A novel form of 4-1BBL has better immunomodulatory activity than an agonistic anti-4-1BB Ab without Ab-associated severe toxicity

Agonistic Abs to select costimulatory members of CD28 and TNFR family have shown efficacy in various preclinical cancer immunotherapeutic settings. However, the use of agonistic Abs is often associated with severe toxicity due to non-specific activation of lymphocytes. We hypothesized that natural costimulatory ligands may serve as more potent and safer alternative to agonistic Abs for immunotherapy. In this communication, we focused on 4-1BBL as the molecule of choice because of the pleiotropic effects of 4-1BB signaling in the immune system and the demonstrated therapeutic efficacy of 4-1BB agonistic Abs in preclinical cancer and infection models. We report that a novel form of soluble ligand, SA-4-1BBL, delivered more potent and qualitatively different signals to T cells than an agonistic Ab. Importantly, while treatment of naïve mice with the agonistic Ab resulted in severe toxicity, as assessed by enlarged spleen and peripheral LNs, non-specific T cell proliferation, hepatitis, and systemic inflammatory cytokine production, treatment with SA-4-1BBL lacked these immune anomalies. Agonistic Ab treatment produced full toxicity in FcγR^−/− or complement C1q^−/− or C3^−/− knockout mice, suggesting lack of involvement of stimulatory FcγRs or complement system in the observed toxicity. Naïve and memory T cells served as direct targets of anti-4-1BB Ab-mediated toxicity. Potent immunostimulatory activity combined with lack of toxicity rationalizes further development of soluble SA-4-1BBL as an immunomodulatory component of therapeutic vaccines against cancer and chronic infections.     

4-1BB信号拮抗肿瘤上清诱导的树突状细胞凋亡及其机制

目的研究4-1BB信号对肿瘤上清诱导的小鼠骨髓来源树突状细胞（DCs）凋亡的拮抗作用及其机制。方法IL-4和GM-CSF诱导C57BL/6小鼠骨髓细胞,得到未成熟DCs,磁珠纯化。以抗4-1BB激发型抗体2A或CD40激发型抗体1c10刺激DCs,在不同条件下检测DCs的凋亡情况。以抗体标记NFκ-Bp65亚基,激光共聚焦显微镜检测抗4-1BB激发型抗体2A处理后DCs内NFκ-Bp65亚基向核内的转位情况。结果DCs上4-1BB信号的激发能拮抗由B-16肿瘤上清诱导的DCs凋亡,效果低于CD40信号,并能引起NFκ-Bp65亚基向核区转位。结论4-1BB信号的激发提高了DCs抵抗肿瘤上清诱导凋亡的能力,此作用通过包含NFκ-B通路的相关胞内信号传导途径实现。     

纳络酮治疗新生儿中、重度缺氧缺血性脑病临床观察

目的研究纳洛酮治疗新生儿中、重度缺血缺氧性脑病的临床疗效。方法对于我院新生儿科2005年1月～2007年10月收治的71例中重度缺氧缺血性脑病患儿,回顾性的分为治疗组及对照组,两组在基本治疗的基础上,治疗组予纳洛酮维持,分别于治疗前后测量磷酸肌酸激酶同功酶(CK-BB),及进行新生儿行为神经测定(NBNA)。结果治疗组的CK-BB为(21.5±2.3)μmol/L,对照组为(27.5±3.6)μmol/L,两组比较有显著意义(p<0.01),而治疗组的NBNA评分为(37.3±1.92),对照组为(31.32±1.95),两组比较有显著意义(p<0.01)。结论纳洛酮能有效治疗新生儿中、重度缺氧缺血性脑病,值得临床推广。     

Selective lobar bronchial blockade using a double-lumen endotracheal tube and bronchial blocker

We report our experience of a selective lobar bronchial blockade (SLBB) technique with a bronchial blocker (BB) which was employed successfully with a routine double-lumen endotracheal tube (DLT) in three patients. For the first case, we selectively blocked the infected left lower lobe in a surgical patient with a lung abscess in a DLT setting. For the second case, we applied this method to block the right middle and lower lobes in order to assess air leakage from the upper lobe during video-assisted thoracic surgery (VATS). For the third case, selective continuous positive airway pressure (CPAP) to the blocked lobes on the operative side resulted in oxygenation improvement with one-lung ventilation (OLV) in a DLT. This novel technique provides benefits during general thoracic surgery by preventing contamination, providing a better operative field, and improving oxygenation with lobar CPAP.     

