Assessing the contribution of tumor mutational phenotypes to cancer progression risk

Cancer occurs via an accumulation of somatic genomic alterations in a process of clonal evolution. There has been intensive study of potential causal mutations driving cancer development and progression. However, much recent evidence suggests that tumor evolution is normally driven by a variety of mechanisms of somatic hypermutability, which act in different combinations or degrees in different cancers. These variations in mutability phenotypes are predictive of progression outcomes independent of the specific mutations they have produced to date. Here we explore the question of how and to what degree these differences in mutational phenotypes act in a cancer to predict its future progression. We develop a computational paradigm using evolutionary tree inference (tumor phylogeny) algorithms to derive features quantifying single-tumor mutational phenotypes, followed by a machine learning framework to identify key features predictive of progression. Analyses of breast invasive carcinoma and lung carcinoma demonstrate that a large fraction of the risk of future clinical outcomes of cancer progression—overall survival and disease-free survival—can be explained solely from mutational phenotype features derived from the phylogenetic analysis. We further show that mutational phenotypes have additional predictive power even after accounting for traditional clinical and driver gene-centric genomic predictors of progression. These results confirm the importance of mutational phenotypes in contributing to cancer progression risk and suggest strategies for enhancing the predictive power of conventional clinical data or driver-centric biomarkers.     

Design,synthesis, and biological evaluation of 4-phenoxyquinoline derivatives as potent c-Met kinase inhibitor

A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydro-quinoxaline moiety were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG) in vitro. Most of the tested compounds exhibited more potent inhibitory activities than the positive control foretinib. Compound 1b, 1s and 1t were further examined for their inhibitory activity against c-Met kinase. The most promising compound 1s (with c-Met IC₅₀ value of 1.42 nM) showed remarkable cytotoxicity against A549, H460, HT-29, MKN45 and U87MG cell lines with IC₅₀ values of 0.39 μM, 0.18 μM, 0.38 μM, 0.81 μM, respectively. Their preliminary structure-activity relationships (SARs) study indicated that the replacement of the aromatic ring with the cyclohexane improved their antiproliferative activity.     

鄱阳湖沙地蔓荆灌丛沙堆形态特征及空间分布格局

目前灌丛沙堆研究主要集中在干旱半干旱区的沙质草原和沙漠边缘,对亚热带湿润区灌丛沙堆的形成、演变过程并不清楚。以鄱阳湖沙地为研究区,通过样方调查和地统计学的方法,研究不同沙化程度下蔓荆灌丛沙堆的形态特征及分布格局。结果表明:鄱阳湖沙地蔓荆沙堆的形态以盾形为主,其冠幅变化幅度为1.2—18.2 m~2,固定和半固定沙地显著高于流动沙地;对灌丛沙堆的形态参数来说,其长轴与短轴在固定和半固定沙地上呈极显著的线性相关关系,流动沙地上呈二次函数关系;半固定和流动沙地上沙堆底面积与沙堆高度呈二次函数关系(r0.6);3种类型沙地上灌丛底面积与沙堆体积之间极显著线性相关,其中半固定沙地线性函数的斜率最大;除固定沙地的沙堆高度和半固定沙地的灌丛高度外,3种沙地上蔓荆灌丛与沙堆的其他形态参数间均极显著相关,说明随着沙地的固定,蔓荆灌丛有利于沙堆水平尺度的增长;3种沙地上蔓荆沙堆均呈随机分布。     

海南岛翼手目物种多样性现状与分布预测

海南岛位于我国南部, 地处热带北缘, 其独特的岛屿气候环境孕育了丰富的生物资源, 为我国生物多样性热点地区之一。为探究岛内的翼手目物种多样性状况, 本研究组使用雾网、蝙蝠竖琴网等工具, 于2002年至2016年先后对海南岛进行了15次翼手目多样性调查, 并根据其外形与头骨特征及系统发育学方法进行标本鉴定。共获取了1,025号标本, 隶属5科15属31种, 其中2016年12月21日在海南琼中捕获的艾氏管鼻蝠(Murina eleryi)为海南岛蝙蝠分布新记录。结合前人调查及发表结果统计, 岛内共有翼手类8科20属41种。同时基于本调查采集位点和前人调查位置信息(共计363个位点), 结合WorldClim 32种气候数据, 运用最大熵模型(MaxEnt)对海南岛翼手目物种的分布进行预测, 结果显示五指山、吊罗山、鹦哥岭、尖峰岭及海口火山口国家地质公园等地为翼手目物种多样性较丰富的区域, 而三亚、澄迈、屯昌、临高、琼海等地翼手目物种多样性较低。本研究结果为海南岛翼手目资源分布及多样性状况提供了基础资料, 也为岛内后续开展翼手目资源保护管理、蝙蝠疾病防控等提供了重要的参考依据。     

Follicle‐stimulating hormone promotes age‐related endometrial atrophy through cross‐talk with transforming growth factor beta signal transduction pathway

