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关键词： 细胞因子   肿瘤类型   年龄   性别   季节  

摘要： 目的 探讨外周血中12种细胞因子（IL-1β、IL-1Ra、IL-4、IL-6、IL-13、IL-17、Eotaxin、IP-10、MCP-1、RANTES、G-CSF、PDGF-BB）在不同肿瘤类型、年龄、性别及季节的表达差异,系统解析机体免疫状态,为肿瘤免疫治疗提供新思路。方法 回顾性纳入2016年3月～2023年7月于解放军总医院就诊的1 842例恶性肿瘤患者临床资料,所有患者均完成外周血细胞因子检测。入组患者的肿瘤类型包括肺癌、肝癌、胃癌、乳腺癌、结直肠癌、胰腺癌、卵巢癌和食管癌。其中男性1 266例、女性576例;年龄25～92岁。季节分为春季（3～5月）、夏季（6～8月）、秋季（9～11月）、冬季（12～2月）。比较不同肿瘤类型间细胞因子表达差异及同类型肿瘤中细胞因子随年龄、性别、季节的变化及相关性。结果 IL-1Ra、IL-13、IL-17、Eotaxin、G-CSF、IP-10、MCP-1、PDGF-BB和RANTES 9种细胞因子在8种肿瘤中的表达均呈现瘤种差异,差异均有统计学意义（χ2=36.17、21.75、40.02、32.19、28.67、19.08、48.75、26.62、21.37,P <0.001）。其中,IL-1Ra在胰腺癌显著低表达;IL-13在结直肠癌较肝癌升高;IL-17在卵巢癌高表达,而在食管癌低表达;RANTES在肺癌高表达;MCP-1在食管癌高表达;Eotaxin在卵巢癌高表达、肺癌低表达;IP-10在肺癌浓度显著高于结直肠癌;PDGF-BB在胰腺癌低表达;G-CSF在食管癌上调,胰腺癌下调。而IL-1β、IL-4、IL-6 3种细胞因子在8种肿瘤中的表达差异均无统计学意义（P> 0.05）。细胞因子表达与年龄也呈现相关性,IL-4在乳腺癌中与年龄呈正相关（r=0.306,P <0.001）;IP-10在肺癌和结直肠癌中与年龄呈弱正相关（r=0.127、0.294,P <0.001）;Eotaxin在肺癌、肝癌、乳腺癌及结直肠癌中均随年龄升高（r=0.102、0.301、0.506、0.265,P <0.05）;PDGF-BB在肝癌、胃癌、乳腺癌及结直肠癌中呈年龄依赖性下调（r=-0.284、-0.168、-0.316、-0.308,P <0.001）。细胞因子的性别差异性显示,男性肺癌的Eotaxin、肝癌的PDGF-BB、胃癌的G-CSF显著高于女性（Z=-2.29、-3.98、-2.71,P <0.05）;女性肝癌的IL-4、IL-17、Eotaxin、IP-10及胃癌的RANTES均显著高于男性（Z=-2.9、-3.63、-3.39、-2.94、-2.71,P <0.05）。细胞因子的季节特征显示,肺癌IL-1β、IL-17水平呈夏季高[0.60（0.16,1.77）、20.29（13.69,57.18）]、冬季低波动[0.41（0.16,0.94）、16.69（12.28,31.92）],两者比较差异有统计意义（χ2=3.10、2.98,P <0.05）;肝癌IL-1β呈春季表达低谷,与秋、冬季节比较差异有统计学意义（χ2=-3.69、-3.20,P <0.05）,胃癌IL-6、IL-13、IL-1β在秋季表达下调,与春、夏、冬季节比较差异有统计学意义（χ2=3.64、3.05、-4.36,3.91、2.02、-2.16,4.37、2.10、-4.89,P <0.05）。结论 常见恶性肿瘤外周血细胞因子谱受肿瘤类型、年龄、性别及季节因素影响。细胞因子波动可能反映免疫状态,已有证据表明细胞因子与肿瘤免疫治疗疗效及不良反应有关,如何结合这些细胞因子特征优化肿瘤免疫治疗值得未来进一步研究。

