Secretion of human soluble programmed cell death protein 1 by chimeric antigen receptor-modified T cells enhances anti-tumor efficacy

Background aimsChimeric antigen receptor (CAR) T cells have achieved favorable responses in patients with hematologic malignancies, but the outcome has been far from satisfactory in the treatment of tumors with high expression of immunosuppressive molecules. To overcome this limitation, we modified CAR T cells to secrete types of human soluble programmed cell death protein 1 (PD-1) called sPD-1 CAR T cells.MethodsTo compare the effector function between second (conventional second-generation CAR targeting CD19) and sPD-1 CAR T cells, we measured cytotoxicity, cytokine secretion and activation markers incubated with or without tumor cells expressing CD19 and/or programmed cell death ligand 1 (PD-L1). Furthermore, the anti-tumor efficacy of second and sPD-1 CAR T cells was determined using an NSG mouse model bearing NALM-6-PD-L1. Finally, the underlying mechanism was investigated by metabolic parameters and RNA sequencing analysis of different CAR T cells.ResultsCompared with second CAR T cells, sPD-1 CAR T cells enhanced killing efficiency toward CD19⁺PD-L1⁺ tumor cells in vitro. Furthermore, sPD-1 CAR T cells reduced the tumor burden and prolonged overall survival of the NSG (NOD-SCID-IL2rg) mice bearing NALM-6-PD-L1. To explore the effect of soluble PD-1 on CAR T cells, we found that sPD-1 CAR T cells exhibited higher levels of activation and ameliorative profiles of differentiation, exhaustion, glycolysis and apoptosis.ConclusionsWith constitutive soluble PD-1 secretion, sPD-1 CAR T cells have tended to eradicate tumors with a high expression of PD-L1 more effectively than second CAR T cells. This may be due to soluble PD-1 enhancing apoptosis resistance, aerobic metabolism and a more “stem” differentiation of CAR T cells. Overall, our study presents a feasible strategy to increase the efficacy of CAR T cells.     

Soluble Co-Signaling Molecules Predict Long-Term Graft Outcome in Kidney-Transplanted Patients

Co-signaling molecules are responsible for full T-cell activation after solid organ transplantation. Their increased expression can lead to the release of a soluble form that can modulate the immune response post-transplantation. We analyzed the presence of co-signaling molecules (sCD30, sCD40, sCD137, sCTLA-4, sCD80, sCD28, sCD40L, sPD-1, and sPD-L1) in serum from kidney-transplanted patients (n = 59) obtained at different times (before transplantation, and 15 days, 3 months and 1 year post-transplantation) and their contribution to graft outcome was evaluated using principal component analysis. Before transplantation, high levels of soluble co-signaling molecules (mainly sCD30, sCD137 and sCD40) were detected in all patients. These molecules were modulated soon after receiving an allograft but never attained similar levels to those of healthy controls. A signature based on the determination of six soluble co-stimulatory (sCD30, sCD40, sCD137 and sCD40L) and co-inhibitory (sPD-1 and sPD-L1) molecules at 3 months post-transplantation allowed a group of patients to be identified (27.12%) with a worse long-term graft outcome. Patients with high levels of soluble molecules showed a progressive and gradual deterioration of kidney function (increased creatinine and proteinuria levels and decreased estimated glomerular filtration rate) over time and a higher risk of graft loss at 6 years post-transplantation than patients with low levels of these molecules (62.55% versus 5.14%, p<0.001). Thus, our data show an aberrant expression of soluble co-signaling molecules in kidney-transplanted patients whose quantification at 3 months post-transplantation might be a useful biomarker of immune status and help to predict long-term graft evolution.     