It is widely believed that endometrial atrophy in postmenopausal women is due to an age‐related reduction in estrogen level. But the role of high circulating follicle‐stimulating hormone (FSH) in postmenopausal syndrome is not clear. Here, we explored the role of high circulating FSH in physiological endometrial atrophy. We found that FSH exacerbated post‐OVX endometrial atrophy in mice, and this effect was ameliorated by lowering FSH with Gonadotrophin‐releasing hormone agonist (GnRHa). In vitro, FSH inhibited endometrial proliferation and promoted the apoptosis of primary cultured endometrial cells in a dose‐dependent manner. In addition, upregulation of caspase3, caspase8, caspase9, autophagy‐related proteins (ATG3, ATG5, ATG7, ATG12 and LC3) and downregulation of c‐Jun were also observed in endometrial adenocytes. Furthermore, smad2 and smad3 showed a time‐dependent activation in endometrial cells which can be partly inhibited by blocking the transforming growth factor beta receptor II (TβRII). In conclusion, FSH regulated endometrial atrophy by affecting the proliferation, autophagy and apoptosis of endometrial cells partly through activation of the transforming growth factor beta (TGFβ) pathway.     

aPKC Phosphorylation of HDAC6 Results in Increased Deacetylation Activity

The Class II histone deacetylase, HDAC6, has been shown to be involved in cell motility, aggresome formation and mitochondria transport. HDAC6 deacetylase activity regulates α-tubulin acetylation levels and thus plays a critical role in these processes. In turn, HDAC6 activity can be regulated by interaction with various proteins including multiple kinases. Kinase mediated phosphorylation of HDAC6 can lead to either increased or reduced activity. Our previous research has shown that sequestosome1/p62 (SQSTM1/p62) interacts with HDAC6 and regulates its activity. As SQSTM1/p62 is a scaffolding protein known to interact directly with the zeta isoform of Protein Kinase C (PKCζ), we sought to examine if HDAC6 could be a substrate for PKCζ phosphorylation and if so, how its activity might be regulated. Our data demonstrate that HDAC6 is not only present in a protein complex with PKCζ but can also be phosphorylated by PKCζ. We also show that specific phosphorylation of HDAC6 by PKCζ increases HDAC6 deacetylase activity resulting in reduced acetylated tubulin levels. Our findings provide novel insight into the molecular mechanism by which HDAC6, PKCζ and SQSTM1/p62 function together in protein aggregate clearance. These results also highlight a new research direction which may prove fruitful for understanding the underlying cause of several neurodegenerative diseases.     

金黄色葡萄球菌凝集因子B的原核表达及其抗血清调理吞噬活性

金黄色葡萄球菌是导致医院院内感染的主要病原。由于金黄色葡萄球菌极易产生抗药性,因此疫苗免疫是预防该细菌感染的主要手段。作为一个粘附分子,凝集因子B(ClfB)的作用是使金黄色葡萄球菌能够在宿主黏膜定植,是预防该菌感染的一个重要的靶分子。本研究成功地在大肠杆菌中表达了可溶的ClfB N1-N3结构域蛋白(Truncated-ClfB),并且利用亲和层析、离子交换层析和凝胶过滤技术对其进行了纯化。用纯化后的Truncated-ClfB免疫新西兰大白兔,收集三免后的血清检测其抗体水平并且利用流式细胞术检测抗血清的调理吞噬活性。检测结果表明,三免后的兔源Truncated-ClfB抗血清抗体效价高达1:640 000;与免疫前兔源血清相比,兔源Truncated-ClfB抗血清能够显著增加多形核白细胞(Polymorphonuclear leukocytes,PMN)对金黄色葡萄球菌的吞噬效率(P0.01)。结果表明Truncated-Clf B有希望作为金黄色葡萄球菌疫苗的候选抗原。     

Evaluation of Tetrahydropalmatine Enantiomers on the Activity of Five Cytochrome P450 Isozymes in Rats Using a Liquid Chromatography / Mass Spectrometric Method and a Cocktail Approach

The aim was to evaluate the effects of tetrahydropalmatine (THP) enantiomers on the activity of five cytochrome P450 (CYP450) isozymes in vivo. A liquid chromatography / mass spectrometric (LC‐MS) method was developed for simultaneous determination of five specific probe substrates including metoprolol (2D6), caffeine (1A2), dapsone (3A4), chlorzoxazone (2E1), and tolbutamide (2C9) in rat plasma. Analytes were separated with the mobile phase consisting of 0.1% acetic acid aqueous solution and acetonitrile in a gradient elution. The mass spectrometric detection via selected ion monitoring (SIM) was operated in both positive ion mode (for metoprolol m/z 268, caffeine m/z 195, and dapsone m/z 249) and negative ion mode (for chlorzoxazone m/z 168 and tolbutamide m/z 269) in the same run. Linear correlation was obtained (r² > 0.99) over the concentration range of 0.050–25.0 µg/mL for caffeine and dapsone, 0.025–10.0 µg/mL for metoprolol, 0.050–50.0 µg/mL for chlorzoxazone, and 0.25–100.0 µg/mL for tolbutamide. Intra‐ and interday precision were less than 12.09%. The matrix effect ranged from 87.50% to 109.25% and the absolute recoveries were greater than 70%. The method was successfully applied to evaluate the effect of THP enantiomers on the activity of CYP450 isozymes by a cocktail approach. The pharmacokinetic results of five probe drugs indicated that there were stereoselective differences between the two THP enantiomers, i.e., d‐THP had the potential to inhibit the activities of CYP2D6 and CYP1A2 isozymes, while l‐THP inhibited CYP1A2 isozyme and induced CYP3A4 and CYP2C9 isozymes. Chirality 27:551–556, 2015. © 2015 Wiley Periodicals, Inc.