糖原磷酸化酶同工酶 BB 对急性冠状动脉综合征早期诊断价值

目的：检测急性冠状动脉综合征（ACS）患者血清糖原磷酸化酶同工酶BB（GPBB）水平并探讨其早期诊断价值。方法选择ACS患者84例（ACS组）及同期健康体检者20例（对照组）,根据胸痛发生时间将ACS组分为0～2、3～4、5～6、7～12、13～24 h 5个亚组。入选者均检测血清GPBB、肌钙蛋白T（cTnT）、肌红蛋白（Mb）。结果 ACS组GPBB、cTnT、Mb水平分别是（5．74±2．67）、（1．10±2．18）、（276．30±378．26）ng/mL ,对照组分别是（3．25±0．77）、（0．01±0．01）、（35．85±10．73）ng/mL ,差异均有统计学意义（P＜0．05）。ACS组中0～2 h组GPBB阳性率（76．47％）明显高于cTnT （35．29％）及 Mb（41．18％）,差异有统计学意义（P＜0．05）。0～4 h组GPBB ROC曲线下面积（AUC）比cTnT、Mb高,差异有统计学意义（P＜0．05）（AUC分别为0．922、0．732、0．823）。结论 GPBB可以用于ACS患者的早期诊断。     

Administration of Optimum Sustained-Insulin Release PLGA Microcapsules to Spontaneous Diabetes-Prone BB/WorTky Rats

To show the possibility of sustained-release insulin formulation composed of PLGA, the optimum one was administered to BioBreeding rat, a model of spontaneous type I diabetes mellitus (IDDM). Every 2 weeks subcutaneous administration made their blood glucose level depend on the insulin release and food intake. However, all of them kept alive with little change or rather a little gain in body weight. Furthermore, some of pregnant rats with intermittent treatment bore fetuses, although additional insulin therapy seemed necessary. Therefore, the formulation could become a new tool as a provider of basal insulin for IDDM patients.     

阻断4-BB/4-1BB配体信号通路对抑制大鼠肝脏移植免疫排斥反应的实验研究

Background Blocking the 4-1BB/4-1BB ligand （4-1BBL） signal may modulate the secretion of Th1/Th2 cytokines and prolong the survival of the grafts, which play a key role in organ transplantation tolerance. The aim of this study was to investigate the role of blockade of the 4-1BB/4-1BBL co-stimulatory pathway with 4-1BBL monoclonal antibody （mAB） in acute rejection of rat orthotopic liver transplantation. Methods The orthotopic liver transplantation model was set up, while male Lewis rats were used as liver donors and Brown-Norway rats as recipients. The recipient rats were intravenously injected with anti 4-1BBL mAB or isotype control antibody. Groups were monitored for graft survival after transplantation. Plasma chemistry, including aspartate transaminase （AST）, alanine aminotransferase （ALT）, and bilirubin （BIL）, was assayed. The concentrations of interleukin （IL）-2, IL-10 and interferon （IFN）-γ in plasma were also measured by enzyme-linked immunosorbent assay. Allograft histology images were collected under light microscope and electron microscope. Results Isotype antibody treated recipients exhibited elevated plasma levels of liver injury markers including AST, ALT and BIL, progressive portal and venous inflammation and cellular infiltration of the liver ailografts, and a mean graft survival time （MST） of 10.9 days. Administration of anti 4-1BBL mAB resulted in a decrease in plasma levels of liver injury markers and the concentrations of IL-2, IL-10 and IFN-γ. The histological grade of rejection on day 7 decreased and MST （17.3 days） increased substantially. Conclusions These results demonstrate that attenuation of acute rejection follows the blockade of the 4-1BB/4-1BBL co-stimulatory pathway with 4-1BBL monoclonal antibody and strongly suggest it is a promising strategy to prevent progression of graft rejection by suppressing T cell-mediated immunity.     

慢性乙型肝炎的血清血小板衍生生长因子BB检测相关性分析

目的通过对慢性乙型肝炎（CHB）患者血清血小板衍生生长因子BB（PDGF-BB）与血清HBV DNA水平、肝功能损害程度和肝纤维化的相关性分析,以探讨血清PDGF-BB水平在CHB中的应用价值。方法对CHB血清PDGF-BB水平与血清HBV DNA水平、肝功能、血清肝纤维化指标进行相关性分析;并将CHB分为轻度、中度、重度3组,分析血清PDGF-BB水平与血清HBV DNA水平、肝功能分级和肝纤维化指标的相关性。结果 CHB患者血清PDGF-BB水平与肝功能、血清肝纤维化指标均显著相关（P〈0.01）;与肝功能分级和血清肝纤维化指标均呈正相关（P〈0.05）;与血清HBV DNA水平无相关性,差异无统计学意义（P〉0.05）。结论血清PDGF-BB水平与CHB病情发展密切相关,不但可反映CHB患者的肝功能损害程度,也可反映CHB肝纤维化程度,可应用于CHB的肝功能和肝纤维化程度的评估。     

The preventive and therapeutic effects of GCPII (NAALADase) inhibition on painful and sensory diabetic neuropathy

Excitotoxic glutamate release occurs in several neurological disorders. One source is derived from the hydrolysis of the neuropeptide N-acetyl aspartyl glutamate (NAAG) by glutamate carboxypeptidase II (GCPII, also known as NAALADase). Drugs that attenuate glutamate transmission have been shown to relieve neuropathic pain, however side effects have limited their clinical use. It appears that GCPII is exclusively recruited to provide a glutamate source in hyperglutamatergic, excitotoxic conditions and therefore would be devoid of such side effects. Here we report on the therapeutic effects of an orally bio-available GCP II inhibitor on established painful and sensory neuropathy in the spontaneously diabetic BB/Wor rat. It significantly improved hyperalgesia, nerve conduction velocity and underlying myelinated fiber atrophy. The data suggest that GCP II inhibition may provide a meaningful and effective approach to the treatment of painful diabetic neuropathy.