银屑病患者血清sPD-1、C反应蛋白及LRG1的表达与病情严重程度的关系

摘要 目的：探讨银屑病患者血清sPD-1、C反应蛋白及LRG1的表达与病情严重程度的关系。方法：选取2019年1月至2022年12月我院收治的银屑病患者70例纳入研究组,并选取同期体检健康者70例纳入对照组。按照患者病情将研究组患者进行进一步分组,分为进行期（21例）、静止期（22例）、退行期（27例）。采用ELISA检测sPD-1、CRP、LRG1的表达水平。采用Pearson检验分析sPD-1、CRP、LRG1的表达与银屑病患者病情的关系;采用logistics回归分析分析银屑病患者不同分期的独立危险因素;采用受试者工作曲线（ROC）分析sPD-1、CRP、LRG1对银屑病患者病情发展的预测价值。结果：三组患者年龄和性别比较（P＞0.05）;进行期sPD-1、CRP、LRG1、PASI积分显著高于静止期和退行期（P<0.05）,静止期sPD-1、CRP、LRG1、PASI积分显著高于退行期（P<0.05）;sPD-1、CRP、LRG1的表达与银屑病分期及PASI评分均显著相关(P<0.05),而与年龄和性别无关（P＞0.05）;多因素logistic回归分析结果显示,sPD-1、CRP、LRG1是影响银屑病患者病情分期的独立危险因素;sPD-1、CRP、LRG1拟合诊断预测银屑病患者病情分期的敏感度86.00%,特异度89.00%,AUC值为0.813。结论：sPD-1、CRP、LRG1的表达上调与银屑病患者疾病分期密切相关,临床早期可通过监测sPD-1、CRP、LRG1的表达对银屑病患者病情的发展做出可靠的预测评估。     

High Serum Level of Soluble Programmed Death Ligand 1 is Associated With a Poor Prognosis in Hodgkin Lymphoma

Blockade of the programmed cell death 1-programmed cell death ligand 1 pathway is a new and promising therapeutic approach in Hodgkin lymphoma (HL). To our knowledge, the impact of soluble programmed cell death ligand 1 (sPD-L1) serum levels on HL patient prognosis has not yet been investigated. In this study, the prognostic value of sPD-L1 was assessed in patients with HL. We measured serum sPD-L1 levels and identified their prognostic value in 108 newly diagnosed HL patients using an enzyme-linked immunosorbent assay (ELISA). We found higher serum sPD-L1 concentrations in HL patients than in healthy controls. The best sPD-L1 cutoff value for predicting disease progression risk was 25.1674 ng/ml. The 4-year progression-free survival (PFS) rates for the high-sPD-L1 and low-sPD-L1 groups were 78.8% and 93.3%, respectively. Multivariate survival analysis showed that advanced stage and higher sPD-L1 levels (>25.1674 ng/ml) were independent prognostic factors for shorter PFS. In addition, higher sPD-L1 levels were positively correlated with advanced stage and negatively correlated with peripheral blood monocyte number. The serum sPD-L1 level is an independent prognostic factor for PFS in HL patients and may allow identification of a subgroup of patients who require more intensive therapy and who may benefit from anti-PD-1 agents.     

可溶性人sPD-L1及其抗体的制备和鉴定

通过固定化金属离子亲和层析进行柱上复性与纯化,获得高纯度的可溶性PD-L1胞外域(sPD-L1),其纯度达95%,纯化的sPD-L1经免疫印迹分析得到验证,并具有与其受体PD-1的特异性结合活性;以该抗原免疫小鼠获得高滴度的抗血清,并以制备的sPD-L1-HiTrap亲和层析柱纯化获得高纯度特异性抗体;将该抗体与另一商业化抗体结合建立了一种灵敏的双夹心ELISA法,检测范围为1ng/mL~100ng/mL,可用于分析可溶性PD-L1的含量。可溶性sPD-L1及其抗体的制备不仅可用于人体内特异性抗体和可溶性PD-L1的检测,同时也为进一步研究其体内外活性及其受体的性质提供了条件。     

Induction of IL-13 production and upregulated expression of protease activated receptor-1 by RANTES in a mast cell line

PD-L1 (CD274) is a critical membrane-bound costimulatory molecule that inhibits immune responses through its receptor, PD-1. Previous data have showed that this molecule is associated with autoimmune diseases, chronic viral infections and tumor immune escape. However, the existence and role of soluble form of human PD-L1 (sPD-L1) remain unknown. We show here that a novel enzyme-linked immunosorbent assay (ELISA) was developed to detect the sPD-L1 protein. Many culture supernatants of the PD-L1⁺ cell lines contain high levels of this factor. Interestingly, the sPD-L1 is detectable in human serum and the concentration increases in an age-dependent manner. Human sPD-L1 has a unique protein form in the serum and the matrix metalloproteinase inhibitor (MMPI) could suppress sPD-L1 production. Moreover, the sPD-L1 could specially bind to PD-1. Together, these data demonstrate that the existence of circulating sPD-L1 in human serum might play an important role in immunoregulation.     

