课程文献中心 更多>>

摘要： On August 1, 2024, the FDA granted accelerated approval to afamitresgene autoleucel, a melanoma-associated antigen A4 (MAGE-A4)-directed genetically modified autologous T-cell immunotherapy, for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, who are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive, and whose tumors express MAGE-A4 as determined by FDA-approved or cleared companion diagnostic devices. Approval was based on results from the phase II, single-arm, open-label, multicenter Study ADP-0044-002. Patients received a single dose of afamitresgene autoleucel following lymphodepleting chemotherapy. Of the 44 efficacy-evaluable patients, the overall response rate was 43.2% (95% confidence interval, 28.4-59.0), with complete response in two patients (4.5%). The median duration of response was 6.0 months (95% confidence interval, 4.6-not reached) with a median follow-up of 21.9 months. Among the 44 patients, cytokine release syndrome occurred in 75% (grade >= 3, 2%), warranting a boxed warning. Grade >= 3 infections occurred in 14% of patients, and prolonged severe cytopenias also occurred. One patient developed grade 1 immune effector cell-associated neurotoxicity, and one patient developed Epstein-Barr virus-positive lymphoproliferative disease. Notably, during review of this application, the FDA identified issues with data quality and study conduct that prompted an independent re-review of imaging assessments. The results of the re-review were the basis for the FDA's determination of substantial evidence of effectiveness. This represents the first FDA approval of a T-cell receptor gene therapy. It is also the first FDA approval specifically for synovial sarcoma, representing a new treatment modality for this rare population that lacks effective therapies.

关键词： ST段抬高型心肌梗死   非ST段抬高型心肌梗死   淋巴细胞   纤维蛋白原   Logistic模型  

摘要： 目的分析非ST段抬高型心肌梗死(non-ST-segment elevation myocardial infarction,NSTEMI)患者和ST段抬高型心肌梗死(ST-elevated myocardial infarction,STEMI)患者血小板与淋巴细胞比值(platelet to lymphocyte ratio,PLR)、中性粒细胞与淋巴细胞比值(neutrophil to lymphocyte ratio,NLR)、淋巴细胞与单核细胞比值(lymphocyte to monocyte ratio,LMR)及凝血功能指标检测的意义。方法选择2021年1月至2023年12月蚌埠市第三人民医院心血管内科收治的老年(>60岁)急性心肌梗死患者182例,根据心电图特征分为NSTEMI组104例和STEMI组78例,另选取同期于蚌埠市第三人民医院体检的健康者80例作为对照组。入院后检测所有受试者的PLR、NLR、LMR、D-二聚体及纤维蛋白原(fibrinogen,FIB)水平。对比3组血清PLR、NLR、LMR、D-二聚体、FIB水平,采用二元logistic回归分析法构建基于PLR、NLR、LMR、D-二聚体、FIB的评估模型,以ROC曲线分析PLR、NLR、LMR、D-二聚体、FIB评估NSTEMI与STEMI患者的价值。结果STEMI组和NSTEMI组的血清PLR、NLR、LMR、D-二聚体、FIB水平明显高于对照组(P<0.05)。血清PLR、NLR、LMR、D-二聚体、FIB水平为STEMI和NSTEMI患者的独立影响因子(OR=25.078,95%CI:3.147~199.865;OR=32.852,95%CI:4.398~245.417;OR=28.703,95%CI:3.310~248.867,OR=67.491,95%CI:8.518~534.729;OR=46.759,95%CI:8.219~266.006;OR=2.573,95%CI:1.026~6.451;OR=3.442,95%CI:1.750~6.768,OR=2.971,95%CI:1.799~4.907;OR=68.375,95%CI:12.598~371.103;OR=7.471,95%CI:1.759~31.737,P<0.01)。ROC曲线显示,血清PLR、NLR、LMR、D-二聚体、FIB联合评估NSTEMI的曲线下面积(area under curve,AUC)为0.996,敏感性为99.04%,特异性为95.00%;联合评估STEMI的AUC为0.995,敏感性为94.87%,特异性为97.50%,效能优于各指标单独评估(P<0.05)。结论NSTEMI患者与STEMI患者的PLR、NLR、LMR、D-二聚体、FIB水平明显升高,各指标联合测定对于NSTEMI和STEMI的早期诊断具有重要的参考价值。

