大量PC有脱髓鞘病变以及轴突和树突丢失的现象（P<0.01， P<0.01），NLRP3炎症通路下游蛋白表达水平显著升高。TEM显示，PC突触密度显著降低，突触后致密区（PSD）长度变短、厚度变薄，神经元内线粒体嵴消失，线粒体空泡化，DIP干预后，小鼠的运动协调性和平衡能力明显好转，PC的数量及形态恢复正常，检测到NLRP3炎症通路下游蛋白表达水平明显降低，GFAP和Iba-1阳性细胞的表达数量显著下降以及PC的突触数量增加、PSD长度增长、厚度增加以及神经元内线粒体形态有所改善。结论：DIP能够通过抑制NLRP3炎症通路缓解乙醇对小鼠小脑PC的损伤、运动能力损伤以及PC超微结构得到改善，抑制PC发生焦亡。

关键词： Artemisia annua   Allergic rhinitis   IL-17A   Sublingual immunotherapy (SLIT)  

摘要： The mechanisms underlying immune tolerance induction during sublingual immunotherapy (SLIT) of seasonal allergic rhinitis (SAR) remain insufficiently understood. This study aimed to investigate the molecular and immunological process involved in SLIT. RNA sequencing (RNA-seq) and bioinformatics analyses were performed to examine the functions of differentially expressed genes (DEGs) in leukocytes from 11 SAR patients at three time points: baseline, peak pollen phase (PPP), and end-of-treatment. Patients received a 4-month SLIT course with Artemisia annua (A. annua) extract (n = 5) or placebo (n = 6). Plasma cytokine levels were measured in a validation cohort of 15 SAR patients (9 in the SLIT group and 6 in the placebo group) using Luminex assays. The results showed that A. annua SLIT inhibited the upregulation of IL-17A-associated pathways and the expression of inflammatory mediators, including CXCL1, CCL7, and PLPP3, while enhancing myeloid immune cell function by increasing the expression of CD36, TYROBP, FCGR1A, and FCER1G. Additionally, A. annua SLIT reactivated myeloid immune cell-associated genes that were downregulated during PPP and significantly reduced IL-17A and GRO-β levels in plasma, compared to the placebo group. These findings suggest that A. annua SLIT alleviates SAR by modulating IL-17A pathways, reducing inflammatory responses, and enhancing myeloid immune cell function.

关键词： Spinal cord injury   PRP-Derived exosomes   Cerebrolysin   Drug delivery   Target therapy  

摘要： Context/objectiveSpinal cord injury (SCI) is a severe condition characterized by neuronal apoptosis and inflammation, with limited therapeutic options. This study aimed to assess the effects of platelet-rich plasma (PRP)-derived exosomes (Exo), Cerebrolysin (CBL), and Cerebrolysin-loaded exosomes (CLE) on inflammation, apoptosis, tissue organization, and motor function recovery in a mouse model of compression *** experimental study using a mouse model of SCI, investigating the effects of Exo, CBL, and CLE ***-based research in a controlled *** healthy adult female BALB/c mice, aged 8-10 weeks, weighing 24 +/- 2 g were used. SCI was induced via compression to model *** with induced SCI were treated with Exo, CBL, or CLE. Apoptosis was assessed by Bax and Bcl2 expression. Inflammatory markers TNF-alpha and IL-10 were measured. Histological analysis examined tissue organization, and motor function recovery was evaluated using the Basso-Beattie-Bresnahan (BBB) locomotor *** measuresThe study measured Bax and Bcl2 expression, TNF-alpha and IL-10 levels, tissue organization, and motor function *** treatment significantly modulated Bax and Bcl2 expression, reducing apoptosis and enhancing neuronal survival. TNF-alpha levels decreased, indicating reduced inflammation, while IL-10 levels increased, showing anti-inflammatory effects. Histological assessment revealed improved tissue organization, and motor function recovery was significantly enhanced as measured by BBB *** showed neuroprotective and anti-inflammatory effects, reducing apoptosis and inflammation while promoting tissue repair and motor function recovery in SCI, making it a promising therapeutic candidate.

