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关键词： RNA sequencing   gene expression   cytokine burden   ixekizumab   guselkumab   abs   absolute value   BL   baseline   BSA   body surface area   CD   Cluster of Differentiation   DEG   differentially expressed gene   FC   fold change   FDR   false discovery rate   GSVA   gene set variation analysis   GUS   guselkumab   IFE   immunofixation electrophoresis   IFNα   interferon α   IFNγ   interferon γ   IL   interleukin   IPA   Ingenuity Pathway Analysis   IXE   ixekizumab   KRT17   keratin   KC   keratinocyte   log   logarithm   LS   lesion   LXR   liver X receptor   NCBI   National Center for Biotechnology Information   NGS   next-generation sequencing   PASI   Psoriasis Area and Severity Index   PC   principal component   PCA   principal component analysis   S100A7   psoriasin   PSTR   psoriasis disease transcriptome   RAG   recombination activating gene   RNAseq   RNA sequencing   RXR   retinoid X receptor   sPGA   static Physician’s Global Assessment of Disease   TNF   tumor necrosis factor   TNFα   tumor necrosis factor α   TNFi   tumor necrosis factor inhibitor   TRM   tissue-resident memory   W   week  

摘要： Ixekizumab, an IL-17A antagonist, and guselkumab, an IL-23p19 antagonist, are common psoriasis treatments. This longitudinal analysis assessed gene expression profiles in ixekizumab- and guselkumab-treated patients with plaque psoriasis through Week 4. In IXORA-R (NCT03573323), a head-to-head Phase 4 study, adults with moderate-to-severe plaque psoriasis were assigned 1:1 to receive ixekizumab or guselkumab. RNA expression was assessed in lesional tissue (N=72) from ixekizumab, guselkumab, and healthy control groups (199 samples total). Empirical Bayes modeled RNA-seq data; differential expression was analyzed by tissue type, treatment, and timepoint, correcting for random effects. At Week 1, lesions from ixekizumab-treated patients had greater numbers of differentially expressed genes (392 up-regulated, 696 down-regulated) than guselkumab-treated patients (0 up-regulated; 0 down-regulated). By Week 4, the numbers of differentially expressed genes increased in both groups (ixekizumab: 1,882 up-regulated, 1,649 down-regulated; guselkumab: 318 up-regulated, 131 down-regulated). Molecular shifts from baseline to Week 4 occurred earlier with greater magnitude in ixekizumab- versus guselkumab-treated patients. Rapid normalization of transcriptomic changes in patients receiving an IL-17A antagonist reflected down-regulation of key inflammatory genes in psoriatic epidermis. Differentially expressed genes involved in epidermal IL-17A and IL-36 responses correlated with PASI 100 response.

关键词： 心房颤动   β   肾上腺素受体   射频消融术   术后复发  

摘要： 目的 探讨β3肾上腺素受体(β3-AR)的表达水平对心房颤动（房颤）患者射频消融术后复发的预测价值。方法 选取2022年01月至2024年02月在昆山市第一人民医院心内科进行首次射频消融的房颤患者（房颤组，n=166）以及同期健康体检者（对照组，n=100）。依据随访结果，患者被划分为两个组别：未复发组124例，复发组42例。收集房颤患者的一般临床资料及相关实验室指标。采用荧光实时定量PCR法检测淋巴细胞β3-AR相对表达量。采用多因素Logistic回归分析房颤术后复发的危险因素；采用受试者工作特征（ROC）曲线分析β3-AR表达水平预测房颤复发的价值。结果 射频消融术后随访9个月，166例房颤患者复发42例，复发率为25.3%。与未复发组相比，复发组患者的LAD及sST2、IL-6水平显著升高，差异有统计学意义（P <0.05）。复发组β3-AR mRNA表达水平显著高于未复发组，差异有统计学意义（P <0.05）。多因素logistic回归分析显示，LAD、sST2、IL-6、β3-AR是房颤术后复发的独立危险因素（P＜0.05）。ROC显示，β3-AR表达水平预测房颤消融术后复发的ROC曲线下面积为0.884（CI95%：0.794～0.975；P <0.05）。结论 房颤患者术前高表达水平的β3-AR与射频消融术后复发有关，β3-AR可作为预测房颤复发潜在的生物学指标。

关键词： Duplex recombinase polymerase amplification   Centrifugal microfluidics   Allele identification   HLA-B*58:01   Point-of-care  

摘要： We developed a fully integrated, portable centrifugal microfluidic platform to detect HLA-B*58:01 allele, a strong genetic risk factor for severe hypersensitivity reactions to allopurinol. This allele is located within the human leukocyte antigen (HLA) locus, which is characterized by its polymorphism and high GC content. The platform is capable of performing on chip lysis, duplex recombinase polymerase amplification (RPA) and realtime fluorescence detection of genomic DNA directly from buccal swab samples. A localized contact heating module was customized to enable fast and efficient sample lysis using a thermophilic proteinase, and a build-in internal control was incorporated to minimize diagnostic errors. All reagents are pre-stored in a disposable microfluidic chip and the swab samples can be added directly without any pre-treatment, achieving a fully automated, walk-away test. As a verification, our platform could simultaneously detect the HLA-B*58:01 allele and the beta-globin gene as an internal control, with a limit of detection (LOD) of 30 pg/mu L and 3 pg/mu L, respectively. Validation using buccal swabs from 12 volunteers demonstrated 100 % concordance with the gold-standard sequencing-based typing (SBT) methods. The platform demonstrated high specificity, reproducibility, and reliability. Compared to SBT, our platform significantly reduces the time-to-result (50 min vs. up to 16 h) while minimizing extensive manual labor. Its fully automated integration of sample lysis and genomic DNA analysis provides a new direction for pharmacogenetic screening, enabling personalized medicine in resource-limited settings.

关键词： 免疫球蛋白轻链   肾功能不全   抗体   单克隆   单克隆免疫球蛋白沉积病   达雷妥尤单抗  

摘要： 目的评估达雷妥尤单抗治疗单克隆免疫球蛋白沉积病（monoclonal immunoglobulin deposition diseases，MIDD）肾损害患者的疗效及安全性。方法该研究为病例系列分析研究，纳入2021年12月至2023年10月在上海交通大学医学院附属瑞金医院肾脏内科开始接受达雷妥尤单抗治疗的MIDD肾损害患者作为研究对象，收集其确诊时及随访期间的临床资料，评估其血液学、肾脏疗效，并记录不良反应事件。结果该研究共纳入7例MIDD患者，男女比例为5∶2，年龄为46（43，52）岁，1例为轻-重链沉积病，余6例为轻链沉积病。5例为经治患者（一线与二线治疗为环磷酰胺、硼替佐米、地塞米松方案），2例为初治患者，其中1例确诊时已开始血液透析。接受达雷妥尤单抗治疗前，7例患者血清游离轻链差值（difference of serum free light chain，dFLC）为52（7，295）mg/L；除1例透析患者外，余6例24 h尿蛋白量为1.1（0.2，4.7）g，血肌酐为178.5（157.8，279.8）μmol/L，估算肾小球滤过率为33.9（24.2，41.1）ml·min-1·（1.73 m2）-1。患者接受达雷妥尤单抗的治疗剂量为17（10，20）次，治疗时间为17（9，23）个月，随访时间为24（13，32）个月。治疗后，5例经治患者中，1例基线dFLC<20 mg/L复查骨髓微小残余病灶阴性，余4例达到或优于完全缓解；肾脏疗效评估中，除1例为部分缓解外，余4例均达到或优于非常好的部分缓解（very good partial response，VGPR）；2例初治患者中，血液学疗效均达到或优于VGPR，1例肾脏疗效达完全缓解，另1例依赖透析。7例患者dFLC为4.9（2.1，11.5）mg/L，其中6例非透析患者24 h尿蛋白量为0.19（0.06，0.42）g，血肌酐为153.0（120.8，188.0）μmol/L，估算肾小球滤过率为40.4（35.2，57.3）ml·min-1·（1.73 m2）-1。达雷妥尤单抗治疗期间，无严重不良反应发生。结论达雷妥尤单抗用于治疗MIDD肾损害患者具有良好的疗效和安全性。所有患者均获得高质量血液学缓解，肾脏达到或优于VGPR的缓解率较高，肾功能改善。

关键词： 牛嵴病毒   结构蛋白   单克隆抗体   双抗体夹心ELISA  

摘要： 本研究旨在制备牛嵴病毒（bovine kobuvirus，BKV）单克隆抗体，并建立一种双抗体夹心ELISA检测方法。利用pET-30a(+)载体，原核表达BKV结构蛋白VP0，VP3和VP1，纯化后分别免疫BALB/c小鼠，三次免疫后分离小鼠脾细胞，与SP2/0细胞融合制备杂交瘤细胞，通过间接ELISA方法筛选，以制备的单克隆抗体为捕获抗体和检测抗体，优化抗体浓度和孵育时间等条件，建立特异性检测BKV的双抗体夹心ELISA方法。结果显示：获得2株稳定分泌单克隆抗体的杂交瘤细胞，分别命名为2A12和5E11，均为抗VP1蛋白抗体；叠加ELISA及抗体可变区序列分析结果表明其识别不同的抗原位点，单抗特异性检测结果显示，2株单抗特异性结合BKV，不与其它牛腹泻病毒结合；分别用RT-PCR方法和本研究建立的双抗体夹心ELISA方法，对107份临床样品进行检测，结果显示双抗体夹心ELISA方法与RT-PCR方法的阳性符合率为92.2%，阴性符合率为95.3%，总符合率为93.5%。综上，本研究制备了2株BKV单克隆抗体，并建立BKV的双抗体夹心ELISA方法，该方法特异性、重复性和敏感性良好，为BKV的快速诊断与防控奠定了基础。

关键词： 急性荨麻疹   过敏原检测   免疫球蛋白E   特异性免疫球蛋白E   白细胞介素6   C反应蛋白   临床价值  

摘要： 目的 探究急性荨麻疹患者血清免疫球蛋白（immunoglobulin E,IgE）、特异性免疫球蛋白（specific immunoglobulin e,s IgE）、白细胞介素-6(interleukin-6,IL-6)、C反应蛋白（C-reactive protein,CRP）水平表达及临床价值。方法 选取2023年3月至2024年3月驻马店市中心医院收治的120例急性荨麻疹患者资料行回顾性研究，并按1∶1比例选取同期体检健康者120例行病例对照研究，比较两组血清IgE、sIgE、IL-6、CRP水平的差异，通过ROC曲线分析血清IgE、sIgE、IL-6、CRP水平诊断急性荨麻疹的价值，以及IgE、s IgE、IL-6、CRP水平的相关性。结果 相较于对照组，研究组吸入性过敏原总检测率、食入性过敏原总检测率更高（P <0.05）；研究组总IgE抗体、过敏原s IgE抗体、CRP、IL-6水平也更高（P <0.05）。ROC曲线分析显示，血清IgE、s IgE、IL-6、CRP水平诊断急性荨麻疹的AUC分别为0.783、0.733、0.784、0.748；敏感度分别为0.492、0.508、0.492、0.500，特异度均为1.000。将上述因素纳入Logistic回归模型，通过回归系数（β值分别为0.028、2.167、0.681、0.257）统计分析得出联合数据（联合数据=0.028×IgE+2.167×sIgE+0.681×IL-6+0.257×CRP）。联合数据诊断急性荨麻疹的AUC为0.865，敏感度、特异度为0.850、0.883。Pearson相关性显示，血清IgE、sIgE、IL-6、CRP水平均呈正相关（r=0.494、0.568、0.576、0.461、0.403,P <0.05）。结论 急性荨麻疹患者血清存在多种过敏原，IgE、s IgE、IL-6、CRP水平表达可作为临床诊断急性荨麻疹的有效指标，且联合数据诊断价值更好。

摘要： Interleukin (IL)-23 is the master pathogenic cytokine in psoriasis and neutralization of IL-23 alleviates psoriasis. Psoriasis relapses after the withdrawal of anti-IL-23 antibodies, and the persistence of IL-23-producing cells potentially contributes to such recurrence, but the cellular source of IL-23 is unclear. Here we show that IL4I1CD200CCR7 dendritic cells (CCR7 DC) are the main producer of IL-23 by concomitantly expressing the IL-23A and IL-12B subunits in human psoriatic skin. Deletion of CCR7 DC completely abrogates IL-23 production in a mouse model of psoriasis, while enforced expression of IL-23a in CCR7 DC elicits not only αβT cell-driven psoriasis-like skin disease, but also arthritis. CCR7 DC co-localize with CD161 IL-17-producing T cells and KRT17 keratinocytes, which are located in the outermost layers of psoriatic epidermis and exhibit IL-17 downstream signatures. Our data thus identify CCR7 DC as the source of IL-23 in psoriasis, and paves the way for IL-23-targeting therapy for suppressing the relapse of chronic inflammatory disorders like psoriasis.

关键词： Anti-IL-6 receptor antibody   Glucocorticoid   Osteoporosis   Aquaporin-4   IL-6   NMOSD  

摘要： Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease characterized by the production of autoantibodies against aquaporin-4 (AQP4). Treatment with prednisolone (PSL) or anti-IL-6 receptor (IL-6R) antibody can reduce the frequency of relapse in patients with AQP4 antibody-positive NMOSD. We previously established a mouse model of paralysis induced by intradermal immunization with AQP4 peptide. In this study, we investigated the effects of PSL and anti-IL-6R antibody treatment on paralysis and on bone fragility in this NMOSD mouse model. Prednisolone and anti-IL-6R antibody treatment each suppressed the clinical scores and incidence of paralytic symptoms in AQP4 peptide-immunized mice. High-PSL treatment induced thinning of cortical bone and reduction of tissue mineral density in the femoral shaft and a decrease in femoral bone strength, although it increased bone volume/tissue volume in the trabecular bone of the distal femur. In contrast, anti-IL-6R treatment showed no significant differences in bone strength or cortical thickness compared to the non-immunized naive group. Bone morphometric analysis showed that high-PSL treatment reduced the bone formation rate in both cortical and trabecular bone, with a predominance of bone resorption, whereas anti-IL-6R treatment demonstrated no notable effect on bone metabolism. These results suggest that anti-IL-6R antibody can prevent the development of paralytic symptoms in AQP4 peptide-immunized mice without reducing bone strength.

关键词： DQB1 mismatch   HLA matched unrelated donor   MMUD   MUD   PTCy   donor age   mismatched unrelated donor  

摘要： Background In unrelated donor hematopoietic cell transplantation (HCT) with post-transplantation cyclophosphamide (PTCy), the clinical relevance and interplay between an isolated HLA-DQB1 mismatch and donor age remain unclear. Methods We conducted a single-center retrospective analysis of 988 consecutive patients with hematologic malignancies undergoing a first unrelated donor HCT with PTCy prophylaxis between 2017 and 2024. We compared outcomes among recipients of 10/10 matched unrelated donors (10/10-MUD; n=854), 8/8 MUD with an isolated HLA-DQB1 mismatch (n=47), and 7/8 mismatched unrelated donors (7/8-MMUD, n=87). Multivariable analyses were performed using Cox proportional hazards models for cause-specific hazards for outcomes with competing risks. Outcomes included overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM), relapse, and acute and chronic GVHD, adjusting for relevant covariates. Results In multivariable analysis, there was no statistically significant difference in OS, PFS, NRM, or relapse between the three donor groups. Compared to the 10/10 MUD group, the adjusted hazard ratio (HR) for OS was 1.10 (95% CI, 0.75–1.61, p=0.64) in the 7/8-MMUD group and 0.84 (95% CI, 0.48–1.48, p=0.55) in the DQB1 mismatch group. Similarly, for NRM (p=0.69), adjusted HRs were 1.24 (95% CI, 0.73–2.11) for 7/8-MMUD and 0.92 (95% CI, 0.45–1.89) for DQB1 mismatch. For relapse (p=0.46), HRs were 0.79 (95% CI, 0.46–1.34) and 0.72 (95% CI, 0.34–1.53), respectively. Chronic GVHD risk was not significantly different (p=0.21), with HRs of 1.53 (95% CI, 0.85–2.76) for 7/8-MMUD and 0.61 (95% CI, 0.23–1.64) for DQB1 mismatch. Acute GVHD risks, however, differed. The 7/8-MMUD group had a significantly higher risk of grade III-IV acute GVHD (HR=2.91; 95% CI, 1.43–5.92; p=0.003), whereas the DQB1 mismatch group had an increased risk of grade II-IV acute GVHD (HR=1.63; 95% CI, 0.98–2.71; p=0.062), though this did not reach statistical significance. Donor

关键词： Rheumatoid arthritis   autoimmune disease   disease activity score   erythrocyte sedimentation rate   seronegative rheumatoid arthritis   seropositive rheumatoid arthritis   tumor necrosis factor alpha  

摘要： INTRODUCTION:14-3-3η (eta), an intracellular chaperonin, is elevated in the serum of patients with Rheumatoid Arthritis, a progressive inflammatory "autoimmune" disease that impacts joint function and daily activities. This study aimed to assess 14-3-3η levels in DMARD-naïve Rheumatoid Arthritis patients and analyze their association with TNF-α, MMP-1, RA factor, ACCP, and disease activity. METHODS:A cross-sectional study was conducted on 90 DMARD-naïve RA patients. The clinical evaluation included the Health Assessment Questionnaire-Disability Index (HAQ-DI) and the Disease Activity Score of 28 joints using ESR (DAS28-ESR). Serum levels of RF, ACCP, 14-3-3η, TNF-α, and MMP-1 were measured using ELISA. Mann-Whitney and Spearman correlation tests were applied, with p < 0.05 considered statistically significant. RESULTS:Among 90 RA patients (76 females, 14 males), 68(75.6%) were seropositive. Serum levels of 14-3-3η and TNF-α differed significantly between seropositive and seronegative groups. TNF- α correlated positively with both 14-3-3η (r = 0.397, p < 0.001) and MMP-1 (r = 0.284, p = 0.007). DISCUSSION:The correlation between 14-3-3η and TNF-α suggests a possible role for 14-3-3η as an adjunctive biomarker in early RA. While findings are promising, the small sample size and lack of follow-up warrant cautious interpretation. Further longitudinal studies are needed to confirm its clinical utility and integration within composite biomarker models. CONCLUSION:Serum 14-3-3η may serve as a supportive biomarker for the diagnosis of early rheumatoid arthritis and assessment of disease activity. Its correlation with TNF-α reflects a potential link to inflammatory burden. Further large-scale, longitudinal studies are needed to confirm its clinical utility.