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关键词： 胫骨横向骨搬移术   糖尿病足溃疡   免疫球蛋白   创面愈合机制   截肢率  

摘要： 目的探讨胫骨横向骨搬移术(tibial transverse transport,TTT)治疗Wagner 3~4级2型糖尿病足溃疡的临床疗效以及免疫球蛋白水平变化趋势。方法回顾分析2022年5月—2023年9月采用TTT治疗的68例(73足)Wagner 3~4级2型糖尿病足溃疡患者临床资料。其中男49例,女19例;年龄44~91岁,平均67.3岁。糖尿病足溃疡Wagner分级为3级40例、4级28例。2型糖尿病病程5~23年,平均10年。观察并记录创面愈合例数、愈合时间、截肢例数、死亡例数及并发症发生情况。收集TTT治疗糖尿病足的6个关键时间点[术前1 d及术后3 d、7 d(向上横搬移第1天)、14 d(向下横搬移第1天)、21 d(搬移结束后第1天)、36 d(搬移装置去除后第1天)]血清标本,采用流式细胞术检测血清免疫球蛋白水平,包括免疫球蛋白G(immunoglobulin G,IgG)、IgA、IgM、IgE、补体C3(complement C3,C3)、C4、免疫球蛋白轻链κ(immunoglobulin light chainκ,KAP)、免疫球蛋白轻链λ(immunoglobulin light chainλ,LAM)。结果术后68例患者均随访至6个月。术后发生钉道感染3例、切口感染2例。其中5例患者(7.4%)于术后59~103 d截肢、8例患者(11.8%)于术后49~77 d死亡;余55例患者(80.9%)创面均愈合,愈合时间48~135 d,平均80 d。随访至6个月无溃疡复发、截骨周围骨折及截骨区域皮肤坏死发生。55例创面愈合患者血清免疫球蛋白水平检测示,与术前比较,术后3、7 d IgG、IgM水平显著下降(P<0.05),14 d后逐渐恢复至术前水平,36 d达峰值。IgA水平随时间延长持续下调,各时间点与术前比较差异均有统计学意义(P<0.05)。IgE水平变化表现出显著的时间异质性,术后21 d较术前明显下降(P<0.05);其他时间点均高于术前,但差异无统计学意义(P>0.05)。C3水平呈现明确的治疗相关性升高,术后7、14、21 d较术前显著提升(P<0.05),峰值出现在14 d。C4水平变化趋势与C3基本一致但变化幅度较小,术后7、14 d与术前比较差异有统计学意义(P<0.05)。KAP/LAM水平手术前后各时间点差异均无统计学意义(P>0.05)。结论TTT可加速创面愈合,有效治疗糖尿病足溃疡,降低截肢率,临床疗效确切。初步发现TTT治疗糖尿病足溃疡的潜在机制包括,通过动态调控IgG、IgA、IgM和IgE水平平衡炎症与修复过程,C3、C4水平的阶段性升高可能促进组织清理、血管再生和抗感染防御。

关键词： Autoantibodies   Integrin αvβ6   Primary Sclerosing Cholangitis   Prognosis   Ulcerative Colitis   ALP   alkaline phosphatase   anti-αvβ6   anti-αvβ6 autoantibodies   AST   aspartate aminotransferase   AUC   area under the ROC curve   CALiD   Consortium for Autoimmune Liver Disease   CCL11   C-C motif chemokine 11   CCL20   C-C motif chemokine 20   CD   Crohn’s disease   CDCP1   CUB domain-containing protein 1   CD5   T-cell surface glycoprotein CD5   CD244   natural killer cell receptor 2B4   CI   confidence interval   CV-AUC   AUC based on 10-fold cross-validation   ELISA   enzyme-linked immunosorbent assay   GDNF   glial cell line-derived neurotrophic factor   IBD   inflammatory bowel disease   IL-8   interleukin 8   IL-10   interleukin 10   IL-17A   interleukin 17A   IQR   interquartile range   LSM   liver stiffness measurement   Mayo-ES   Mayo Endoscopic Score   MMP-10   matrix metalloproteinase-10   MRCP   magnetic resonance cholangiopancreatography   MRE   magnetic resonance elastography   MSH   Mount Sinai Hospital   NPX   normalized (relative) protein expression   PD-L1   programmed cell death ligand 1   PSC   primary sclerosing cholangitis   ROC   receiver operating characteristic   SCF   stem cell factor   SD   standard deviation   SES-CD   Simple Endoscopic Score for Crohn’s Disease   TB   total bilirubin   TGF   transforming growth factor   TNF   tumor necrosis factor   UC   ulcerative colitis   UC Davis   University of California at Davis   VCTE   vibration-controlled transient elastography  

