（11.15 -- 11.21 / 2010）
恒峰g22国际集团:陶国新 

　　本周动态蕴含以下内容：玄色素瘤与肿瘤干细胞模型不符；科学家研造出新型细胞造就系统；钻研揭示miRNA在先天免疫中作用；钻研揭示肺炎习染人体反映机造；FTO基因过度活跃可导致肥胖；维生素D不及可导致白血病恶化。

1. 玄色素瘤与肿瘤干细胞模型不符

【提要】ScienceDaily (Nov. 15, 2010)
　　美国Michigan大学的钻研人员发现大无数类型的玄色素瘤细胞都能形成恶性肿瘤，为玄色素瘤这一最致命的皮肤癌不切合越来越盛行的肿瘤干细胞模型提供了新证据。另表，钻研人员还发现玄色素瘤细胞能通过开关分歧的基因扭转自体态态而成为神秘的变形者来逃避医治。

【点评】
　　该发现作为一个反证批注癌症发生的肿瘤干细胞模型可能是谬误的，癌症的起因依然有待说明。

【原文摘录】Cancer Cell, 2010; 18 (5): 510-523 DOI: 10.1016/j.ccr.2010.10.012
Phenotypic Heterogeneity among Tumorigenic Melanoma Cells from Patients that Is Reversible and Not Hierarchically Organized.
Elsa Quintana, Mark Shackleton, Hannah R. Foster, et al.
We investigated whether melanoma is hierarchically organized into phenotypically distinct subpopulations of tumorigenic and nontumorigenic cells or whether most melanoma cells retain tumorigenic capacity, irrespective of their phenotype. We found 28% of single melanoma cells obtained directly from patients formed tumors in NOD/SCID IL2Rnull mice. All stage II, III, and IV melanomas obtained directly from patients had common tumorigenic cells. All tumorigenic cells appeared to have unlimited tumorigenic capacity on serial transplantation. We were unable to find any large subpopulation of melanoma cells that lacked tumorigenic potential. None of 22 heterogeneously expressed markers, including CD271 and ABCB5, enriched tumorigenic cells. Some melanomas metastasized in mice, irrespective of whether they arose from CD271 or CD271+ cells. Many markers appeared to be reversibly expressed by tumorigenic melanoma cells.

2. 科学家研造出新型细胞造就系统
 
【提要】
　　美国威斯康辛大学麦迪逊分校的科学家们近日开发出一套新细胞造就系统，有望为细胞医治提供越发一致和安全的细胞造就物。11月14日的《天然—步骤学》登载了这一成就。辅导这项钻研的Laura Kiessling教授暗示这套系统并不昂贵，可承担多能细胞造就中的大量预估工作。这项技术“很单一”，“任何人都能使用”。目前，大部门人类胚胎干细胞的造就都是作为尝试室钻研用处的，而通常所选取的造就步骤又容易造成各类传染。这套新系统选取一种化学合成造得的可与干细胞相结合的蛋白片段底物，并通过与特定造就基结合，可将细胞造就固定在未分化阶段达三个月或者更长功夫。据汇报显示，该系统亦可用于诱导多职能干细胞造就。“科学家此刻普遍选取的造就系统都有着非特定的弊端，并且不足一致性，以至出现质量差距”， 辅导这项钻研的Laura Kiessling教授诠释，“我们研发的这套系统特定性很好，并且并不贵”。（科学网 张笑/编译）

【点评】
越发一致、不变和安全的细胞造就物对于干细胞造就和钻研的质量节造大有益处。这一技术可能会推进干细胞钻研领域的发展。

【原文摘录】Nature Methods, 14 November 2010 DOI: 10.1038/nmeth.1532
A defined glycosaminoglycan-binding substratum for human pluripotent stem cells
Joseph R Klim, Lingyin Li, Paul J Wrighton, et al.
To exploit the full potential of human pluripotent stem cells for regenerative medicine, developmental biology and drug discovery, defined culture conditions are needed. Media of known composition that maintain human embryonic stem (hES) cells have been developed, but finding chemically defined, robust substrata has proven difficult. We used an array of self-assembled monolayers to identify peptide surfaces that sustain pluripotent stem cell self-renewal. The effective substrates displayed heparin-binding peptides, which can interact with cell-surface glycosaminoglycans and could be used with a defined medium to culture hES cells for more than 3 months. The resulting cells maintained a normal karyotype and had high levels of pluripotency markers. The peptides supported growth of eight pluripotent cell lines on a variety of scaffolds. Our results indicate that synthetic substrates that recognize cell-surface glycans can facilitate the long-term culture of pluripotent stem cells.

