A Phase I Dose Escalation Study of the Safety,Tolerability, and Pharmacokinetics of Ipilimumab in Chinese Patients with Select Advanced Solid Tumors

Lessons Learned

• The overall safety profiles of ipilimumab 3 mg/kg and 10 mg/kg administered every 3 weeks, were consistent between Chinese patients with solid tumors in the current study and patients from previous U.S. ipilimumab monotherapy studies. No new safety signals were identified.
• The mean systemic exposures to ipilimumab (assessed by first dose area under the curve during the dosing interval and maximum serum concentration) were numerically lower in the Chinese patient population than in U.S. patients for both 3 mg/kg and 10 mg/kg doses; however, the range of serum concentrations in the Chinese and U.S. populations overlapped (3 mg/kg and 10 mg/kg), suggesting that ipilimumab pharmacokinetics was ethnically insensitive in this study.

BackgroundThis phase I, open‐label study assessed ipilimumab safety, tolerability, pharmacokinetics (PK), immunogenicity, and antitumor activity in Chinese patients with unresectable, metastatic, recurrent malignant melanoma (MM) or nasopharyngeal carcinoma (NPC).MethodsOf 39 patients enrolled, 25 received ipilimumab (11 patients received 3 mg/kg, and 14 patients received 10 mg/kg). Reasons for not receiving treatment were withdrawal of consent (3 patients), no longer meeting the criteria (10 patients), and one recorded as “other.” During the induction phase, patients received ipilimumab (3 mg/kg, i.v.), on day 1 of a 3‐week cycle, to a maximum of four doses or progressive disease (PD). During the maintenance phase at week 24, patients received ipilimumab (3 mg/kg, i.v.) on day 1 of a 12‐week cycle, to a maximum of 3 years or PD. Considering the co‐primary safety and PK endpoints, the successive dosing required nine patients with two or fewer dose‐limiting toxicities during the 42‐day observation period to proceed with a new cohort of nine patients at 10 mg/kg.ResultsIpilimumab safety and PK profiles were similar in Chinese and predominantly White populations. Ipilimumab was well tolerated. Most adverse events (AEs) were grades 1–2 and experienced by 11 patients treated with 3 mg/kg and 14 patients treated with 10 mg/kg. There were no new safety concerns. Incidence of anti‐ipilimumab antibodies was low (1 of 10 in the 3 mg/kg patients and 2 of 13 in the 10 mg/kg patients) and without safety implications. In the 3 mg/kg group, 8 of 11 patients had PD. In the 10 mg/kg group (all NPC, 0 MM patients), 11 of 14 patients had PD. Three patients had stable disease (one at 3 mg/kg and two at 10 mg/kg).ConclusionIpilimumab was well tolerated in Chinese patients, showing similar safety and PK to previous studies in predominantly White populations.     

提高与保证生物化学教学质量的探讨

随着生物化学和分子生物学的快速发展,生物化学的理论和技术被广泛应用于各种研究领域.因此不断提高教师的业务素质、采用先进的教学手段和教学模式、改革生物化学的实验教学,是提高与保证生物化学教学质量的前提,也是衔接后期研究生教学的重要环节.     

几种谷物,鱼肉及贝肉中DNA含量测定

核酸是遗传的物质基础。近年来的某些研究表明，外源核酸在促进和改善大脑，骨髓，肠粘膜及血细胞等组织器官的代及功能活动上具有重要作用。本文采用经典的紫外分光光度法对几种谷物和几种鱼肉及贝肉中的ＤＮＡ含量进行了测定，为外源核酸的材料选择提供了参考。     

Differential expression of decorin and biglycan genes during palatogenesis in normal and retinoic acid-treated mice.

Proteoglycans are involved in secondary palate formation. In the present study, we focused on two small leucine-rich proteoglycans, decorin and biglycan, because they assembled extracellular matrix molecules such as collagens and modulated signaling pathway of transforming growth factor-beta. To investigate the functions of decorin and biglycan in palatogenesis, we compared their mRNA expression patterns between normal palate and retinoic acid-induced cleft palate in mice by using in situ hybridization analysis during the period of embryonic day 13.5 (E13.5) to E15.5. On E13.5, decorin mRNA was expressed in the epithelia and mesenchyme on the nasal side of the developing secondary palate. During the period the palate shelves were fusing (E14.5), decorin mRNA was strongly expressed in the mesenchyme but its expression pattern was asymmetric; decorin mRNA expression area in the nasal side was broader than that in the oral side. The expression of decorin mRNA was hardly detected in the mesenchyme on either side of the medial edge epithelium. After fusion (E15.5), its expression converged to the mesenchyme just around the palatine bone. Biglycan mRNA was ubiquitously distributed throughout the palatal mesenchyme for the mid-gestation period. Its expression area became limited to the ossification area within the palate after the late gestation period. In the retinoic acid-treated mice, the area of the decorin gene expression expanded to the core region of the palate primordium where little signal was observed in control mice. On the other hand, biglycan in the retinoic acid-treated mice did not show remarkable change in its distribution patterns compared with that in the control mice. These findings suggest that decorin and biglycan play distinct roles in palatogenesis, and decorin was more actively involved in the process of secondary palate formation than biglycan. Up-regulation of decorin gene expression in the retinoic acid-treated mice might influence the pathogenesis of cleft palate.     