摘要： Background & Aims Anti-integrin αvβ6 autoantibodies (anti-αvβ6) are found in more than 50% of individuals with ulcerative colitis (UC). We aimed to determine the prevalence of anti-αvβ6 in patients with primary sclerosing cholangitis (PSC) and their association with liver disease severity. Methods Four cohorts of pre-liver transplant patients with PSC were recruited. Patients with inflammatory bowel disease (IBD) and healthy controls (HCs) served as comparators. Total IgG and anti-αvβ6 levels were measured using enzyme-linked immunosorbent assay. Olink inflammation panel was run on a subset of samples. Multivariable linear regression analysis was performed to assess the association between anti-αvβ6 and indices of liver disease severity. Results A total of 137 patients with PSC (including 76 with PSC-UC, 33 with PSC-Crohn’s disease (CD), and 28 with PSC alone) and 160 controls (including 91 with IBD and 69 HCs) were enrolled. Anti-αvβ6 levels were significantly higher in PSC-UC and PSC-CD compared with PSC alone ( P < .0001 and P < .003) and HCs ( P < .0001 and P < .0001). However, anti-αvβ6 levels in PSC alone were not increased compared with HCs. In patients with PSC-IBD, anti-αvβ6 levels correlated with markers of liver disease severity, including alkaline phosphatase level (r = 0.32; P = .004), the revised Mayo PSC risk score (r = 0.25; P = .02), and liver stiffness measurement (r = 0.43; P = .008) after adjusting for age, gender, race/ethnicity, and IBD subtype. Additionally, anti-αvβ6 levels were associated with markers of systemic inflammation and tissue remodeling. Conclusion Anti-αvβ6 autoantibodies identify a subset of patients with PSC with concomitant IBD.

关键词： 母-胎免疫耐受   泛素化   免疫检查点   FBXo38   PD-1  

摘要： 目的探讨FBXo38通过介导PD-1泛素化降解调控妊娠免疫耐受的机制;方法流式细胞术分选复发性自然流产(unexplained recurrent spontaneous abortion,URSA)患者及正常妊娠孕妇外周血及蜕膜组织中CD4^(+)T及CD8^(+)T细胞,qRT-PCR检测免疫细胞表面PD-1及FBXo38的RNA表达水平,Western印迹法检测其表面PD-1及FBXo38蛋白的表达;免疫共沉淀验证CD4^(+)T和CD8^(+)T表面PD-1与FBXo38之间是否存在相互作用;体外及体内实验观察IL-2对CD4^(+)T细胞表面PD-1及FBXo38在RNA和蛋白水平表达的影响;结果与正常妊娠组相比,URSA患者外周血及蜕膜组织CD4^(+)T及CD8^(+)T细胞表面PD-1及FBXo38的RNA表达水平无明显变化;URSA患者蜕膜组织CD4^(+)T表面PD-1蛋白表达水平明显下降,FBXo38蛋白表达水平明显升高;URSA患者蜕膜组织PD-1表达显著下降而FBXo38明显增加。两组患者CD8^(+)T表面PD-1与FBXo38蛋白表达水平在外周血和局部蜕膜组织中均无明显差异。Co-IP实验证实CD4^(+)T细胞表面存在FBXo38及PD-1的相互作用。IL-2在蛋白水平能增加FBXo38的表达,且能增加正常妊娠模型孕鼠的胚胎丢失率。免疫组织化学检测结果证实IL-2可诱导蜕膜局部组织FBXo38的高表达,同时抑制PD-1的表达。结论URSA患者蜕膜组织CD4^(+)T细胞表面PD-1的蛋白表达水平显著下降,同时FBXo38蛋白呈现高表达,这可能是IL-2通过调控FBXo38的表达介导PD-1的过度降解所致,但其具体机制尚待后续实验进一步证实。