Elevated Concentrations of Circulating Intercellular Adhesion Molecule 1 (ICAM-1) and of Vascular Cell Adhesion Molecule 1 (VCAM-1) in HIV-1 Infection

The aim of this study was to determine whether elevated levels of circulating forms of the soluble adhesion molecules, Intercellular Adhesion Molecule-1 (cICAM-1), Vascular Cell Adhesion Molecule-1 (cVCAM-1) and E-Selectin (cE-Selectin) are observed in the sera of HIV-1 infected individuals as compared to healthy HIV seronegative adults and whether these elevated levels can be correlated with disease progression. Significantly elevated levels of cICAM-1—ranging from 184 to 1116 ng/ml with a mean of 617 ng/ml—and cVCAM-1—ranging from 653 to 3456 ng/ml with a mean of 1500 ng/ml—were observed in the sera of 29 HIV-1 infected individuals as compared to controls-ranging from 152 to 354 ng/ml with a mean of 248 ng/ml for cICAM-1 and from 328 to 792 ng/ml with a mean of 560 ng/ml for cVCAM-1 (P < 0.001). The serum concentrations of cE-Selectin of the HIV-1 infected individuals did not differ from those of the healthy controls. The elevated levels of cICAM-1, cVCAM-1 did not correlate with the CD4 count or the serum concentration of C-reactive protein. However, a significant correlation was observed between the serum concentrations of cVCAM-1 and those of neopterin. Since cICAM-1 as well as cV-CAM-1 can interfere with adhesion events leading to immunological functions, it can be suggested that the high amounts of these circulating forms of adhesion molecules, when present in the sera of HIV-1 positive individuals, can further disturb the immune system of these patients. In addition, the present study also suggests that the seric concentrations of cVCAM-1 can be used as pronostic indicators.     

Higher serum sPD-L1 levels after radiotherapy indicate poor outcome in hepatocellular carcinoma patients

BackgroundOur preclinical research reveals that radiotherapy (RT) promoted PD-L1 upregulation in tumor tissues and that higher PD-L1 after RT worsened the prognosis through immunosuppression. We sought to validate our experimental results in clinical cohorts and promote clinical application.Patients and methodsIn cohort 1, formalin-fixed paraffin-embedded samples were obtained from 46 HCC patients, 23 of whom received preoperative RT and the other 23 received direct surgery. A prospectively collected database contained 122 HCC patients treated with liver RT were enrolled in cohort 2. Blood samples were taken a day before and two weeks after RT. Patients in cohort 2 were further divided into two groups, exploration (73 patients) and validation (49 patients) groups.ResultsIn cohort 1, RT increased the expression of PD-L1 in tumor tissues (p = 0.001), and PD-L1 levels were associated with decreased cytotoxic T-cell infiltration and a trend toward poor prognosis (p = 0.14). Moreover, PD-L1 expression in tumor tissue positively correlated with soluble (s) PD-L1 in serum (R = 0.421, p = 0.046). Then, in cohort 2, we revealed RT increased sPD-L1 in serum (p < 0.001), which was associated with the number of circulating CD8+ T cells (R = -0.24, p = 0.036), indicating poor survival. Furthermore, patients with higher rate of sPD-L1 increase after RT have better treatment response (p < 0.001), PFS (p = 0.032) and OS (p = 0.045).ConclusionHigher post-RT serum sPD-L1, which may potentiate immune suppression effects, indicates a poor prognosis for HCC patients treated with RT.     

