24小时热门版块排行榜

>论坛更新日志 (2854)
>虫友互识 (390)
>导师招生 (137)
>文献求助 (123)
>硕博家园 (76)
>休闲灌水 (73)
>考博 (27)
>博后之家 (26)
>论文投稿 (24)
>基金申请 (22)
>公派出国 (19)
>教师之家 (17)
>找工作 (17)
>考研 (17)
>论文道贺祈福 (15)
>标准与专利 (15)

返回列表

当前只显示满足指定条件的回帖，点击这里查看本话题的所有回帖

seen163

新虫 (初入文坛)

应助: 0 (幼儿园)
金币: 30.8
帖子: 25
在线: 1.5小时
虫号: 512388
注册: 2008-02-26
专业: 中药生药学/中药材的仪器分

[交流] 【求助】求3篇nature全文已有4人参与

第一篇：Nature Reviews Drug Discovery 9, 431 (June 2010)
题目：Anticancer drugs: A Notch closer
作者：Sarah Crunkhorn

第2篇：Nature Reviews Drug Discovery 9, 432-433 (June 2010)
题目：Antiviral drugs: New oral HCV drug shows promise
作者：Man Tsuey Tse

第3篇：Nature Medicine 16, 614 (2010)
doi:10.1038/nm0610-614b
题目：Diabetes drug woes spell trouble for the entire drug family
作者：Meredith Wadman

回复此楼

» 猜你喜欢

有院领导为了换新车，用横向课题经费买了俩车已经有8人回复
博士延得我，科研能力直往上蹿已经有8人回复
酰胺脱乙酰基已经有12人回复
同年申请2项不同项目，第1个项目里不写第2个项目的信息，可以吗已经有4人回复
有时候真觉得大城市人没有县城人甚至个体户幸福已经有10人回复
天津大学招2026.09的博士生，欢迎大家推荐交流（博导是本人）已经有5人回复
CSC & MSCA 博洛尼亚大学能源材料课题组博士/博士后招生｜MSCA经费充足、排名优已经有6人回复
面上项目申报已经有3人回复
遇见不省心的家人很难过已经有22人回复

» 本主题相关价值贴推荐，对您同样有帮助:

求2005年Nature Materials一篇已经有1人回复

1楼 2010-06-12 16:36:52

已阅回复此楼关注TA 给TA发消息送TA红花 TA的回帖

xuxia778

金虫 (正式写手)

应助: 0 (幼儿园)
金币: 1386.1
散金: 7
红花: 1
帖子: 699
在线: 65.4小时
虫号: 504955
注册: 2008-02-16
性别: MM
专业: 药物分析

引用回帖:

Originally posted by seen163 at 2010-06-12 16:36:52:
第一篇：Nature Reviews Drug Discovery 9, 431 (June 2010)
题目：Anticancer drugs: A Notch closer
作者：Sarah Crunkhorn

第2篇：Nature Reviews Drug Discovery 9, 432-433 (June 2010)
题目：A ...

Aberrant signalling of the Notch pathway has been linked to numerous diseases, particularly many cancers. Although the potential of therapeutically targeting this pathway in cancer is being actively investigated, strategies used so far have been nonspecific or have been associated with significant side effects. Now, writing in Nature, Wu and colleagues characterize antibodies that selectively inhibit either NOTCH1 or NOTCH2 receptor signalling, exerting anticancer activity in mice without toxicity.

The Notch family of transmembrane receptors comprises four members, with roles in the regulation of cell fate and growth. Following ligand binding, a conformational change in the receptor negative regulatory region (NRR) occurs, which ultimately facilitates initiation of the downstream Notch transcriptional programme. The authors therefore proposed that targeting this vital step in Notch pathway signalling may represent a new therapeutic approach.

First, using phage display technology, the authors generated fully human immunoglobulin G1 NRR1-specific and NRR2-specific antibodies, which selectively inhibited NOTCH1 or NOTCH2 signalling. Receptor specificity was confirmed in vivo by the ability of the NRR1-specific and NRR2-specific antibodies to reduce the population of mouse T cells and splenic marginal zone B cells, respectively. Characterization of the crystal structure of the NRR1-specific antibody Fab fragment bound to human NRR1 suggested that the antibody mediates its inhibitory effects through interference with the conformational changes required for receptor activation.

Next, the potential anticancer activity of the NRR1-specific antibody was investigated. Activating NOTCH1 mutations within the NRR are commonly observed in patients with T-cell acute lymphoblastic leukaemia (T-ALL) and allow ligand-independent signalling. In a NOTCH1 mutant T-ALL cell line, the NRR1-specific antibody significantly induced cell cycle arrest and reduced cell proliferation. Moreover, it also decreased cell size and increased apoptosis — effects that correlated with NOTCH1 inhibition. In addition, signalling activated by two of the most common T-ALL mutations (L1594P and L1575P), one of the strongest activating mutations (I1681N), as well as a PEST domain truncation (representative of another common cluster of T-ALL mutations), were inhibited in cell models.

Screening a panel of 45 cancer cell lines for sensitivity to the NRR1-specific antibody also discovered activity in the MT-3 human colon cancer cell line, which was due to a single activating NOTCH1 mutation, A1702T. Moreover, in mouse xenograft T-ALL and colon cancer models, the antibody induced significant tumour regression and slowing of growth, respectively. Interestingly, it was shown to also act by an anti-angiogenic mechanism, in both in vitro and in vivo models.

ADVERTISEMENT

Finally, they assessed whether their antibodies induced intestinal toxicity, as this has been associated with pan-Notch inhibitors. Mice treated with both the NRR1-specific and NRR2-specific antibodies rapidly lost weight, whereas mice treated with either antibody alone maintained weight. Although the combination of both antibodies induced severe intestinal crypt goblet cell metaplasia, no such effect was detected with the NRR2-specific antibody alone, and only a mild effect was observed with the NRR1-specific antibody.

It seems that Notch receptor-specific antibodies represent a significant advance over existing Notch pathway inhibitors, and may prove to be valuable in the future treatment of cancers, as well as other indications linked to dysregulated Notch signalling.