3. 钻研揭示miRNA在先天免疫中作用
 
【提要】
　　11月10日，国际权威学术期刊〖疫学期刊》（Journal of Immunology）在线颁发了中科院上海巴斯德所最新钻研成就，该成就揭示了microRNA在先天免疫中的作用以及调控机造，并钻研了这种作用在地塞米松抗炎症效应中的职位。这项成就是博士钻研生朱清源在戈宝学钻研员领导下实现的。先天免疫中炎症因子的调节必要被精密地节造，过多或者过少的炎症因子都可能会造成机体的负面反映。MAPK是掌管炎症因子产生的重要信号通路，能够在TLR激活的免疫反映中通过磷酸化来诱导下游转录因子激活炎症因子转录。而同时，这个信号通路的激活会导致MKP-1的产生，这是一种能够通过对MAPK进行去磷酸化作用使炎症反映下调的分子。MAPK与MKP-1组成了一个尺度的负反馈调节茎环结构。
　　钻研人员发现一种microRNA (miR-101)能够通过靶向MKP-1 mRNA的3’- UTR来调节MAPK的反映，进而影响下游炎症因子的排泄。更进一步的尝试批注，PI3K/AKT通路能够调控miR-101的表白，从而影响MKP-1以及MAPK的表白和活化情况，这暗示P3IK/AKT通路能够通过miR-101与MAPK通路进行串扰。钻研发现，在地塞米松的抗炎症作用中，miR-101被抑造，至少部门是由于地塞米松导致MKP-1大幅度上调而降低了MAPK活化作用。这项钻研为今后对细胞因子排泄引起的免疫疾病的医治战术提供了新的靶标。此项钻研得到科技部、国度天然科学基金、上海市科学技术委员会和中国科学院的资金赞助，并已经申请了有关专利。（起源：中科院上海巴斯德所）

【点评】
　　微核糖核酸miR-101 通过作用于使炎症反映下调的MKP-1信号通路调节巨噬细胞对细菌脂多糖的先天免疫反映。该发现丰硕了炎症与免疫反映的机理上的意识，有助于开发新的抗炎步骤。

【原文摘录】The Journal of Immunology, 2010, doi:10.4049/jimmunol.1000798
MicroRNA-101 Targets MAPK Phosphatase-1 To Regulate the Activation of MAPKs in Macrophages
Qing-Yuan Zhu, Qin Liu, Jian-Xia Chen, et al.
MAPK phosphatase-1 (MKP-1) is an archetypical member of the dual-specificity phosphatase family that deactivates MAPKs. Induction of MKP-1 has been implicated in attenuating the LPS- or peptidoglycan-induced biosynthesis of proinflammatory cytokines, but the role of noncoding RNA in the expression of the MKP-1 is still poorly understood. In this study, we show that MKP-1 is a direct target of microRNA-101 (miR-101). Transfection of miR-101 attenuates induction of MKP-1 by LPS as well as prolonged activation of p38 and JNK/stress-activated protein kinase, whereas inhibition of miR-101 enhances the expression of MKP-1 and shortens p38 and JNK activation. We also found that expression of miR-101 is induced by multiple TLR ligands, including LPS, peptidoglycan, or polyinosinic-polycytidylic acid, and that inhibition of PI3K/Akt by LY294002 or Akt RNA interference blocks the induction of miR-101 by LPS in RAW264.7 macrophage cells. Moreover, treatment of cells with dexamethasone, a widely used anti-inflammatory agent, markedly inhibits miR-101 expression and enhances the expression of MKP-1 in LPS-stimulated macrophages. Together, these results indicate that miR-101 regulates the innate immune responses of macrophages to LPS through targeting MKP-1.