关键词： clinical trial   immune checkpoint inhibitors   melanoma   T cells   TNF  

摘要： Resistance to immune checkpoint inhibitors (ICI) in cancer patients is not fully understood, and predictive biomarkers are lacking. MELANF alpha (NCT03348891) is an open-label, prospective, multicenter cohort of 60 patients with advanced melanoma receiving ICI (bitherapy: ipilimumab + nivolumab;monotherapy: pembrolizumab or nivolumab). The primary objective was to evaluate whether changes in plasma TNF between baseline (W0) and week 12 (W12) identified patients with non-progressive disease at W12. Secondary and exploratory objectives were to assess the association between plasma TNF, tumor response, and changes in circulating T cells. Plasma TNF increased along therapy, but its W12/W0 fold change was not associated with non-progressive disease at W12. However, plasma TNF levels at W12 were significantly higher in non-responders than in responders across therapies (p = .0129). The remodeling of circulating T cell subpopulations was mostly triggered by bitherapy. Increased proportions of circulating central memory and effector memory CD8 T cells after bitherapy were positively and negatively associated with response to treatment, respectively. In this cohort, circulating T cells from responders and non-responders also displayed distinct molecular characteristics. Indeed, responders showed an increased proportion of CD8 T cells with low enrichment of TNF-related pathways and high cytotoxic potential, while non-responders displayed increased proportions of circulating CD8 EM T cells enriched for TNF-related pathways and directed toward cytokine expression. In conclusion, our study shows that elevated plasma TNF and enriched TNF pathways in T cells are associated with poorer clinical outcomes, reinforcing the notion that TNF may dampen ICI efficacy.

关键词： 配对免疫球蛋白受体B   神经炎症   炎性小体   痛性糖尿病周围神经病变  

摘要： 目的:探讨配对免疫球蛋白受体B(paired immunoglobulin-like receptor B,PIRB)在痛性糖尿病周围神经病变(diabetic peripheral neuropathic pain,DPNP)中的作用及其潜在机制,特别关注其在神经炎症和炎性小体活化中的作用。方法:将小鼠按简单随机抽样方法随机分为4组:假手术组(Sham)、模型组(DPNP)、模型+PIRB阴性对照组(DPNP+AAV control)、模型+PIRB腺相关病毒组(DPNP+PIRB),每组8只。采用腹腔注射链脲佐菌素(streptozotocin,STZ)构建小鼠DPNP模型,并通过血糖升高及机械性痛觉过敏确认模型的成功建立。使用免疫印迹和qRT-PCR评估DPNP小鼠脊髓组织中PIRB的表达水平。通过鞘内注射腺相关病毒(adeno-associated virus,AAV)降低小鼠脊髓中PIRB的表达以进一步研究其作用。采用qRT-PCR检测神经炎症标志物(如IL-1β、IL-6、TNF-α),使用免疫印迹检测NF-κB p65的水平,并通过免疫印迹和免疫组化观察NLRP3炎性小体成分的变化。结果:与Sham组相比,DPNP组小鼠出现显著机械性痛觉过敏,并观察到PIRB的蛋白和mRNA表达水平均显著上调(P<0.05)。通过AAV介导的PIRB敲低实验中,结果显示DPNP+PIRB组小鼠机械性痛觉过敏减轻(P<0.05),并且神经炎症标志物(IL-1β、IL-6、TNF-α)的表达减少。此外,DPNP+PIRB组较DPNP+AAV control组的NF-κB p65和NLRP3炎性小体成分(如Caspase-1、GSDMD和IL-1β)的表达也显著降低。结论:PIRB可能通过调节神经炎症和激活NLRP3炎性小体在DPNP的发展中发挥了关键作用,抑制PIRB的表达可以减轻痛觉过敏现象并减少神经炎症。