关键词： 小儿慢性腹泻   双歧杆菌   维生素AD  

摘要： 分析双歧杆菌联合维生素AD在治疗小儿慢性腹泻中的整体效果。方法 研究获取56例于2024年3月-2025年2月在门诊就诊的小儿慢性腹泻患儿资料,将其随机分组后,对照组纳入的28例病例采取的是常规用药结合双歧杆菌治疗;观察组纳入的28例病例,患者不仅采取双歧杆菌治疗,还结合维生素AD治疗。治疗过程中,记录患者治疗不同时间段的病情变化,统计症状改善情况;评估单药治疗及联合用药的临床疗效;于患者治疗前进行免疫功能评估,治疗结束复查,对比数据变化;统计远期机体免疫情况,随访3个月,统计患儿罹患感染性疾病的比例。结果 经患者治疗时间数据统计,观察组患者较对照组更早康复(P<0.05);对患者的临床疗效评估中,观察组治疗总有效比例偏高于对照组(P<0.05);在患者免疫功能的评估中,经过联合治疗,对照组免疫球蛋白指标相比对照组偏高(P<0.05);随访患儿到出院3个月,观察组患儿罹患感染性疾病的比例偏低于对照组(P<0.05)。结论 双歧杆菌治疗基础上维生素AD的应用,利于小儿慢性腹泻患儿康复,缩短病程的同时,提升了患儿的免疫功能水平,避免感染性疾病发生。

关键词： HIV   pancreas   kidney   transplantation   outcomes   ART   antiretroviral therapy   BMI   body mass index   DDI   drug-to-drug interaction   DM   diabetes mellitus   EBV   Epstein-Barr virus   HR   hazard ratio   HIV   human immunodeficiency virus   HLA   human leukocyte antigen   HOPE   HIV Organ Policy Equity   ISD   immunosuppressant drug   PAK   pancreas after kidney   PLWH   people/patients living with human immunodeficiency virus   PTA   pancreas transplant alone   PWK   pancreas with kidney   SPK   simultaneous pancreas-kidney   UNOS   United Network for Organ Sharing  

摘要： There is limited information on access and outcomes of patients living with human immunodeficiency virus (PLWH) who have undergone pancreas transplantation. We conducted a retrospective cohort study analyzing data from the United Network for Organ Sharing from July 1, 2001, to June 30, 2021. Recipients of pancreas transplant were stratified by HIV serostatus. Graft and patient survival were analyzed using Kaplan-Meier product limit estimates. Multivariable Cox proportional hazard models were generated to identify factors associated with increased mortality or graft loss. Fifty PLWH and 16 380 patients without HIV underwent pancreas (with kidney) transplantation. PLWH were more often male ( P < .001), Black/African American ( P = .009), and on Medicare ( P = .004). There were no significant differences in waiting time ( P = .159) or proportion of patients treated for rejection within 1 year of transplant ( P = .189) between groups. There were no differences in pancreas graft survival ( P = .964) and overall patient survival ( P = .250) between the cohorts. Dialysis status was negatively associated with graft survival. Although PLWH were more likely to represent a historically marginalized population, their outcomes after pancreas transplant were similar to their counterparts without HIV.

