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天下生命科学前沿动态周报（三十七）
（12.20-12.31/2010）
一竞技国际集团:陶国新
---2010再生科学年度希望
本次动态包括以下内容：耐力磨炼使心肌细胞增殖的机理；癌症干细胞基因表达高癌症治疗效果差；无需标记实时视察活组织中分子运动；果蝇激活生殖细胞遗传基因来爆发肿瘤；癌细胞自我杀绝与自我�；さ男藕欧肿�；细小RNA表达模式的整体图谱区分干细胞种别 。以及2010各期中泛起过的较量突出的几项再生科学希望的小结 。
1. 耐力磨炼使心肌细胞增殖的机理
【摘要】
人们都知道磨炼身体可以增进新陈代谢，有益于心血管康健，但此前科学家对运动事实怎样影响心脏却所知甚少 。美国哈佛大学医学院的研究职员日前报告说，他们首次从分子水平发明运动有益心脏康健的机理，这一发明将有助于开发出治疗心血管疾病的新疗法 。研究职员通过小鼠实验发明，经常运动可以使小鼠体内的C/EBPβ转录因子水平显著下降，其效果会增进小鼠心脏肌肉细胞增殖，有益于心脏生长 。别的，研究职员还发明，体内C/EBPβ水平较低的小鼠对心力衰竭具有对抗能力 。研究职员体现，这项研究对心脏肌肉再生的潜力有了深入明确 。加入研究的哈佛大学医学院教授安东尼·罗森茨魏希体现，通过这项研究可以开发出针对那些无法运动的心脏病患者的疗法 。这项研究效果揭晓在新一期美国《细胞》杂志上 。（泉源：新华社）
【点评】
该研究所发明的心肌增殖机理同样有助于明确非药物方法实现组织再生的机制并增进此类自然再生要领的推广 。
【原文摘录】Cell, Volume 143, Issue 7, 1072-1083, 23 December 2010
C/EBPβ Controls Exercise-Induced Cardiac Growth and Protects against Pathological Cardiac Remodeling
Pontus Boström, Nina Mann, Jun Wu, et al.
The heart has the ability to grow in size in response to exercise, but little is known about the transcriptional mechanisms underlying physiological hypertrophy. Adult cardiomyocytes have also recently been proven to hold the potential for proliferation, a process that could be of great importance for regenerative medicine. Using a unique RT-PCR-based screen against all transcriptional components, we showed that C/EBPβ was downregulated with exercise, whereas the expression of CITED4 was increased. Reduction of C/EBPβ in vitro and in vivo resulted in a phenocopy of endurance exercise with cardiomyocyte hypertrophy and proliferation. This proliferation was mediated, at least in part, by the increased CITED4. Importantly, mice with reduced cardiac C/EBPβ levels displayed substantial resistance to cardiac failure upon pressure overload. These data indicate that C/EBPβ represses cardiomyocyte growth and proliferation in the adult mammalian heart and that reduction in C/EBPβ is a central signal in physiologic hypertrophy and proliferation.
2. 癌症干细胞基因表达高癌症治疗效果差
【摘要】
据美国物理学家组织网12月22日（北京时间）报道，斯坦福大学研究职员通过对白血病干细胞的基因表达方法研究发明，癌症干细胞基因表达水平更高的病人比表达水平低的病人预后效果要差许多，该发明首次通过临床数据证实晰癌症干细胞看法 。医疗职员可据此展望群体病人的治疗效果，并资助开发新的临床疗法 。研究揭晓在12月22日的《美国医学会杂志》（JAMA）上 。几年条件出的癌症干细胞看法以为，某些癌症起源于一小撮自我更新能力很强的细胞，这一小撮细胞即是癌症干细胞 。这些癌症干细胞能一直增补天生新的癌症细胞，癌症要彻底治疗，必需扫除这些干细胞 。癌症干细胞对抗治疗已经在一些固状肿瘤和血癌的动物模子中获得验证，虽然有大宗实验室证据支持，但至今还缺乏临床证据 。论文合著者、斯坦福癌症中心医务部艾什·埃里沙德和同事拉文达·马杰提今年9月曾在实验室小鼠中，对非霍奇森淋巴瘤癌症干细胞外貌发明的卵白质CD47研究发明，CD47是癌症干细胞的“�；ど �，有了它，许多药物对这些细胞无效 。CD47在其他几种癌症干细胞中也保存 。马杰提以为这些动物实验中发明的证据在人体中也应该保存 。他们用两种能识别白血病干细胞的外貌标记，从7个白血病患者的肿瘤样本中疏散出这些白血病干细胞，将肿瘤干细胞和其他肿瘤细胞的基因表达方法举行了比照，效果有52%的基因表达差别 。癌症干细胞基因表达方法和正常的血液干细胞很相似，不但能自我更新，还能像正常干细胞在需要时间才破碎 。为了逃避那些针对迅速破碎细胞的古板治疗要领，它会选择少量破碎，潜在着，期待时机“死灰复然” 。
研究职员还对来自1000多位急性骨髓白血病病人的4组肿瘤样本举行了比照研究，发明在“癌症干细胞基因高表达”和“治疗效果差”之间保存很强的相关性 。在一组德国样本中，高表达病人3年内殒命的绝对危害高达78%，而低表达病人仅为57% 。同样，无病生涯率、某个时期再度恶化可能性、对抗首次治疗顽固性等指标也云云 。论文第一作者、斯坦福大学癌症系统生物学中心安德鲁·简托斯体现，白血病干细胞的信号越强，病人寿命越短，病情恶化得越快，治疗效果就更差 。现在，研究小组正在继续研究数据，以最终从种种团结抗体疗法中确定哪些疗法对癌症干细胞高表达基因信号的病人最有用 。（泉源：科技日报 宣布时间：2010-12-23 10:20:47）
【点评】
该研究发明了白血病干细胞基因的高表达与急性粒细胞白血病的治疗效果差之间有自力的相关性，可是并没有证实癌症干细胞是肿瘤爆发的因由 。