卡瑞利珠单抗联合TACE对伴微血管侵犯肝细胞癌患者肿瘤标志物、血管生成因子和血清PD-1、PD-L1的影响

摘要 目的：观察卡瑞利珠单抗联合肝动脉化疗栓塞术（TACE）对伴微血管侵犯肝细胞癌（HCC）患者肿瘤标志物、血管生成因子和血清程序性细胞死亡蛋白-1（PD-1）、程序性死亡配体-1（PD-L1）的影响。方法：根据随机数字表法将2021年6月~2023年7月期间我院收治的121例伴微血管侵犯HCC患者分为对照组（n=60,接受肝癌根治术和TACE治疗）和研究组（n=61,对照组的基础上接受卡瑞利珠单抗治疗）。对比两组疗效、血清肿瘤标志物水平[甲胎蛋白（AFP）、癌胚抗原（CEA）、异常凝血酶原（PIVKA-Ⅱ）、糖类抗原199（CA199）]、血管生成因子水平[血管内皮生长因子受体2（VEGF-R2）、血管生成素-2（Ang-2）、血管内皮生长因子（VEGF）]、血清PD-1、PD-L1水平、不良反应。结果：与对照组相比,研究组的临床总有效率更高（P<0.05）。与对照组治疗后相比,研究组CEA、AFP、CA199、PIVKA-Ⅱ、VEGF、VEGF-R2、Ang-2、PD-1、PD-L1更低（P<0.05）。两组不良反应发生率比较未见差异（P>0.05）。结论：卡瑞利珠单抗联合TACE治疗伴微血管侵犯HCC患者,可改善血清肿瘤标志物,可抑制血管生成和降低血清PD-1、PD-L1水平,有效控制疾病进展。     

Role of circulating soluble CD40 as an apoptotic marker in liver disease

OBJECTIVES: To measure levels of soluble CD40, a laboratory marker of apoptosis in patients with liver disease, determine its origin, and correlate the findings with disease activity and histology. DESIGN: Laboratory research study with comparison group. SETTING: Liver Institute, Laboratory of HLA Typing and Histopathology Department, Rabin Medical Center, Israel. SUBJECTS: One hundred ten patients with liver disease and 20 healthy controls. METHODS: Serum samples were collected from all patients; in addition, paired hepatic and portal vein samples were collected from 23 patients, and bile samples from 5 patients. Soluble CD40 was measured with an enzyme-linked immunosorbent assay. Apoptotic cells in liver tissue were identified by morphological criteria and quantified with the TUNEL assay. RESULTS: Soluble CD40 concentration was significantly higher in patients with liver disease than controls (mean 112.9 +/- 197.2 pg/ml vs. 24.2 +/- 9.1 pg/ml, p = 0.0001), with highest levels in the chronic viral hepatitis group (mean 131.7 +/- 137.5 pg/ml, p = 0.0001). Levels of sCD40 were correlated with serum creatinine, alkaline phosphatase, alpha-feto protein, and the apoptotic index. In the 23 paired samples, CD40 level was higher in the hepatic vein (mean 74.9 +/- 114.5 pg/ml) than the portal vein (mean 51.6 +/- 67.9 pg/ml); it was highly detectable in bile (mean 115.6 +/- 119.6 pg/ml, p = 0.0123). Untreated patients with chronic viral hepatitis (B and C) had higher levels (mean 106.2 +/- 76.5 pg/ml) than treated patients (mean 59.3 +/- 68.6 pg/ml, p = 0.049). CONCLUSIONS: Levels of soluble CD40 increase in different types of liver disease. It probably derives from the liver and is secreted into the bile. Levels correlate with the apoptotic index and are affected by antiviral treatment. Soluble CD40 may serve as a serum marker of apoptosis in liver disease.     

Circulating Programmed Death-1 as a Marker for Sustained High Hepatitis B Viral Load and Risk of Hepatocellular Carcinoma

Objective

Recent evidence indicates a crucial role of the immunoinhibitory receptor programmed death-1 (PD-1) in enforcing T-cell dysfunction during chronic viral infection and cancer. We assessed the impact of circulating soluble PD-1 (sPD-1) levels on long-term dynamics of hepatitis B virus (HBV) load and hepatocellular carcinoma (HCC) risk.

Methods

In a case-cohort study on longitudinal analysis of viral load within a cohort of 2903 men chronically infected with HBV, followed up from baseline (1989–1992) through 2010, we determined sPD-1 levels in baseline plasma with enzyme-linked immunosorbent assay from 126 men who subsequently developed HCC and 1155 men who did not develop HCC. To evaluate whether patients'' characteristics involved the use of sPD-1 as a biomarker, sPD-1 was also tested in 614 newly-diagnosed patients with HBV-related HCC recruited from a multicenter study for comparison with the 1155 noncases in the case-cohort study.