摘要： Optimizing vaccine design to induce CD8 T cell responses has been challenging, but lipid nanoparticle (LNP)-encapsulated mRNA vaccines effectively generate CD8 T cell memory. Interleukin-12 (IL-12) supports CD8 T cell expansion and acquisition of effector function, but the role of IL-12 in the generation of CD8 T responses to mRNA vaccination is unclear. Here, we determine that endogenous IL-12 is not required for CD8 T cell responses to mRNA-LNP vaccination. We assessed the adjuvant activity of an mRNA-LNP encapsulating a codon-optimized mRNA that encodes both subunits of IL-12 (LNP-IL-12). Coadministration of LNP-IL-12 with ovalbumin (OVA) mRNA-LNPs enhanced CD8 T cell expansion and effector function and expanded circulating, effector, and tissue-resident memory CD8 T cells. LNP-IL-12 increased CD8 T cell responses against SARS-CoV-2 and influenza virus antigens and improved protection against -OVA and B16F0-OVA melanoma. Thus, modification of mRNA-LNP formulations to include a cytokine mRNA provides a strategy to enhance CD8 T cell-mediated protection.

关键词： A型口蹄疫病毒   VP1基因   单克隆抗体   cELISA检测方法   血清型特异性  

摘要： 旨在解决传统口蹄疫病毒（FMDV）多克隆抗体ELISA检测中存在的非特异性反应问题，开发针对中国和东南亚地区流行的A型FMDV SEA-97拓扑型毒株的高特异性单克隆抗体的制备与检测方法。通过基于亚洲流行的A型FMDV SEA-97拓扑型毒株的VP1基因，构建重组表达质粒，用原核系统高效表达并纯化VP1蛋白。采用三步筛选策略（间接ELISA初筛、竞争ELISA验证、血清型特异性鉴定），从免疫的BALB/c小鼠中筛选出稳定分泌A型FMDV特异性单克隆抗体的杂交瘤细胞系（10H2-F2），亚型鉴定为IgG1/κ。建立基于单克隆抗体的竞争ELISA，优化抗原包被条件，显著提升检测性能。与O型FMDV及其他9种偶蹄动物病原体（如猪瘟病毒、猪繁殖和呼吸综合征病毒、猪细小病毒、猪圆环病毒、伪狂犬病病毒、蓝舌病病毒、牛病毒性腹泻病毒、羊痘病毒、赤羽病病毒）无交叉反应（抑制率≤22%）；可检测A型FMDV阳性血清256倍稀释样本，较现有方法提升2倍；与血清中和试验的总符合率达97.3%（Kappa=0.945 2）；单克隆抗体在4℃和－20℃保存6个月后抑制率变异系数<0.3%，批间重复性优异（F=0.2，P>0.8）。所以，建立的竞争ELISA方法具有高度特异性、敏感性及稳定性，为亚洲地区A型FMDV抗体精准检测、疫苗免疫效果评估及疫情监测提供了可靠技术支撑，填补了针对区域性流行毒株的特异性诊断工具的空白。

关键词： Melanoma   Bispecific T cell engager - BiTE   Immunotherapy  

摘要： Background Melanoma is a highly aggressive skin cancer, especially in advanced stages. While current treatments such as targeted therapies and immunotherapies have made significant progress, challenges like drug resistance and limited effectiveness in some patients persist. Therefore, ongoing development of novel therapies, particularly for late-stage melanoma, is *** In this study, we explored the expression of interleukin-13 receptor subunit alpha-2 (IL13R alpha 2) in melanoma patient-derived xenograft models. We investigated IL13R alpha 2 as a potential target for melanoma treatment by employing an IL13R alpha 2-CD3 bispecific T-cell engager (BTE). We tested the effect of IL13R alpha 2-CD3 BTE on T cell activity by flow cytometry. We studied the potency of IL13R alpha 2-CD3 BTE in tumor killing assay in vitro. For in vivo studies, we administered DNA expression cassettes encoding IL13R alpha 2-CD3 BTE (IL13R alpha 2-CD3 DNA encoding BTE (dBTE)) into immunodeficient mice for direct in vivo expression. The mice were challenged with A375 cells and then treated with IL-13R alpha 2-CD3 dBTE versus control and reconstituted with human peripheral blood mononuclear cells (PBMCs) or T cells. Tumor development was monitored, and T cell infiltration in the tumor was analyzed throughflow *** Our findings revealed heterogeneous expression of IL-13R alpha 2, particularly in samples from advanced stages of melanoma. The IL13R alpha 2-CD3 BTE facilitated T-cell activation and proliferation by bridging melanoma cells and T cells. We also observed the ability of IL13R alpha 2-CD3 BTE to direct T cells to kill multiple melanoma patient-derived cell lines through xCELLigence assay in vitro, including those with various mutations associated with late-stage metastatic melanoma. IL13R alpha 2-CD3 dBTE expressed in vivo led to notable tumor regression through inducing increased T-cell infiltration and activation within the tumor *** The