【原文摘录】 JAMA. 2010;304(24):2706-2715. doi: 10.1001/jama.2010.1862
Association of a Leukemic Stem Cell Gene Expression Signature With Clinical Outcomes in Acute Myeloid Leukemia
Andrew J. Gentles, Sylvia K. Plevritis, Ravindra Majeti, Ash A. Alizadeh
Abstract
Context In many cancers, specific subpopulations of cells appear to be uniquely capable of initiating and maintaining tumors. The strongest support for this cancer stem cell model comes from transplantation assays in immunodeficient mice, which indicate that human acute myeloid leukemia (AML) is driven by self-renewing leukemic stem cells (LSCs). This model has significant implications for the development of novel therapies, but its clinical relevance has yet to be determined.
Objective To identify an LSC gene expression signature and test its association with clinical outcomes in AML.
Design, Setting, and Patients Retrospective study of global gene expression (microarray) profiles of LSC-enriched subpopulations from primary AML and normal patient samples, which were obtained at a US medical center between April 2005 and July 2007, and validation data sets of global transcriptional profiles of AML tumors from 4 independent cohorts (n = 1047).
Main Outcome Measures Identification of genes discriminating LSC-enriched populations from other subpopulations in AML tumors; and association of LSC-specific genes with overall, event-free, and relapse-free survival and with therapeutic response.
Results Expression levels of 52 genes distinguished LSC-enriched populations from other subpopulations in cell-sorted AML samples. An LSC score summarizing expression of these genes in bulk primary AML tumor samples was associated with clinical outcomes in the 4 independent patient cohorts. High LSC scores were associated with worse overall, event-free, and relapse-free survival among patients with either normal karyotypes or chromosomal abnormalities. For the largest cohort of patients with normal karyotypes (n = 163), the LSC score was significantly associated with overall survival as a continuous variable (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.08-1.22; log-likelihood P <.001). The absolute risk of death by 3 years was 57% (95% CI, 43%-67%) for the low LSC score group compared with 78% (95% CI, 66%-86%) for the high LSC score group (HR, 1.9 [95% CI, 1.3-2.7]; log-rank P = .002). In another cohort with available data on event-free survival for 70 patients with normal karyotypes, the risk of an event by 3 years was 48% (95% CI, 27%-63%) in the low LSC score group vs 81% (95% CI, 60%-91% ) in the high LSC score group (HR, 2.4 [95% CI, 1.3-4.5]; log-rank P = .006). In multivariate Cox regression including age, mutations in FLT3 and NPM1, and cytogenetic abnormalities, the HRs for LSC score in the 3 cohorts with data on all variables were 1.07 (95% CI, 1.01-1.13; P = .02), 1.10 (95% CI, 1.03-1.17; P = .005), and 1.17 (95% CI, 1.05-1.30; P = .005).
Conclusion High expression of an LSC gene signature is independently associated with adverse outcomes in patients with AML.
