Family matters: How MYC family oncogenes impact small cell lung cancer

Small cell lung cancer (SCLC) is one of the most deadly cancers and currently lacks effective targeted treatment options. Recent advances in the molecular characterization of SCLC has provided novel insight into the biology of this disease and raises hope for a paradigm shift in the treatment of SCLC. We and others have identified activation of MYC as a driver of susceptibility to Aurora kinase inhibition in SCLC cells and tumors that translates into a therapeutic option for the targeted treatment of MYC-driven SCLC. While MYC shares major features with its paralogs MYCN and MYCL, the sensitivity to Aurora kinase inhibitors is unique for MYC-driven SCLC. In this review, we will compare the distinct molecular features of the 3 MYC family members and address the potential implications for targeted therapy of SCLC.     

The fetal programming effect of prenatal smoking on Igf1r and Igf1 methylation is organ- and sex-specific

The impact of prenatal smoke exposure (PSE) on DNA methylation has been demonstrated in blood samples from children of smoking mothers, but evidence for sex-dependent smoke-induced effects is limited. As the identified differentially methylated genes can be associated with developmental processes, and insulin-like growth factors (IGFs) play a critical role in prenatal tissue growth, we hypothesized that PSE induces fetal programming of Igf1r and Igf1. Using a mouse model of smoking during pregnancy, we show that PSE alters promoter methylation of Igf1r and Igf1 and deregulates their gene expression in lung and liver of fetal (E17.5) and neonatal (D3) mouse offspring. By further comparing female versus male, lung versus liver, or fetal versus neonatal time point, our results demonstrate that CpG site-specific aberrant methylation patterns sex-dependently vary per organ and time point. Moreover, PSE reduces gene expression of Igf1r and Igf1, dependent on organ, sex, and offspring's age. Our results indicate that PSE may be a source of organ-specific rather than general systemic fetal programming. This is exemplified here by gene promoter methylation and mRNA levels of Igf1r and Igf1, together with a sex- and organ-specific naturally established correlation of both parameters that is affected by prenatal smoke exposure. Moreover, the comparison of fetuses with neonates suggests a CpG site-dependent reversibility/persistence of PSE-induced differential methylation patterns.     

黑线姬鼠两亚种(中国东北地区及俄罗斯远东地区的东北亚种和朝鲜半岛的朝鲜亚种) 的线粒体DNA 序列缺少趋异性

为了检测黑线姬鼠两亚种(来自中国东北地区、俄罗斯远东地区的东北亚种和朝鲜半岛的朝鲜亚种)线
粒体DNA 的变异水平并确定朝鲜亚种的分类地位,我们测序分析了两亚种的线粒体DNA 细胞色素b 的部分序列
(1 054 bp)和控制区的部分序列(860 bp),并与基因库中黑线姬鼠相应的单倍型序列进行了比较。可以看出东
北亚种的序列显示出某些分异,可以被分为2 或3 个亚群,所以我们提出需要更多标本的DNA 分析来确定东北
亚种的分类地位。另外,来自韩国的朝鲜亚种的序列,与来自中国东北地区龙江和哈尔滨的东北亚种的两个亚
群相似(1 个亚群是细胞色素b 的两个单倍型,另1 个是控制区的两个单倍型),表明基于线粒体DNA 序列的遗
传多样性与现今基于形态特征对这些姬鼠的分类所得结果是不一致的。因此我们认为来自韩国的朝鲜亚种是一
个只在形态特异上不同于东北亚种的地方亚种,我们建议通过其他DNA 标记来进一步验证其亚种地位。我们还
认为朝鲜半岛不是最近的冰川期黑线姬鼠残遗种的保护区。     