关键词： 桥本甲状腺炎   甲状腺过氧化物酶抗体   外周血液单核细胞趋化蛋白1   白介素-13   甲状腺功能  

摘要： 探究桥本甲状腺炎患者血清甲状腺过氧化物酶抗体(TpoAb)、外周血液单核细胞趋化蛋白1(MCP-1)联合白介素-13(IL-13)水平变化。方法 我院2022年1月至2023年12月收治的62例桥本甲状腺炎患者设为患病组,同期62例健康者设为健康组。对两组均检测血清TpoAb、MCP-1、IL-13水平及甲状腺功能指标(TSH、TT4、TT3,采用化学发光免疫法检测)。对比两组指标并绘制ROC曲线,确定TpoAb、MCP-1、IL-13对桥本甲状腺炎的诊断价值。结果 患病组血清TpoAb、MCP-1、IL-13水平高于健康组(P<0.05);TSH高于健康组,TT4低于健康组(P<0.05)。伴临床加减患者、亚临床加减、单纯桥本甲状腺炎患者血清TpoAb、MCP-1、IL-13水平比较有差异(P<0.05),由高到低依次是伴临床加减、伴亚临床加减、单纯桥本甲状腺炎。三组患者血清TSH、TT4水平有差异(P<0.05)。绘制ROC曲线,曲线表面积由高到低依次是联合TpoAb、MCP-1、IL-13(0.875)、TpoAb(0.867)、IL-13(0.800)、MCP-1(0.732)。结论 桥本甲状腺炎患者血清TpoAb、MCP-1、IL-13水平均异常升高,临床可通过检测该指标诊断疾病、评估病情进展,联合诊断能提高诊断价值。

摘要： Interleukin 23 (IL23) is a key driver of autoimmune inflammatory pathology and has been successfully targeted by therapeutic antibodies for the treatment of psoriasis and ulcerative colitis. Identifying small-molecule inhibitors of IL23 signaling is of potential interest for drug development. We report the identification of an induced-fit orthosteric binding pocket on the IL23p19 subunit that may be suitable for small-molecule inhibition. X-ray crystallography was used to determine the structure of the IL23 heterodimer when bound to inhibitory peptide 23-446 and to confirm peptide binding to the IL23p19 subunit at the location of its interface with the IL23 receptor (IL23R). We then applied structure-based design to modify peptide 23-446. This process involved identifying key residues responsible for inhibitory activity and generating structure-activity relationship-optimized peptides with low nanomolar affinity for IL-23 and corresponding inhibitory potency against IL-23R binding. These optimized peptides show promise as potential therapeutic candidates in their own right and may also serve as valuable starting points for further discovery. The most potent of these peptides was used to develop a fluorescence polarization probe and to design a high-throughput screening assay, which was validated through a pilot screen using a small fragment-based compound library. This screening strategy has the potential to support the discovery of peptides or small molecules that bind to the orthosteric pocket, thereby blocking the IL-23R interaction and downstream signaling.

摘要： 偏头痛影响全球超10亿人，其造成的健康寿命损失年总和超过其他神经系统疾病之和。传统预防性治疗药物（如普萘洛尔、托吡酯等）常因疗效不佳或不良反应而被迫停用。即使降钙素基因相关肽（calcitonin gene-related peptide, CGRP）的单克隆抗体及小分子拮抗剂用于治疗偏头痛，仍有40%~70%患者无临床疗效，即每月偏头痛日数减少不足50%。因此，探索新的治疗靶点迫在眉睫。

关键词： arthritis   K/BxN mice   recombinant Fc-hexamer   human IgG1 rFc-mu TP-L309C   Th17 cells   T-regulatory cells   interleukin-1  