关键词： B淋巴细胞肿瘤   (68)Ga-Pentixafor   PET   研究进展  

摘要： B淋巴细胞增殖性疾病和肿瘤在第5版《WHO造血与淋巴系统肿瘤分类》中被归为独立类别,该分类为不同类型B淋巴细胞肿瘤的研究和临床管理奠定了新的框架。^(68)Ga-Pentixafor PET显像不仅为低葡萄糖代谢特征的B淋巴细胞肿瘤的诊断与分期提供了重要的辅助手段,同时通过揭示潜在的分子靶点,推动了诊疗一体化新技术的开发。本文主要综述了^(68)Ga-Pentixafor PET在部分B淋巴细胞肿瘤中的应用进展,包括其在诊断、分期和疗效监测中的最新研究结果,这些研究进展为患者的风险分层、治疗前评估及后续随访提供了新的可能性。

关键词： 皮肌炎   瘙痒症   胸腺基质淋巴细胞生成素   肺疾病,间质性   临床无肌病性皮肌炎  

摘要： 目的按探讨皮肌炎(DM)和临床无肌病性皮肌炎(CADM)患者血清胸腺基质淋巴细胞生成素(TSLP)水平与皮肤瘙痒及肺间质病变之间的联系。方法回顾性分析2019年2月至2022年3月上海交通大学医学院附属瑞金医院61例DM/CADM患者的临床资料,纳人同期35例健康对照采用酶联免疫吸附试验(ELISA)检测DM/CADM患者血清TSLP以及抗黑色素瘤分化相关基因5(MDA5)抗体水平,采用多因子流式检测试剂盒检测血清中12种细胞因子[干扰素(IFN-α2、IFN-、白细胞介素(IL)-4、IL-5等]水平。使用视觉模拟评分评估DM/CADM患者的瘙痒程度,利用GraphPadPrism8.0.1和R(4.3.2)软件分析患者TSLP水平与皮损、炎症指标及肺间质病变严重程度的关系。结果61例DM/CADM患者,男18例(13例DM,5例CADM),女43例(30例DM,13例CADM),年龄(53.08±14.97)岁病程(6.27±4.27)个月。DM/CADM组与健康对照组性别、年龄分布差异均无统计学意义(均P>0.05)。61例患者中,15例(24.59%)抗MDA5抗体阳性,31例(51.67%)伴间质性肺病(ILD),其中11例伴急性/亚急性间质性肺炎(A/SIP)。61例患者VAS瘙痒评分3(0,6)分,20例(32.79%)无瘙痒,11例(18.32%)轻度瘙痒,17例(27.87%)中度瘙痒,13例(21.31%)重度瘙痒。DM/CADM患者血清TSLP水平显著高于健康对照[91.0(34.6,273.0)pg/ml比25.0(0.0,83.5)pg/ml,Z=1502.50,P<0.001]。DM/CADM患者血清TSLP水平与丙氨酸转氨酶(ALT)、乳酸脱氢酶、C反应蛋白、红细胞沉降率以及血清铁蛋白水平之间呈显著正相关,与VAS瘙痒评分、嗜酸性粒细胞(EOS)比例、EOS计数呈显著负相关(均P<0.05)。抗MDA5抗体阳性患者血清TSLP水平显著高于MDA5抗体阴性患者[273.0(103.8,2576.0)pg/ml比67.4(16.9,218.7)pg/ml,P=0.002]。合并A/SIP的患者血清TSLP水平显著高于不合并A/SIP的患者[390.0(168.2,2869.6)pg/ml比67.5(21.8,235.9)pg/ml,P<0.001]。受试者工作特征曲线显示,血清TSLP水平联合MDA5抗体检测对于DM/CADM患者合并A/SIP的预测价值(AUC=0.922)比单独使用MDA5抗体(AUC=0.831)或TSLP(AUC=0.824)更高。结论DM/CADM患者血清TSLP水平显著高于健康对照,其中抗MDA5抗体阳性患者以及合并A/SIP的患者血清TSLP水平更高。TSLP水平与多种反映病情活动度的指标具有相关性,血清TSLP水平联合MDA5抗体对于A/SIP的预测价值高于单独使用MDA5抗体或血清TSLP水平。