3. 无需标记实时视察活组织中分子运动
【摘要】
美国哈佛大学科学家将受激拉曼散射（SRS）显微镜和核磁共振成像（MRI）手艺团结，研制出一种最新的生物医学成像装备，极大拓展了SRS显微镜的视野 。其速率之快精度之高，犹如“视频”，足以使科学家直接眼见分子在活组织中的运动 。研究论文揭晓在最新一期《科学》杂志上 。“此前，SRS显微镜每分钟只能拍摄一幅画面，用于活的动物某人体就太慢了 。”哈佛大学化学与化学生物学教授谢晓亮说，“我们大大提高了收罗数据的速率，使拍摄抵达了视频速率 。”研究小组还用这种新型SRS显微镜追踪药物在皮肤下的移动，其能清晰显示出药物实时吸收情形 。如与内镜检查术团结，还能一层一层视察组织的三维结构 。新型SRS显微镜的事情原理是探测原子之间化学键的内在震惊，由于融合了MRI手艺，在透视深度上更适合拍摄体内器官和其他大目的，既可普遍用于拍摄器官和组织结构的静态图像，也能在亚细胞水平以流动画面视察细胞中的卵白质、脂质和水 。
同多种常用的视察生物分子的手艺相比，新型SRS显微镜优势显着 。它能收罗剖析照射生物样本的近30%激光，比古板SRS显微镜横跨30倍；并且不需要插入荧光标记，阻止了绿色荧光标记卵白质扰乱生物路径或压住较小生物分子的问题 。别的，古板的红外显微镜空间区分率太低，并需要给样本脱水；自然的拉曼显微镜需要很高的激光能量，整体耗时很长，在活样本中的应用受到限制；相关反斯托克拉曼散射显微镜在拍摄除了脂质以外的大大都分子时比照度不敷，而新型SRS显微镜都能突破这些局限 。研究职员体现，新型SRS显微镜在医疗领域的应用远景辽阔 。好比，手术之前必需将样本送检以用于组织剖析，这个历程约莫要花20分钟，其间病人需要等在手术台上，而新手艺可提供实时扫描透视，有助于加速外科手术，扫除肿瘤和其他损伤 。谢晓亮说：“这一项目最先于11年前，核磁共振手艺花了30多年才用于临床，我们期望这种SRS显微镜尽早应用于医院 。”泉源：科技日报 常丽君
【点评】
该项手艺将会极大的增进心理生化尤其是新陈代谢的研究，如能成熟地运用于人体，关于人体心理学及医学研究将有重大的资助 。
【原文摘录】 Science Vol. 330 no. 6009 pp. 1368-1370 DOI: 10.1126/science.1197236
Video-Rate Molecular Imaging in Vivo with Stimulated Raman Scattering
Brian G. Saar1,Christian W. Freudiger, Jay Reichman, et al.
Optical imaging in vivo with molecular specificity is important in biomedicine because of its high spatial resolution and sensitivity compared with magnetic resonance imaging. Stimulated Raman scattering (SRS) microscopy allows highly sensitive optical imaging based on vibrational spectroscopy without adding toxic or perturbative labels. However, SRS imaging in living animals and humans has not been feasible because light cannot be collected through thick tissues, and motion-blur arises from slow imaging based on backscattered light. In this work, we enable in vivo SRS imaging by substantially enhancing the collection of the backscattered signal and increasing the imaging speed by three orders of magnitude to video rate. This approach allows label-free in vivo imaging of water, lipid, and protein in skin and mapping of penetration pathways of topically applied drugs in mice and humans.
4. 果蝇激活生殖细胞遗传基因来爆发肿瘤
【摘要】
巴塞罗那的 科学家克日在Science上报道他们发明了果蝇幼虫使用生殖细胞的遗传程序来催生脑部肿瘤 。关闭涉及到的相关基因就会坚持康健的大脑，这是首次发明关闭这些相关基因可以使果蝇脑部肿瘤消逝 。说明这些生殖细胞的遗传基因关于此类肿瘤的爆发有要害作用 。此前十年积累的数据显示某些肿瘤如玄色素瘤和某些类癌的癌细胞会激活生殖细胞的遗传基因 。
【点评】
这项研究说明癌基因并纷歧定是癌症爆发的缘故原由，生殖基因的激活也可能引发癌症 �；蚣せ畹男睦淼骺厥欠裾Ｊ呛苤饕� 。
【原文摘录】 Science, December 23, 2010 DOI: 10.1126/science.1195481
Ectopic expression of germline genes drives malignant brain tumor growth in Drosophila.
Janic A, Mendizabal L, Llamazares S, Rossell D, