肥胖抑素与Ghrelin

体重部分地受大脑或胃肠道合成的肽类激素的调控。Ghrelin前激素原含117个氨基酸残基，经翻译后裂解作用形成Ghrelin，由28个氨基酸组成。我们检索基因库，与另外11种哺乳动物进行Ghrelin前激素原的序列比较，除了已知的Ghrelin信号肽，我们还确定了另一保守区，侧链含有转化酶裂解部位，编码一种23个氨基酸的肽链，其C端侧翼有保守的甘氨酸残基，可能经酰胺化作用。我们称此Ghrelin相关肽为肥胖抑素（Obestatin）。     

Ascorbic acid during cerebral ischemia in newborn piglets

We measured ascorbic acid (reduced and oxidized) in brain, CSF and blood, before, during and after cerebral ischemia in newborn piglets. Bilateral carotid ligation induced a 54% decrease in cerebral blood flow (p < 0.01) and a 43% decrease in the cerebral metabolic rate of oxygen (p < 0.01). After ischemia and reperfusion, we obtained a 60% decrease (p < 0.01) in total brain ascorbic acid content. CSF ascorbic acid increased during reperfusion:+60% at 30min (p < 0.001) and +160% at 120min (p < 0.05). Blood ascorbic acid content did not change. These changes and the absence of massive oxidation of ascorbic acid in brain tissue suggest release of ascorbic acid by the brain during ischemia.     

Benefit‐risk assessment of nivolumab 240 mg flat dose relative to 3 mg/kg Q2W regimen in Japanese patients with advanced cancers

Nivolumab 3 mg/kg every 2 weeks (Q2W) has been approved in Japan for various cancers; however, use of a flat dose is expected to simplify dosing and administration. A quantitative clinical pharmacology approach was used to assess the benefit‐risk profile of nivolumab 240 mg Q2W relative to the approved dose of nivolumab 3 mg/kg Q2W in Japanese patients. Three exposure‐response safety analyses were performed for adverse events that led to discontinuation/death, were grade 3 or higher, and were immune‐mediated and grade 2 or higher for Japanese patients diagnosed with one of multiple tumor types. Exposure‐response analyses of efficacy were evaluated for overall survival and objective response rate. Exposures of nivolumab 240 mg Q2W were 37% higher than those of nivolumab 3 mg/kg Q2W in Japanese patients across the tumor types analyzed. Predicted safety profiles at the two doses differed by less than 2% across tumor types for adverse events leading to discontinuation/death, adverse events of grade 3 or higher, or immune‐mediated adverse events of grade 2 or higher. In addition, the predicted 1‐year and 2‐year overall survival rates, the mean overall survival and the objective response rates were comparable between the doses regardless of the tumor type analyzed. Overall, these results demonstrated that the benefit‐risk of nivolumab 240 mg Q2W was comparable to that of the previously approved 3 mg/kg Q2W dosing regimen, and was the basis for the approval of the 240 mg Q2W as an alternative dosing regimen for treatment in Japanese patients across multiple tumor types.     

TGF-β2对树突状细胞表型和功能的影响

目的: 研究转化生长因子-β2 (TGF-β2)对树突状细胞(dendritic cells, DC)表型和功能的影响. 方法: 体外培养骨髓来源的DC(BMDC)及TGF-β2诱导的DC(TGFβ2-DC). 采用双色免疫荧光化学染色或流式细胞仪(FCM)分析DC的细胞表型. 分离纯化脾脏来源的同种异体T细胞和CD4+ T细胞. 用BMDC及TGFβ2-DC刺激T细胞增殖,并用混合淋巴细胞反应(MLR)测定其能力. 在CD4+ T细胞与BMDC或TGFβ2-DC共培养5 d后,用FCM检测CD4+ T细胞表型的变化. 结果: BMDC表现为CD11c, CD86, MHC class II+和CD8а-的髓系DC. TGF-β2的诱导抑制了DC表面协同刺激分子、MHC classII的表达(P<0.01),并抑制其刺激同种异体T细胞增殖的能力. 与BMDC诱导的CD4+ T细胞相比,TGFβ2-DC诱导的CD4+ T细胞CD152(细胞毒T淋巴细胞相关分子4, CTLA-4)表达上升(P<0.01). 结论: TGF-β2的诱导促使DC表面协同刺激因子表达下降,T细胞合成CTLA-4增加,T细胞的活化和增殖受到明显抑制.