摘要： Background/Objectives: Recombinant Fc proteins have been produced that have a protective effect in mouse models of arthritis, such as the K/BxN rheumatoid arthritis model. We have previously shown that a recombinant human IgG1 Fc with a point mutation at position 309, replacing a leucine with a cysteine, fused to the human IgM tailpiece to form a human IgG1 Fc hexamer, rFc-mu TP-L309C, effectively prevents neutrophil infiltration into the joints and ameliorates arthritis in the K/BxN serum transfer model and in the endogenous chronic arthritis K/BxN model. We have now investigated the effect of rFc-mu TP-L309C on T-cells in the K/BxN chronic arthritis mouse model. Methods: PBMCs were isolated from the spleen, lymph nodes and joint synovial fluid from K/BxN mice having severe chronic arthritis that had been treated with 200 mg/kg rFc-mu TP-L309C or human serum albumin (HSA). Flow cytometry was used to isolate the activated CD4+CD44+ T-cells and T-regulatory cells (Tregs). Intracellular staining was used to identify Th1 and Th17 T-cell subsets, and CD4+CD25+FoxP3+ Tregs. ELISA was used to measure levels of IL-10 and TGF-beta in synovial fluid. Results: We find that amelioration of the arthritis occurs after treatment with rFc-mu TP-L309C and results in a decrease in Th1 cells' production of IFN gamma and Th17 cells' production of IL-17. Amelioration also results in decreased production of GM-CSF. Moreover, amelioration results in increased Tregs and IL-10 production in the synovial fluid. Conclusions: rFc-mu TP-L309C reduces the inflammatory T-cells and increases the regulatory anti-inflammatory T-cells in the chronic arthritis K/BxN mouse model. This effect explains, in part, the ability of rFc-mu TP-L309C to ameliorate the arthritis and reduce damage on the articular cartilage of K/BxN mice.

摘要： Erratum

关键词： Scutellaria baicalensis   epiberberine   rheumatoid arthritis   network pharmacology   molecular docking   molecular dynamics simulation   tumour necrosis factor-alpha blocker  

摘要： Scutellaria baicalensis (SB) is used to treat rheumatoid arthritis (RA), but its active compounds and mechanisms are unclear. Tumour necrosis factor-alpha (TNF-alpha) is a key factor in RA, and finding small-molecule TNF-alpha blockers is challenging. This study identified 24 active ingredients in SB and 293 overlapping target genes related to RA. TNF-alpha and Akt1 were identified as hub genes in RA treatment through protein-protein interaction (PPI) analysis, with TNF and PI3K/Akt signalling pathways as core pathways. Molecular docking and molecular dynamics (MD) simulation showed that epiberberine (EPI) from SB had strong binding affinity to TNF-alpha. In vitro, EPI reduced TNF-alpha-induced proliferation and cytokine production in MH7A cells, with minimal effect on apoptosis. Mechanistically, EPI downregulated Akt activation by suppressing TNF-alpha expression. EPI, the predominant active compound from SB, inhibited MH7A cell activation via the TNF-alpha/PI3K/Akt pathway, showing potential as a novel therapeutic agent for RA.

关键词： endocannabinoids   graft-versus-host disease   inflammation  

摘要： Graft-versus-host disease (GVHD), a secondary complication of bone marrow transplantation, leads to the development of a systemic inflammatory illness in the host, resulting in high mortality and morbidity. Current therapies lack prophylactic effectiveness and often fail to achieve an optimal immunological balance between inflammation and immunosuppression. In this study, we investigated the effects of palmitoylethanolamide (PEA), an endocannabinoid-like lipid mediator with extensively documented anti-inflammatory, analgesic, antimicrobial, immunomodulatory, and neuroprotective effects, on the complex pathology of GVHD. Treatment with PEA reduced clinical disease severity in GVHD mice, leading to an 80% increase in survival rates. Additionally, PEA created an immunoregulatory environment in the spleen by reducing the activation of CD3+CD4+ cells. In the intestine, PEA protected against damage, reduced the number of CD3+CD4+ and CD3+CD8+ cells, and suppressed the activation of CD3+CD8+ cells. PEA also decreased the levels of TNF-alpha in the intestine and increased IL-10 production. Furthermore, in the liver, PEA treatment reduced the number of CD8+ cells, the activation of CD3+CD4+ and CD3+CD8+ cells, and TNF-alpha levels. The effect of PEA on survival was dependent on Peroxisome Proliferator-activated receptor gamma (PPAR-gamma) activation but did not rely on cannabinoid (CB) receptors activation. In addition to GVHD protection, PEA treatment did not interfere in the graft-versus-tumour response. These results demonstrate the therapeutic potential of PEA as a promising option for the treatment of GVHD, balancing inflammation and immunosuppression, and improving both survival and clinical outcomes.