昆虫寄生对栓皮栎坚果特征和萌发行为的影响

有多种昆虫常寄生于栎属植物的坚果中, 进而影响种子的质量、 萌发、 幼苗建成等植物的更新过程。为探讨昆虫寄生与上述过程之间的关系, 本研究于2007年和2008年在太行山济源地区调查了昆虫对栓皮栎Quercus variabilis坚果的寄生情况, 同时探讨了昆虫寄生对坚果单宁水平、 萌发和幼苗生长的影响; 并于2007年9月, 分别将完好的和昆虫寄生的栓皮栎坚果种植于土壤4 cm深处, 对坚果萌发情况、 幼苗出土时间、 叶片数量和生物量等进行了对比分析。结果表明: 1）2007年栓皮栎坚果的虫寄生率为30.04%, 显著低于2008年（47.68%）, 表现出年际变化; 2）虫寄生坚果中单宁酸含量（11.54%±1.36%）显著高于完好坚果（7.36%±1.31%）（P=0.004）; 3）虫寄生坚果的鲜重、 直径、 长度均小于完好坚果; 4）虫寄生坚果的霉烂率（28%）和不完全萌发率（28%）均高于完好坚果（霉烂率0%, 不完全萌发率2%）; 但虫寄生坚果幼苗建成率（56%）低于完好坚果（92%）; 虫寄生坚果幼苗出土持续时间（埋藏后35周）短于完好坚果（埋藏后37周）; 5）在坚果埋藏和幼苗萌出当年的冬季, 由虫寄生坚果和完好坚果建成的幼苗的高度、 叶片数间均无显著差异, 但在翌年的生长季节, 两项指标均出现显著性差异; 6）经过一个完整的生长周期（1年）之后, 由虫寄生坚果所建成幼苗的根长、 根重量和生物量3项指标显著低于完好坚果, 而叶片数、 茎长、 叶重和茎重指标在二者间无显著性差异。研究结果提示, 昆虫寄生会对栎类坚果的种子质量和萌发行为产生一定的影响, 这可能是栎类植物群落更新的适应性选择。     

Basophil-derived mouse mast cell protease 11 induces microvascular leakage and tissue edema in a mast cell-independent manner

Mouse mast cell protease 11 (mMCP-11) is the most recently identified member of the mouse mast cell tryptase family. This tryptase is preferentially produced by basophils in contrast to other members that are expressed by mast cells but not basophils. Although blood-circulating basophils have long been considered as minor and redundant relatives of tissue-resident mast cells, recent studies illustrated that basophils and mast cells play distinct roles in vivo. To explore the in vivo role of basophil-derived mMCP-11, here we prepared recombinant mMCP-11 and its protease-dead mutant. Subcutaneous injection of the wild-type mMCP-11 but not the mutant induced edematous skin swelling with increased microvascular permeability in a dose-dependent manner. No apparent infiltration of proinflammatory cells including neutrophils and eosinophils was detected in the skin lesions. The cutaneous swelling was abolished by the pretreatment of mice with indomethacin, a cyclooxygenase inhibitor, suggesting the major contribution of prostaglandins to the microvascular leakage. Of note, the cutaneous swelling was elicited even in mast cell-deficient mice, indicating that mast cells are dispensable for the mMCP-11-induced cutaneous swelling. Thus, basophil-derived mMCP-11 can induce microvascular leakage via prostaglandins in a mast cell-independent manner, and may contribute to the development of basophil-mediated inflammatory responses.     

Multimerisation of A disintegrin and metalloprotease protein-17 (ADAM17) is mediated by its EGF-like domain

A disintegrin and metalloprotease protein 17 (ADAM17) is a transmembrane zinc dependent metalloprotease. The catalytic activity of the enzyme results in the shedding of a broad range of membrane proteins. The release of the corresponding ectodomains induces a switch in various physiological and pathophysiological processes. So far there is not much information about the molecular mechanism of ADAM17 activation available. As for other transmembrane proteases, multimerisation may play a critical role in the activation and function of ADAM17. The present work demonstrates that ADAM17 indeed exists as a multimer in the cell membrane and that this multimerisation is mediated by its EGF-like domain.