关键词： 噬菌体展示技术   RhE抗原   红细胞同种免疫   小分子多肽   胎儿/新生儿溶血病  

摘要： 目的通过采用噬菌体展示技术鉴定与RhE抗原特异性结合的小分子多肽,为小分子多肽免疫预防RhE同种免疫提供理论基础。方法人工合成具有RhE抗原特异性氨基酸的1条多肽(FLWMFWPSVNSPLLR-SPIQRKNA)作为靶目标,利用噬菌体展示技术,将随机噬菌体十二肽库与人工合成的多肽进行体外筛选,通过2轮体外筛选和单克隆噬菌体ELISA鉴定后,进行扩增纯化。对阳性噬菌体克隆进行测序,推导出与RhE抗原特异结合的外源性多肽氨基酸序列,通过抗体抑制实验鉴定与RhE抗原特异性结合的靶向多肽。结果利用噬菌体随机12肽库对靶多肽进行2轮淘选结果显示,与靶多肽特异性结合的噬菌体明显富集。从富集的噬菌体中随机挑取96个噬菌体克隆进行ELISA检测,结果显示23个与靶多肽有较好亲和力的阳性克隆,再次经过ELISA验证,其中13个噬菌体克隆的检测结果与初次鉴定结果一致,提示这些克隆与靶蛋白具有较好的亲和力。将上述13个噬菌体克隆扩增,提取单链DNA测序分析,翻译获得5条氨基酸序列:THDRNNTPVWRF,TPYETIFDPRTS,TFWQMSADTQAL,AASSTLSIYPPR和SHDTRSPFTWGR。与抗-E抗体的竞争性抑制实验结果显示5个噬菌体展示肽与抗-E均具有竞争性抑制作用。结论基于噬菌体展示技术成功地鉴定出与RhE抗原特异性结合的5个小分子多肽,可能为将来小分子多肽预防HDFN提供研究基础,也为预防RhE抗原同种免疫提供新思路。

关键词： biomarker   cutaneous lupus erythematosus   cytokines   digital ELISA   interferons   systemic lupus erythematosus  

关键词： UIO-66   Enrichment   Selective adsorption   Photocatalysis   Fenton-like reaction   4-CP  

摘要： Persistent organic pollutants (POPs) represent a significant environmental and health risk due to their high toxicity, persistence, strong accumulation potential, and adverse effects on human health. 4-Chlorophenol (4CP), a type of POP, has low catalytic efficiency at low concentrations and is easily interfered with by other pollutants, making its degradation challenging. A new "recognition-enrichment-in-situ degradation" strategy is introduced to selectively remove chlorophenols from contaminated aqueous environments. In this study, ionic liquids were incorporated into the UIO-66 framework as active sites for selective adsorption. 4-CP contains phenolic hydroxyl groups and exhibits high polarity. The dispersive interactions between 4-CP and ionic liquids, along with hydrogen-bonding interactions between the Tf2N anion and the hydroxyl groups of 4-CP, enhance the selective enrichment of 4-CP within the nanocavities of the metal-organic frameworks (MOFs). Fe3+ was then introduced, enabling in-situ degradation of 4-CP through photo-induced generation of free radicals and cavities from H2O2 catalyzed by Fe-IL@UIO-66. The results indicated that the adsorption capacity of IL@UIO-66 for 4-CP reached 53 %, significantly higher than that for five other organic pollutants. The adsorption capacity of IL@UIO-66 for 4-CP reached 509.5 mg g- 1, 49.9 % greater than that of the original UIO-66. The degradation efficiency of 4-CP by Fe-IL@UIO-66 increased from 61 % to 81 %, and after four cycles, the material retained a catalytic activity with a degradation efficiency of 64.2 %. This study provides valuable insights into the recognition-enrichment-in-situ catalytic strategy for treating low-concentration, highly toxic wastewater.