Design of CD40 Agonists and Their Use in Growing B Cells for Cancer Immunotherapy

CD40 stimulation has produced impressive results in early-stage clinical trials of patients with cancer. Further progress will be facilitated by a better understanding of how the CD40 receptor becomes activated and the subsequent functions of CD40-stimulated immune cells. This review focuses on two aspects of this subject. The first is the recent recognition that signaling by CD40 is initiated when the receptors are induced to cluster within the membrane of responding cells. This requirement for CD40 clustering explains the stimulatory effects of certain anti-CD40 antibodies and the activity of many-trimer, but not one-trimer, forms of CD40 ligand (CD40L, CD154). The second topic is the use of these CD40 activators to expand B cells (“CD40-B cells”). As antigen-presenting cells (APCs), CD40-B cells are as effective as dendritic cells, with the important difference that CD40 B cells can be induced to proliferate in vitro, whereas DCs proliferate poorly if at all. As a result, the use of CD40-B cells as antigen-presenting cells (APCs) promises to streamline the generation of anti-tumor CD8⁺ T cells for the adoptive cell therapy (ACT) of cancer.     

脂联素在骨代谢中的研究进展

上颌窦侧壁开窗提升是增加后牙骨量的有效治疗方式,其成功取决于新骨的形成和植体的长期存活率。影响上颌窦侧壁开窗提升后新骨形成及植体存活率的因素有很多,例如剩余牙槽骨高度、骨窗尺寸、骨窗覆盖方式、植骨方式等。有学者认为减小骨窗面积能保留更多骨壁,而覆盖生物屏障膜或游离骨块能防止软组织侵入,对于新骨生成和提高植体存活率有一定积极作用。有学者提出将具有分化潜能的成体干细胞、生长因子替代自体骨与其他骨替代材料混合应用以促进新骨形成。有学者提出同期种植时剩余牙槽骨高度的降低或不植骨的侧壁开窗提升方式不会影响新骨形成和植体存活率,从而扩大上颌窦侧壁开窗提升的手术适应证。本文就这几个因素展开讨论。     

Leptin, but not adiponectin, predicts stroke in males

OBJECTIVE: To test whether leptin and adiponectin are risk markers for a first-ever stroke. RESEARCH DESIGN, METHODS AND SUBJECTS: A nested case-referent study identified 276 cases with first-ever stroke (234 cases with ischaemic and 42 with haemorrhagic stroke). Prior to the stroke, they had participated in population-based health surveys in northern Sweden (median time between survey and stroke was 4.9 years). Referents were matched for sex, age, date and type of health survey, and geographical region. Putative risk markers for first-ever stroke, including blood pressure (BP), diabetes, smoking, body mass index (BMI), cholesterol, leptin, and adiponectin, were analysed by conditional logistic regression analysis. RESULTS: Increased BMI, high cholesterol and fasting glucose levels, diabetes mellitus and hypertension were found in future stroke patients. Whereas leptin levels were higher in male subjects (P = 0.004), adiponectin did not differ between groups. A high leptin level independently predicted stroke in men (OR = 2.46; 95% CI 1.08-5.62) but not in women. Adiponectin levels did not predict stroke. Males with high leptin levels developed stroke faster than males with low leptin levels (P = 0.0009), independently of traditional risk factors. CONCLUSIONS: Leptin may be an important link to the development of cerebrovascular disease in men, whereas adiponectin does not associate with future stroke.     

脂联素与缺血性脑血管病

脂联素是一种由脂肪细胞分泌的具有抗炎和抗动脉粥样硬化作用的肽类物质。现已发现,脂联素可阻止动脉粥样硬化的发生和发展。文章对脂联素在脑血管病,特别是缺血性卒中方面的最新研究做了综述,同时阐述了脂联素与其他传统血管性危险因素之间的密切关系。     

脂联素对大鼠慢性间歇性低氧所致心肌重塑的影响

目的：探讨慢性间歇性低氧（chronic intermittent hypoxia,CIH）对心肌重塑的影响及脂联素（adiponectin, Ad）的干预作用。方法将45只Wistar大鼠随机分为3组：正常对照组（NC）,CIH组和CIH＋Ad组。CIH 35d后,使用马松染色分析方法检测左室纤维化程度及使用Western blot方法来衡量Ⅰ型胶原蛋白、Ⅲ型胶原蛋白和TGF-β/smad2/3通路蛋白的表达。通过RT-PCR方法来研究基质金属蛋白酶-2（MMP2）/基质金属蛋白酶的组织抑制剂-2（TIMP-2）的mRNA表达比值情况。结果慢性间歇性低氧处理后,CIH组左心室的纤维化程度显著高于NC组和CIH＋Ad组（P＜0.05）,但NC组和CIH＋Ad组之间差异具有统计学意义（P＜0.05）。CIH组Ⅰ型胶原蛋白和Ⅲ型胶原蛋白和MMP2/TIMP-2的mRNA比值表达最高,NC组表达最低,CIH＋Ad组居中,3组之间均差异具有统计学意义（P＜0.05）。TGF-β/smad通路蛋白在CIH组中表达显著高于NC组和CIH组（P＜0.05）,且NC组和CIH＋Ad组差异具有统计学意义（P＜0.05）。结论慢性间歇性低氧可引起左室重构,而Ad可能通过抑制TGF-β/smad2/3通路改善此损害。     

血清脂联素和一氧化氮及内皮素在糖尿病周围神经病患者中的相关性研究

目的探讨血清脂联素,NO及内皮素在糖尿病周围神经病(DPN)中的作用及其相关性。方法选择糖尿病患者及健康体检者88例,采用病例-对照方法研究,分为3组,其中DPN患者30例为DPN组,单纯糖尿病患者28例为糖尿病组,健康体检者30例为对照组。采用ELISA法测定受试者血清脂联素水平,硝酸还原酶法测定血清NO水平,放射免疫法测定血浆内皮素水平。进行相关性分析。结果与对照组比较,DPN组及糖尿病组血清脂联素和NO水平明显降低,血浆内皮素水平明显增高,差异有统计学意义(P<0.01)。与糖尿病组比较,DPN组血清脂联素和NO水平明显降低(P<0.05),血浆内皮素水平明显升高(P<0.01)。DPN组脂联素与NO呈正相关(r=0.423,P<0.05),NO与内皮素呈负相关(r=-0.440,P<0.05),脂联素与内皮素不相关(r=-0.159,P>0.05);糖尿病组及对照组中脂联素与NO及内皮素不相关(P>0.05)。结论血清脂联素和NO水平降低及内皮素水平增高可能参与了DPN的发病过程,NO作用可能与脂联素的调控有关。     

脂联素通过减轻氧化应激治疗动脉粥样硬化的研究

观察不同滴度的脂联素腺病毒载体对高脂饮食载脂蛋白E基因敲除小鼠动脉粥样硬化模型的影响,以探讨脂联素抗动脉粥样硬化（AS）是否与减轻氧化应激有关。将48只健康成年12周龄载脂蛋白E基因敲除小鼠随机分为4组,对照组,模型组,低剂量脂联素组,高剂量脂联素组。对照组给予正常饮食8周;模型组给予高脂饮食8周;低剂量脂联素组每两周经尾静脉注射脂联素腺病毒载体1．0×108p．f．u,实验期间高脂饮食;高剂量脂联素组每两周经尾静脉注射脂联素腺病毒载体5．0×108p．f．u．实验期间高脂饮食。实验结束后,摘眼球采血取血清,测定总胆固醇（TC）,甘油三酯（TG）,低密度脂蛋白（LDL-C）,高密度脂蛋白（HDL-C）,以及血清脂联素（APN）含量,超氧化物歧化酶（SOD）活性,丙二醛（,MDA）含量,取小鼠主动脉血管。实时荧光定量扩增法（RT-PCR）测定小鼠主动脉血管APN,内皮型一氧化氮合酶（eNOS）的表达。与模型组比较,外源性的脂联素降低了血清TG,TC,LDL-C,MDA的含量,血清SOD活性增加,上调动脉血管中APN和eNOS的表达。AS损伤面积明显减少,分别降低了26％和31％（P＜0．05）,脂纹区的脂滴直径降低极显著（P＜0．01）,随着APN剂量的增加,AS损伤逐步减轻,但是低剂量脂联素组和高剂量脂联素组的差异没有统计学意义。减轻氧化应激是脂联素抑制动脉粥样硬化的一种保护机制和途径。     

Adiponectin protects rat heart from left ventricular remodeling induced by chronic intermittent hypoxia via inhibition of TGF-β/smad2/3 pathway

Objective

Obstructive sleep apnea syndrome (OSAS) is associated with many cardiovascular disorders. Chronic intermittent hypoxia (CIH) is the primary player in OSAS of the many associated factors. This study was in order to investigate the effects of the Adiponectin (Ad) on left ventricular remodeling induced by CIH.

Methods

Forty-five rats were randomly divided into three groups: normal control (NC) group, CIH group and CIH plus Ad supplemented (CIH + Ad) group. After 35 days’ CIH exposure, masson analysis was used to detect the left ventricular fibrosis and western blot was used to measure the protein expression of collagen I, collagen III and TGF-β/smad2/3 pathway. Gene analysis by RT-PCR was used to study the MMP2 and TIMP2.

Results

After CIH exposure, the fibrosis of left ventricular in CIH group was significantly remarkable than that in both NC and CIH + Ad groups (P<0.05), although statistical difference existed between NC and CIH + Ad groups (P<0.05). In addition, the protein expression of collagen I as well as collagen III and the ratio of mRNA levels of MMP2/TIMP2 were the highest in CIH group but the lowest in NC group, with CIH + Ad group in between. There was a significant difference among three groups (all P<0.05). The TGF-β/smad2/3 pathway was activated obviously in CIH group, but less noticeably in CIH + Ad group (P<0.05) with a significant difference in the two groups.

Conclusions

The present study showed that Ad could ameliorate the left ventricular remodeling induced by CIH via inhibition of the expression of TGF-β/smad2/3 pathway.     

脂联素通过AMPK调节HepG2细胞中支链氨基酸的代谢

目的:探讨脂联素(APN)对HepG2细胞支链氨基酸(BCAA)分解代谢的影响及其作用机制。方法:将培养的HepG2细胞系随机分为对照组、APN组、APN+腺苷酸活化蛋白激酶(AMPK)抑制剂(Compound C,CpC)组(APN+CpC)组和AMPK激动剂(AICAR)组。用Western blot检测AMPK、P-AMPK、BCKD E1α(BCAA分解代谢过程中的关键酶,磷酸化时为失活状态)及P-BCKD E1α蛋白的表达,用ELISA方法检测培养HepG2细胞上清中BCAA的含量。结果:与对照组相比,APN组和AICAR组均可以显著上调细胞P-AMPK的水平(P0.05,P0.01),显著降低细胞p-BCKD E1α及上清中BCAA的水平(P0.05,P0.01)。与APN组比较,APN+CpC组,其细胞内PAMPK水平显著下降(P0.01),P-BCKD E1α及上清中BCAA的水平明显上升(分别为P0.05及P0.01)。结论:APN可显著促进HepG2细胞BCAA的分解代谢,其作用机制与AMPK磷酸化作用的上调相关。