Results

Plasma quartile levels of sPD-1 were positively associated with HCC risk for men in the case-cohort analysis (vs. quartile 1: adjusted odds ratios [95% confidence intervals] for quartile 2-quartile 4 were 1.51 [0.75–3.03], 2.15 [1.12–4.13], and 2.29 [1.20–4.38], respectively), and in the case-control study regardless of age-of-onset and clinical stage. Furthermore, we found longitudinal effect of elevated sPD-1 levels to maintain higher viral load for 4 or more years, with greater and more prolonged effect among HBV genotype C- vs. non-C-infected participants. High levels of viral load and sPD-1 (vs. absence of both) was associated with a 6.29-fold increase in risk of HCC, and combining both conditions with HBV genotype C yielded an odds ratio of 30.47 with significant additive interaction (relative excess risk due to interaction: 27.08 [95% confidence interval = 8.76–45.41]).

Conclusions

Our data suggest plasma sPD-1 as an important immune-related marker for assessment of HBV activity and HCC risk.     

TRIM34 modulates influenza virus-activated programmed cell death by targeting Z-DNA-binding protein 1 for K63-linked polyubiquitination

Z-DNA-binding protein 1 (ZBP1) is an innate sensor of influenza A virus (IAV) that participates in IAV-induced programmed cell death. Nevertheless, little is known about the upstream signaling pathways regulating ZBP1. We found that a member of the tripartite motif (TRIM) family, TRIM34, interacted with ZBP1 to promote its K63-linked polyubiquitination. Using a series of genetic approaches, we provide in vitro and in vivo evidence indicating that IAV triggered cell death and inflammatory responses via dependent on TRIM34/ZBP1 interaction. TRIM34 and ZBP1 expression and interaction protected mice from death during IAV infection owing to reduced inflammatory responses and epithelial damage. Additionally, analysis of clinical samples revealed that TRIM34 associates with ZBP1 and mediates ZBP1 polyubiquitination in vivo. Higher levels of proinflammatory cytokines correlated with higher levels of ZBP1 in IAV-infected patients. Taken together, we conclude that TRIM34 serves as a critical regulator of IAV-induced programmed cell death by mediating the K63-linked polyubiquitination of ZBP1.     

Evaluation of oxidative stress, 3-Nitrotyrosine,and HMGB-1 levels in patients with wet type Age-Related Macular Degeneration

BackgroundThis study aims to compare serum HMGB-1, 3-nitrotyrosine (3-NT), TAS, TOS, and OSI levels in Wettype Age-Related Macular Degeneration (wAMD) patients and healthy controls to determine the correlation of these parameters with each other.MethodsThirty patients with Wet-type Age-Related Macular Degeneration (wAMD) and 27 healthy adults, as controls were enrolled in the study. We determined the TAS and TOS levels in serum samples of both groups using commercial kits on a microplate reader. Serum HMGB-1 and 3-NT levels were measured with the enzyme-linked immunosorbent assay method.ResultsHMGB-1 levels were significantly higher in the patient group (137.51 pg/mL, p=0.001), while there was no difference between the two groups in serum 3-NT levels (p=0.428). A statistically significant difference found in the levels of TOS and OSI (p=0.001 and p=0.045, respectively) between the patients and controls, however, no significant difference was observed between the groups in terms of TAS levels (p=0.228).ConclusionsOxidative stress and HMGB-1 levels were increased in wAMD patients and enhanced oxidative stress may be associated with increased tissue necrosis and inflammation. Thus administration of antioxidant treatment in addition to routine therapy should be considered in wAMD.     

Circulating proangiogenic molecules PIGF, SDF-1 and sVCAM-1 in patients with systemic lupus erythematosus

Serum concentrations of three angiogenic cytokines: vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1) and placental growth factor (PIGF) and soluble vascular cell adhesion molecule 1 (sVCAM-1), were investigated in the serum of 61 patients with systemic lupus erythematosus (SLE) and 20 healthy subjects. The possible association between serum levels of these proteins and SLE activity, as well as correlation between the concentrations of cytokines were also analysed. All of these factors were detectable in all SLE patients and the healthy control group. The median concentration of VEGF was higher in active SLE (386 pg/mL) than in inactive disease (327 pg/mL) or in the control group (212 pg/mL, p<0.004). The median serum level of SDF-1 was higher in SLE patients (1,814 pg/mL) than in the control group (1,507 pg/mL, p<0.02). The median concentration of PIGF was higher (14 pg/mL) in SLE patients than in the control group (12 pg/mL, p=0.03), and particularly in active disease (17 pg/mL) as compared to the inactive phase (13 pg/mL, p=0.01). The correlations between the levels of cytokines examined and clinical features, laboratory abnormalities and the type of treatment were also analysed. We found a positive correlation between serum concentrations of PIGF and SLE activity according to SLAM score (p=0.33, p=0.13).     