关键词： 白介素-33   ST2   免疫调节   炎症   肾脏疾病  

摘要： 白介素-33(interleukin-33,IL-33)是白介素-1的超家族成员,是机体炎症的“预警因子”,当细胞坏死或组织损伤时,IL-33被大量释放,与其受体ST2结合形成复合体从而发挥多种生物学效应。在急性肾损伤、梗阻性肾病、糖尿病肾病、IgA肾病、狼疮性肾炎、移植肾等多种肾脏疾病中IL-33/ST2信号通路被激活,通过调节肾脏固有免疫和适应性免疫反应,在炎症及肾脏纤维化中发挥重要作用。本文综述了IL-33/ST2信号在常见肾脏疾病中的研究进展,希望为肾脏疾病的治疗提供新的靶点和思路。

关键词： 体外循环   炎症   细胞因子吸附器   血液吸附   专家共识  

摘要： 体外循环过程中多种原因可引起炎症激活,导致全身炎症反应,进而影响患者预后。本文基于《改善体外循环相关全身炎症反应专家共识》,结合现有临床研究证据及循证医学证据,对细胞因子吸附器在体外循环中的应用价值进行综合分析,为细胞因子吸附器在体外循环过程中的应用提供参考。

关键词： 单克隆抗体   疑难问题   教学建议  

摘要： 人教版高中生物学教材以图文结合的方式详细介绍了单克隆抗体的制备步骤,但在实际教学中仍有许多细节值得探讨。对“特定抗原的注射部位”“骨髓瘤细胞的来源”“制备过程中胎牛血清的使用”“体外培养法与腹水制备的优劣比较”“单克隆抗体药物的安全性评估”等关键问题进行了梳理,促进教师严谨传授知识,提高自身专业素养。

关键词： 猪繁殖与呼吸综合征病毒   NSP9   原核表达   蛋白纯化   多克隆抗体  

摘要： 旨在获得猪繁殖与呼吸综合征病毒(PRRSV)的非结构蛋白NSP9及制备PRRSV NSP9的多克隆抗体。本研究应用PCR技术扩增出全长NSP9目的基因,将其克隆至原核表达载体pET-28a中,同时插入His和Flag融合标签,获得重组质粒pET-28a-NSP9;然后将重组质粒转化至BL21感受态细胞,经IPTG诱导并优化诱导温度和时间,SDS-PAGE和Western blot鉴定,观察NSP9蛋白的表达情况,确定NSP9蛋白的最佳表达条件,应用镍柱亲和层析纯化NSP9蛋白;最后将纯化后的NSP9蛋白免疫BALB/c小鼠,获得多克隆抗体,用ELISA测定抗体效价,Western blot鉴定抗体反应原性。结果:含有pET-28a-NSP9重组质粒的大肠杆菌,在IPTG终浓度为0.2 mmol/L诱导,16℃培养32 h的条件下,NSP9蛋白主要以可溶性形式表达,经镍柱亲和层析纯化成功获得高纯度的NSP9蛋白,经间接ELISA和Western blot测定成功获得特异性的NSP9多克隆抗体。综上,本研究以全长NSP9基因为模板,克隆转化后表达出72 kDa左右的可溶性重组蛋白,利用其作为抗原免疫制备的抗PRRSV多克隆抗体具备良好的生物活性,为后续PRRSV检测、免疫血清诊断试剂的研发及研究PRRSV NSP9的生物学功能奠定了重要基础。

关键词： Hepatitis B virus (HBV)   HBsAg loss   Pegylated interferon α   Outcome   Hepatocellular carcinoma  

摘要： To investigate the risk and influencing factors of long-term liver adverse events in chronic hepatitis B patients achieving hepatitis B surface antigen (HBsAg) clearance after pegylated interferon α (Peg-IFN α) treatment, a retrospective analysis was conducted on 456 patients at Beijing Ditan Hospital from 2008 to 2023 who achieved HBsAg clearance and discontinued Peg-IFN α treatment. The baseline was defined as the time of HBsAg clearance and treatment cessation. The endpoint was the first occurrence of liver adverse events (hepatocellular carcinoma or ascites) or last follow-up. Subsequently, we evaluated the incidence and risk factors of liver adverse events, along with changes in liver fibrosis, cirrhosis, and liver function indicators. During a median follow-up of 70 months, the incidence of liver adverse events was 2.30%, hepatocellular carcinoma 1.76%, and ascites 0.55%. Older age and cirrhosis were significant risk factors (HR 1.075 and 41.393, both P ​< ​0.01). The APRI score significantly improved at follow-up compared to baseline (0.53 vs. 0.25, P ​< ​0.001), and cirrhosis prevalence decreased from 5.70% to 0.88% ( P ​< ​0.001). In conclusion, patients who achieved HBsAg clearance and discontinued Peg-IFN α treatment have a low risk of liver adverse events, while advanced age and cirrhosis remain major risk factors.

关键词： 嗜碱性粒细胞   表型   流式检测   设门  

摘要： 目的研究分析人嗜碱性粒细胞抗原表型特征,探索在多参数流式检测中,对嗜碱性粒细胞进行准确设门分析的标志物。方法选取2022年3月至2023年1月该院的20例健康体检者及26例血液系统疾病患者为研究对象,运用15种抗体对外周血进行多参数流式检测,将嗜碱性粒细胞和成熟中性粒细胞的抗原表达进行比较分析。结果在多参数流式检测中,运用CD123-SSC二维点状图设门可将46例标本的外周血嗜碱性粒细胞明显分群。运用CD203c-SSC二维点状图设门不能将5例健康体检者及7例血液系统疾病患者标本的外周血嗜碱性粒细胞明显分群。碱性粒细胞表达CD203c、CD123、CD63、CD9、CD13、CD33、CD22,不表达CD34、CD117、CD4、CD11b、CD15、CD16、CD64。成熟中性粒细胞表达CD63、CD13、CD33、CD11b、CD15、CD16、CD64,不表达CD34、CD117、CD203c、CD123、CD22。部分标本中性粒细胞表达CD4和CD9。该研究还证实人嗜碱性粒细胞弱表达B淋巴细胞的标志物CD22。结论在多参数流式检测人嗜碱性粒细胞中,CD123是比较稳定的设门标志物,可结合CD45-SSC二维点状图、CD9强表达、CD22弱表达及CD34不表达的特征对嗜碱性粒细胞进行准确设门分析。嗜碱性粒细胞与成熟中性粒细胞均表达CD63、CD13、CD33,嗜碱性粒细胞表达CD203c、CD123、CD9,成熟中性粒细胞表达CD11b、CD15、CD16、CD64。

关键词： 脾脏照射   髓外造血   T淋巴细胞   中性粒细胞   肿瘤微环境  

摘要： 目的观察脾脏照射对荷瘤小鼠肿瘤生长的影响,并探讨其潜在机制。方法将小鼠结肠癌细胞(mouse colon cancer cells,MC38)注射于小鼠右侧背部,建立小鼠单侧皮下瘤模型,待肿瘤最大径达8~10 mm后,将小鼠随机分为对照组与脾脏照射组。另设未荷瘤小鼠组,同时同条件饲养,比较不同组别脾脏变化情况。对照组不进行任何处理,而脾脏照射组则接受每天2 Gy的脾区照射,持续5 d。实验结束时,处死小鼠,收集其肿瘤和脾脏样本,通过流式细胞术分析免疫细胞组成和功能的变化。结果与对照组相比,脾脏照射抑制小鼠肿瘤生长[(586.1±61.3)mm^(3) vs.(945.7±116.5)mm^(3),P<0.001],且肿瘤质量明显降低[(1130±143.4)mg vs.(1800±535.3)mg,P=0.047]。荷瘤小鼠脾脏质量相较于未荷瘤小鼠明显增加,差异有统计学意义[(149.6±38.6)mg vs.(63.2±7.8)mg,P=0.007],而脾脏照射后脾脏质量明显减小,差异有统计学意义[(66.9±6.2)mg vs.(149.6±38.6)mg,P=0.008],且脾脏质量与肿瘤质量呈正相关(r=0.659,P=0.038)。流式细胞术的结果显示,脾脏照射后,CD8^(+)T细胞在脾脏和肿瘤微环境(tumor microenvironment,TME)中的比例明显增加[脾脏:(8.1±0.5)%vs.(5.2±0.6)%,P<0.001;TME:(16.2±3.0)%vs.(11.7±2.2)%,P=0.028]。CD8^(+)T淋巴细胞的杀伤能力[颗粒酶B(granzyme B,GZMB)]和增殖能力(Ki-67)能力在脾脏(GZMB:P=0.030,Ki-67:P=0.033)和TME(GZMB:P=0.031,Ki-67:P=0.027)中也显著提高。此外,荷瘤后小鼠脾脏中中性粒细胞显著增加[(34.3±9.6)%vs.(18.5±4.0)%,P=0.010],而脾脏照射导致中性粒细胞的比例在脾脏[(21.2±4.9)%vs.(34.3±9.6)%,P=0.027]和TME[(9.4±1.8)%vs.(17.4±5.2)%,P=0.012]中明显下降。结论脾脏照射通过抑制荷瘤小鼠髓外造血降低了脾脏和TME中中性粒细胞的比例,并提高了CD8^(+)T淋巴细胞的比例和功能,有效抑制了肿瘤生长。

关键词： blood pressure   endothelium   inflammation   muscle   obesity   smooth  

摘要： BACKGROUND:Loss of endothelial function is a key contributor to obesity-induced hypertension. Obesity can cause chronic, low-grade inflammation, leading to abnormal blood vessel function. The release of inflammatory cytokines is commonly attributed to immune cells, but recent studies suggest that vascular cells can also release these cytokines. We tested the hypothesis that vascular wall-derived inflammatory cytokines act locally to impair endothelial function and elevate blood pressure in obesity. METHODS:The levels of inflammatory cytokines were analyzed in endothelial cells (ECs) and smooth muscle cells (SMCs) from small arteries of high-fat diet-fed mice and individuals with obesity. We utilized inducible, EC- or SMC-specific deletion and receptor inhibition studies to determine whether inflammatory signaling between SMCs and ECs can be targeted to improve endothelial function and lower blood pressure in obesity. RESULTS:TNF (tumor necrosis factor) was selectively upregulated in SMCs from small arteries of obese mice and human subjects with obesity. TNF colocalized with TNFRI (TNF receptor I) at endothelial projections to SMCs or myoendothelial projections in obesity. SMC-specific deletion of TNF or EC-specific deletion of TNFRI improved endothelial function and lowered blood pressure in obese mice. Notably, deleting TNF from ECs or TNFRI from SMCs had no impact on endothelial function or blood pressure in obesity. Furthermore, the deletion of TNF from SMCs or TNFRI from ECs decreased the levels of inducible NO synthase and peroxynitrite, leading to enhanced activity of TRPV4 (transient receptor potential vanilloid 4) ion channels and improved endothelial function. In addition, specific inhibition of TNFRI also rescued endothelial function and lowered blood pressure in obesity. CONCLUSIONS:Overall, these findings show that paracrine signaling from SMCs to ECs via TNF elevates blood pressure in obesity. Consequently, targeting smooth muscle TNF or endothelial TNF