4. 钻研揭示肺炎习染人体反映机造
 
【提要】
　　据英国《逐日电讯报》报路，英国科学家颁发，他们发现了身段天然匹敌引发肺炎和脑膜炎的肺炎链球菌的新方式，朝研造出医治肺炎和脑膜炎的通用型疫苗又前进了一大步。该钻研颁发在美国《科学公共图书馆—病原体》杂志上。英国莱斯特大学和都柏林圣三一学院的钻研人员在论文中以《理解上的巨大突破》为题，揭示了免疫系统若何对肺炎链球菌引发的习染作出反映的机造。钻研人员称，他们初次发现，肺炎会触发一群名叫炎性体的免疫系统蛋白。当被引发时，炎性体味启动一系列事务，导致蕴含白介素在内的活性分子的天生以匹敌习染？蒲Ъ夷芄痪荽搜蟹⒊鲂乱┪，这些药物能触发同样的反映，将疾病扼杀在萌芽状态。莱斯特大学的阿拉斯·卡迪格鲁和圣三一学院的艾德·拉弗勒以为，这一关于毒素若何同免疫系统结合的新认知意味着钻研人员能够研发出新疫苗。此刻，匹敌肺炎链球菌的疫苗能够防御7种分歧的菌株，但新步骤研发出的疫苗应该可能匹敌所有92种菌株？ǖ细衤嘲凳，这是一项极度令人兴奋的发现，提供了一种全新的步骤来匹敌细菌。这个“重大突破”将援手科学家更好地理解每年造成数百万婴儿殒命以及好多老年人患病和殒命的肺炎和脑膜炎这两个罪魁祸首。 （起源：科技日报 刘霞）

【点评】
　　该发现加深了对于人体自身免疫系统作用机造的理解，或许有助于解决现代医学面对的抗生素困境。

【原文摘录】PLoS Pathog 6(11): e1001191. doi:10.1371/journal.ppat.1001191
Pneumolysin Activates the NLRP3 Inflammasome and Promotes Proinflammatory Cytokines Independently of TLR4
McNeela EA, Burke Á, Neill DR, Baxter C, Fernandes VE, et al.
Pneumolysin (PLY) is a key Streptococcus pneumoniae virulence factor and potential candidate for inclusion in pneumococcal subunit vaccines. Dendritic cells (DC) play a key role in the initiation and instruction of adaptive immunity, but the effects of PLY on DC have not been widely investigated. Endotoxin-free PLY enhanced costimulatory molecule expression on DC but did not induce cytokine secretion. These effects have functional significance as adoptive transfer of DC exposed to PLY and antigen resulted in stronger antigen-specific T cell proliferation than transfer of DC exposed to antigen alone. PLY synergized with TLR agonists to enhance secretion of the proinflammatory cytokines IL-12, IL-23, IL-6, IL-1β, IL-1α and TNF-α by DC and enhanced cytokines including IL-17A and IFN-γ by splenocytes. PLY-induced DC maturation and cytokine secretion by DC and splenocytes was TLR4-independent. Both IL-17A and IFN-γ are required for protective immunity to pneumococcal infection and intranasal infection of mice with PLY-deficient pneumococci induced significantly less IFN-γ and IL-17A in the lungs compared to infection with wild-type bacteria. IL-1β plays a key role in promoting IL-17A and was previously shown to mediate protection against pneumococcal infection. The enhancement of IL-1β secretion by whole live S. pneumoniae and by PLY in DC required NLRP3, identifying PLY as a novel NLRP3 inflammasome activator. Furthermore, NLRP3 was required for protective immunity against respiratory infection with S. pneumoniae. These results add significantly to our understanding of the interactions between PLY and the immune system.

5. FTO基因过度活跃可导致肥胖
 
【提要】
　　英国牛津大学11月15日颁布的新闻公报指出，该校钻研人怨匾到了FTO基因会导致肥胖的有力证据，称FTO基因过度活跃会造成饮食过量，从而导致肥胖。有关成就颁发在最近一期《天然—遗传学》杂志上。FTO基因也称肥胖基因，是一种与肥胖有关的等位基因。早在2007年，一个蕴含牛津大学科学家在内的国际钻研幼组通过大型全基因组钻研发现，FTO基因变异与肥胖有关。携带两个FTO基因变异副本的人，其均匀体重迸椎有正常副本的人重3公斤。而在欧洲血统白人中，约莫有16%的人携带两个FTO基因变异副本。这次牛津大学和英国医学理事会的合作钻研中，钻研人员但愿能确定是否就是FTO基因自身活动的差距导致了肥胖。在尝试中，钻研人员造就出拥有有余FTO基因副本的幼鼠，他们发现，这些幼鼠固然也很健全，但与其它正常幼鼠相比，它们的食欲更强，更易饮食过量，体型也更肥硕。那些有两个FTO基因副本的雌性幼鼠，即便食谱与其它正常雌性幼鼠一样，其在20周后的体重也比后者重22%；但对于雄性幼鼠而言，这种体重差距则约莫在10%左右。
　　该项钻研的辅导者、牛津大学的弗朗西斯·阿什克劳夫特教授暗示，该尝试批注，FTO基因是与肥胖有关的重要基因，正是FTO基因过度活跃，才会造成幼鼠饮食过度，从而导致体重大幅增长。钻研论文作者之一、牛津大学的克里斯·丘奇则称，这是钻研人员第一次找到令人折服的证据证明FTO基因可能导致肥胖。而下一步，他们要致力于钻研有关机造，一旦相识了FTO基因导致肥胖的机造，就能够开发出有效的肥胖医治药物。相信这种可能抑造基因活动的药物将拥有很好的利用远景。（起源：科技日报 刘海英）