酚妥拉明联合亚胺培南西司他丁钠对重症肺炎患儿肺功能、炎性因子及血清sTREM-1、sICAM-1水平的影响

目的:研究酚妥拉明联合亚胺培南西司他丁钠对重症肺炎患儿肺功能、炎性因子以及血清可溶性髓系细胞触发受体-1(sTREM-1)、可溶性细胞间黏附分子-1(sICAM-1)水平的影响。方法:选择2018年9月至2019年10月在我院治疗的80例重症肺炎患儿,随机分为对照组(40例)和研究组(40例)。对照组给予静滴亚胺培南西司他丁钠,研究组在对照组基础上静滴酚妥拉明注射液。比较两组患儿临床疗效,对比两组患儿退热时间、肺啰音和咳嗽消失时间及住院时间,比较两组患儿治疗前后肺功能变化情况,测定并比较两组患儿治疗前后血清炎性因子水平变化及血清sTREM-1、sICAM-1水平变化。结果:研究组总有效率(92.50%)明显高于对照组(75.00%),差异具有统计学意义(P0.05);研究组退热时间、肺啰音及咳嗽消失时间和住院时间与对照组相比,均明显减少(P0.05);治疗后,研究组的动脉血氧分压(P_aO_2)和动脉/肺泡氧分压比值(a/APO_2)较对照组明显升高,二氧化碳分压(P_aO_2)较对照组明显降低(P0.05);治疗后,研究组血清白细胞介素(IL)-6、IL-8和C反应蛋白(CRP)及血清中sTREM-1、sICAM-1水平较对照组显著降低(P0.05)。结论:酚妥拉明联合亚胺培南西司他丁钠治疗重症肺炎患儿,可以明显提高肺功能,降低炎性因子水平,降低血清中sTREM-1和sICAM-1水平,促进症状好转,提高疗效,减少住院时间。     

血清TRAF-6、MCP-1、sTREM-1、IL-33水平与脓毒症严重程度及与合并急性肾损伤关系的临床分析

目的:探讨脓毒症患者血清肿瘤坏死因子受体相关因子(Tumor necrosis factor receptor-related factor,TRAF)-6、单核细胞趋化蛋白(Monocyte chemotactic protein,MCP)-1、可溶性髓样细胞触发受体(Soluble myeloid cell trigger receptor,s TREM)-1、白介素(Interleukin,IL)-33水平的变化及与病情严重程度及合并急性肾损伤(acute kidney injury, AKI)的相关性。方法:选择2014年2月到2018年7月在我医院ICU病房进行诊治的脓毒症患者145例,分析脓毒症相关性急性肾损伤(sepsis-associated AKI,SAKI)的发生情况,比较SAKI和非SAKI患者血清TRAF-6、MCP-1、s TREM-1、IL-33水平,采用Pearson相关分析血清TRAF-6、MCP-1、s TREM-1、IL-33含量与APACHEⅡ评分、SOFA评分的相关性,多因素logistic回归分析脓毒症患者发生SAKI的影响因素。结果:在145例患者中,发生SAKI者69例,发生率为47.6%。SAKI组患者的年龄、性别、原发病、白细胞(white blood cell,WBC)计数、C反应蛋白(C reactive protein,CRP)、降钙素原(procalcitonin,PCT)、体重指数、BUN、Scr与eGFR值与非SAKI组患者对比差异均无统计学意义(P0.05)。SAKI组患者APACHEⅡ评分、SOFA评分血清TRAF-6、MCP-1、s TREM-1、IL-33含水平含量均显著高于非SAKI组患者(P0.05)。Pearson相关性分析显示血清TRAF-6、MCP-1、s TREM-1、IL-33水平与SAKI患者的急性生理和慢性健康Ⅱ(acute physiology and chronic health evaluation II,APACHEⅡ)评分、序贯多器官功能障碍(sequential organ failure assessment,SOFA)评分均呈显著正相关性(P0.05)。logistic回归分析显示血清TRAF-6、MCP-1、s TREM-1、IL-33水平升高均为影响SAKI发生的独立危险因素(P0.05)。结论:血清TRAF-6、MCP-1、s TREM-1、IL-33水平与脓毒症严重程度显著相关,可能作为诊断和治疗SAKI的参考指标及干预靶点。     