大白鼠外侧隔核的传入性神经纤维联系—HRP、荧光素法研究

本文应用HRP和荧光素标记法对大白鼠外侧隔核的传入性神经纤维联系进行了研究。实验结果表明,外侧隔核的传入神经纤维来源于端脑海马的CA_(1-4)区、杏仁皮质核、内嗅区皮质、斜角带核、视前内侧核、视前外侧核;丘脑的室周核和带旁核;底丘脑的Forel's H_2区和未定带;下丘脑的前核、外侧核、后核以及乳头体上核;中脑的腹侧被盖区。     

Copper and iron-induced oxidative damage in non-tumor bearing LEC rats

The copper and Iron status in the liver of non-tumor bearing Long-Evans Cinnamon (LEC) rats (average age 17 months) was investigated. A direct quantitation of loosely-bound copper and iron was also investigated by using a chelating agent, nitrilotriacetic acid (NTA-chelatable free copper and iron). Besides the total copper and iron contents, the level of NTA-chelatable free copper was also higher in LEC rats than In LEA rats (P<0.05). But for the free iron level there was no signiflcant difference between the two rat groups (P>0.05). The formation of thiobarbituric acid-reactive substances was higher In LEC rats than In LEA rats (P<0.01). The 4–hydroxy-2–nonenal (HNE)-modified proteins were also clearly demonstrated in LEC rat liver. The copper and iron which produced the most important effect In the process of oxidative damage in LEC rats could not be distinguished. Even though free copper, which could induce free radical injuries, was increased in LEC rats, neither tumor-induction nor preneo-plastic lesions in the experimental LEC rats were observed. Therefore it is speculated that the elevation of a free iron is another important factor. Copper and iron, both important translation metals In the body, may participate In the Induction of DNA damage and oncogenesls     

川陈皮素通过激活SIRT1/FOXO3a信号来减轻肾缺血再灌注损伤

目的：本研究旨在探究川陈皮素（NOB）保护小鼠肾缺血再灌注损伤（RIRI）的可能分子机制。方法：将Balb/c小鼠分为5组（n=6）：假手术组、模型组、NOB组（50 mg/kg）、组蛋白去乙酰化酶沉默信息调节因子1（SIRT1）抑制剂EX527组（5 mg/kg）、NOB+EX527组（50 mg/kg的NOB+5 mg/kg EX527）。在建模前24 h对小鼠进行药物处理。通过阻断小鼠左肾动静脉血流建立RIRI模型。建模24 h后检测肾组织中氧化应激标志物含量。通过苏木精-伊红（HE）染色和天狼星红染色评价肾组织病变和纤维化。通过TUNEL染色检测肾细胞凋亡。通过蛋白质免疫印迹法检测肾组织中SIRT1、叉头框蛋白O3a（FOXO3a）、细胞凋亡和自噬相关蛋白表达。通过实时荧光定量PCR检测肾组织中SIRT1和FOXO3a mRNA的水平。结果：与模型组比较,NOB组小鼠肾脏病变程度减轻,肾脏纤维化面积降低（均P<0.05）。与模型组比较,NOB组肾组织抗氧化作用升高（P<0.05）。与模型组比较,NOB组肾组织中细胞凋亡减少（P<0.05）。与模型组比较,NOB组肾组织中SIRT1和FOXO3a的mRNA和蛋白相对表达量升高,微管相关蛋白轻链(LC)3Ⅱ/LC3Ⅰ蛋白相对表达量升高,而p62降低（均P<0.05）。此外,EX527逆转了NOB对肾脏的保护作用（P<0.05）。结论：NOB通过激活SIRT-1/FOXO3a信号通路介导的自噬来减轻RIRI。     

Inhibitory Effect of recombinant FN polypeptide CH50 on the metastasis and tumor growth

Immunotherapycouldremoveresidualtumorcellsbyenhancinganti-tumorfunc-tionofimmunesystemaftersurgicalre-movaloftumor.ltisatime-consumingtofullyactivateimmunece11sandformstrongcytotoxicityontumorcellsinvivo.ltisim-perativetofindawaytoactivateanti-tumoractivityofimmunecellsquick1yenoughinvivosothattheresidualtumorcellscouldbeattackedasearlyaspossible.CH5oisabifunctiona1-domainrecombinantpolypep-tidewhichcontainsCellIandHepIdo-mainsofhumanfibronectin(FN)andisabIetoexpressinE-coli[lj.Thispolypep-…     

经食管超声心动图评估房颤栓塞危险性的临床研究

目的： 评价经食管超声心动图（ＴＥＥ） 在区分心房颤动（ 房颤） 栓塞高危人群中的应用价值。方法：８６例持续性房颤患者同时接受常规经胸超声心动图（ＴＴＥ） 和ＴＥＥ 检查,根据ＴＥＥ 探测到心房血栓的例数分为血栓阳性组和血栓阴性组,分别纪录以下各项指标：左房自发性超声对比现象（ＬＡＳＥＣ） 、左心耳（ＬＡＡ） 血流排空速率、ＬＡＡ 面积、左房内径、左室收缩功能参数、二尖瓣返流（ ＭＲ） 程度。结果：８６ 例中经ＴＥＥ 探测到２２ 例存在左房和／或左心耳血栓,而ＴＴＥ 仅探测到５ 人存在左房血栓（ Ｐ＜ ０ ．０００１） 。对血栓阳性和阴性组各项测值指标进行对比显示,ＬＡＳＥＣ 严重程度、ＬＡＡ 血流速率降低和ＬＡＡ 面积扩大在两组间存在极显著差异（ Ｐ＜ ０ ．０００１ 和０００１） 。ＬＡＡ面积扩大与ＬＡＳＥＣ 严重程度及ＬＡＡ 速率降低密切相关。结论： ＴＥＥ 探测心房血栓具有显著优势,并可测定与血栓形成密切相关的因素,在区分房颤栓塞高危人群方面具有重要价值