【点评】
　　第一次有直接证据批注FTO基因过度活跃会造成幼鼠饮食过量，从而导致肥胖。这一发现有助于对肥胖及其有关代谢疾病的深刻相识。

【原文摘录】Nature Genetics DOI: doi:10.1038/ng.713
Overexpression of Fto leads to increased food intake and results in obesity
Chris Church, Lee Moir, Fiona McMurray, et al.
Genome-wide association studies have identified SNPs within FTO, the human fat mass and obesity–associated gene, that are strongly associated with obesity. Individuals homozygous for the at-risk rs9939609 A allele weigh, on average, ~3 kg more than individuals with the low-risk T allele. Mice that lack FTO function and/or Fto expression display increased energy expenditure and a lean phenotype. We show here that ubiquitous overexpression of Fto leads to a dose-dependent increase in body and fat mass, irrespective of whether mice are fed a standard or a high-fat diet. Our results suggest that increased body mass results primarily from increased food intake. Mice with increased Fto expression on a high-fat diet develop glucose intolerance. This study provides the first direct evidence that increased Fto expression causes obesity in mice.

6. 维生素D不及可导致白血病恶化
 
【提要】
　　美国一项新钻研发现，机体内维生素D水平与白血病之间存在缜密联系，维生素D不及可能会引起病情恶化，维生素D水平正常则会耽搁病人存活功夫。这项钻研由美国梅奥诊所和艾奥瓦大学的钻研人员共同实现，钻研涉及390名慢性淋巴细胞白血病患者，其中30%的人在刚患病时被发现维生素D不及（即每毫升血液少于25毫微克）。在以来3年的跟踪调查期间，不足维生素D的白血病患者的病情恶化和接受化疗的几率要比其他病人高66%，殒命风险则要高两倍以上。钻研还发现，提高白血病患者的维生素D水平可耽搁他们的存活功夫，这一结论不受与白血病发展有关成分的影响。钻研人员说，他们对另一组白血病患者进行了为期10年的钻研，得出了同样结论。钻研人员指出，这一发现将有助于更有效地医治白血病，由于病人能够凭据必要实时补充维生素D，这一步骤既简易可行，又不会产生副作用。钻研人员说，他们打算在另一项钻研中调度患者的维生素D水平，看是否能以此改善病人的预后。钻研汇报登载在新一期美国粹术期刊《血液》杂志上。（起源：新华网 高原）

【点评】
　　体内维生素D水平与白血病之间存在缜密联系，讲了然营养不良与癌症发生之间肯定的关联性。

【原文摘录】Blood; DOI 10.1182/blood-2010-07-295683.
Vitamin D insufficiency and prognosis in chronic lymphocytic leukemia (CLL)
Tait D. Shanafelt,, Matthew T. Drake, Matthew J. Maurer, et al.
Vitamin D insufficiency is common globally with low levels linked to higher cancer incidence. Although vitamin D insufficiency is related to inferior prognosis in some cancers, no data exist for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). We evaluated the relationship of 25(OH)D serum levels with time-to-treatment(TTT) and overall survival(OS) in newly diagnosed CLL patients participating in a prospective cohort study(discovery cohort) and a separate cohort of previously untreated patients participating in an observational study(confirmation cohort). Of 390 CLL patients in the discovery cohort, 119(30.5%) were 25(OH)D insufficient. After median follow-up of 3 years, TTT(hazard ratio[HR]=1.66; p=0.005) and OS(HR=2.39; p=0.01) were shorter for 25(OH)D insufficient patients. In the validation cohort, 61 of 153 patients(39.9%) were 25(OH)D insufficient. After median follow-up of 9.9 years, TTT(HR=1.59; p=0.05) and OS(HR 1.63; p=0.06) were again shorter for 25(OH)D insufficient patients. On pooled multivariable analysis of patients in both cohorts adjusting for age, sex, stage, CD38, ZAP-70, IGHV, CD49d, and FISH, 25(OH)D insufficiency remained an independent predictor of TTT(HR=1.47; p=0.008), although the association with OS was not significant(HR=1.47; p=0.07). Vitamin D insufficiency is associated with inferior TTT and OS in CLL patients. Whether normalizing vitamin D levels in deficient CLL patients would improve outcome merits clinical testing.