单核细胞趋化蛋白-1、可溶性血管细胞黏附分子-1与小儿紫癜性肾炎及其并发肾损伤的关系研究

摘要 目的：分析单核细胞趋化蛋白-1（MCP-1）、可溶性血管细胞黏附分子-1（sVCAM-1）与小儿紫癜性肾炎及其并发肾损伤的关系。方法：选择我院在2018年1月至2020年12月期间收治的108例紫癜性肾炎患儿作为观察组,另选108例健康体检儿童作为对照组。检测两组血清MCP-1、sVCAM-1表达水平,分析紫癜性肾炎患儿血清MCP-1、sVCAM-1表达水平与肾功能指标的关系,通过受试者工作特征曲线（ROC）下面积（AUC）评价血清MCP-1联合sVCAM-1判断肾损伤的效能。结果：观察组血清MCP-1、sVCAM-1表达水平均高于对照组（P＜0.05）;观察组24 h尿蛋白定量（24 h Upro）、胱抑素C（Cys-C）、血肌酐（SCr）表达水平均高于对照组（P＜0.05）;经Pearson相关性分析,紫癜性肾炎患儿血清MCP-1、sVCAM-1表达水平均与24 h Upro、Cys-C、SCr表达水平呈正相关（P＜0.05）;在108例紫癜性肾炎患儿中,发生肾损伤34例;肾损伤组血清MCP-1、sVCAM-1表达水平均高于非肾损伤组（P＜0.05）;经ROC曲线分析,血清MCP-1联合sVCAM-1判断紫癜性肾炎患儿发生肾损伤的AUC为0.862,明显大于单一指标MCP-1的0.660和sVCAM-1的0.663（P＜0.05）。结论：紫癜性肾炎患儿血清MCP-1、sVCAM-1表达水平升高,与肾脏受累程度有关,联合判断肾损伤的效能较好,为监测病情演变提供了新的参考依据,值得临床予以重视。     

急性脑梗死患者血清Cav-1、VILIP-1、UCH-L1与神经功能损伤程度、脑梗死面积和预后的关系研究

摘要 目的：探讨急性脑梗死（ACI）患者血清陷窝蛋白1（Cav-1）、视锥蛋白样蛋白1（VILIP-1）、泛素羧基末端水解酶1（UCH-L1）与神经功能损伤程度、脑梗死面积和预后的关系。方法：选择2021年6月至2022年6月徐州医科大学附属医院收治的ACI患者120例为ACI组,另选择同期在本院进行健康检查的健康对象76例为对照组;根据美国国立卫生研究院发布的卒中量表（NIHSS）评分将ACI患者神经功能损伤程度分为轻度组、中度组和重度组,根据脑梗死面积分为大面积梗死组、中面积梗死组、小面积梗死组,根据改良Rankin量表（mRS）评分分为预后良好组和预后不良组,比较对照组与ACI组以及ACI各亚组间血清Cav-1、VILIP-1、UCH-L1水平;分析血清Cav-1、VILIP-1、UCH-L1水平与梗死面积、NIHSS评分、mRS评分的相关性,采用受试者工作特征（ROC）曲线分析血清Cav-1、VILIP-1、UCH-L1预测ACI神经功能损伤程度、脑梗死面积和预后的价值。结果：血清Cav-1、VILIP-1、UCH-L1水平对照组低于ACI组（P＜0.05）;轻度组低于中度组,中度组低于重度组（P＜0.05）;小面积梗死组低于中面积梗死组,中面积梗死组低于大面积梗死组（P＜0.05）;预后良好组低于预后不良组（P＜0.05）。ACI患者血清Cav-1、VILIP-1、UCH-L1与NIHSS评分、梗死面积及mRS评分呈正相关（P＜0.05）。血清Cav-1、VILIP-1、UCH-L1联合预测ACI神经损伤程度、脑梗死面积、预后的曲线下面积（AUC）分别为0.927、0.907、0.953,均大于单指标检测。结论：ACI患者血清Cav-1、VILIP-1、UCH-L1水平异常升高,且升高程度与患者神经功能损伤程度、脑梗死面积及预后有关,早期联合检测血清Cav-1、VILIP-1、UCH-L1水平有助于ACI病情及预后评估。     

血清MUC1、SCD-1、NLRP3在溃疡性结肠炎患者中的表达与凝血功能异常的相关性

摘要 目的：探讨与分析血清粘蛋白1（MUC1）、硬脂酰辅酶A脱氢酶-1（SCD-1）、含NLR家族PYRIN域蛋白3（NLRP3）在溃疡性结肠炎患者中的表达与凝血功能异常的相关性。方法：2019年8月到2021年7月选择在本院诊治的溃疡性结肠炎患者78例作为病例组（包括轻度组患者50例与中重度组患者28例）,同期选择在本院进行体检的健康人员78例作为对照组,检测三组血清MUC1、SCD-1、NLRP3水平与凝血指标,同时进行相关性分析与影响因素分析。结果：三组的血小板计数（PLT）、平均血小板体积（MPV）、血红蛋白（HGB）对比无差异（P>0.05）。中重度组与轻度组的血清MUC1、SCD-1、NLRP3含量高于对照组,中重度组高于轻度组（P<0.05）。中重度组与轻度组的部分凝血活酶时间（APTT）、凝血酶原时间（PT）低于对照组,纤维蛋白原（FIB）高于对照组,中重度组与轻度组对比也存在差异（P<0.05）。在病例组中,Pearson 分析显示血清MUC1、SCD-1、NLRP3表达水平与凝血指标存在相关性（P<0.05）。Logistic多元回归方程显示MUC1、SCD-1、NLRP3等都为影响患者病情活动度的重要因素（P<0.05）。结论：溃疡性结肠炎患者多伴随有血清MUC1、SCD-1、NLRP3的高表达,也多伴随有凝血功能异常,MUC1、SCD-1、NLRP3表达与凝血功能异常存在相关性,也是影响患者病情活动度的重要因素。     

Circulating soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as diagnostic and prognostic marker in neonatal sepsis

ObjectiveTriggering receptor expressed on myeloid cells-1 (TREM-1) is an important receptor involved in the innate inflammatory response and sepsis. We assessed soluble TREM-1 (sTREM-1) in 112 septic neonates (63 culture-positive and 49 culture-negative) and 40 healthy controls as a potential early diagnostic and prognostic marker for neonatal sepsis (NS).MethodsStudied neonates were evaluated for early- or late-onset sepsis using clinical and laboratory indicators upon admission. sTREM-1 was measured on initial sepsis evaluation and at 48 h after antibiotic therapy. For ethical reasons, cord blood samples were collected from control neonates and only samples from neonates that proved to be healthy by clinical examination and laboratory analysis were further analyzed for sTREM-1.ResultsBaseline sTREM-1 levels were significantly elevated in culture-proven (1461.1 ± 523 pg/mL) and culture-negative sepsis (1194 ± 485 pg/mL) compared to controls (162.2 ± 61 pg/mL) with no significant difference between both septic groups. Culture-positive or negative septic preterm neonates had significantly higher sTREM-1 compared to full term neonates. sTREM-1 was significantly higher in neonates with early sepsis than late sepsis and was associated with high mortality. sTREM-1 was significantly decreased 48 h after antibiotic therapy compared to baseline or levels in neonates with persistently positive cultures. sTREM-1 was positively correlated to white blood cells (WBCs), absolute neutrophil count, immature/total neutrophil (I/T) ratio, C-reactive protein (hs-CRP) and sepsis score while negatively correlated to gestational age and weight. hs-CRP and sepsis score were independently related to sTREM-1 in multiregression analysis. sTREM-1 cutoff value of 310 pg/mL could be diagnostic for NS with 100% sensitivity and specificity (AUC, 1.0 and 95% confidence interval [CI], 0.696–1.015) while the cutoff value 1100 pg/mL was predictive of survival with 100% sensitivity and 97% specificity (AUC, 0.978 and 95% CI, 0.853–1.13). However, hs-CRP cutoff 13.5 mg/L could be diagnostic for NS with a sensitivity of 76% and specificity of 72% (AUC, 0.762 and 95% CI, 0.612–0.925) and levels were not related to survival as no significant difference was found between dead and alive septic neonates.ConclusionsElevated sTREM-1 could be considered an early marker for NS that reflects sepsis severity and poor prognosis.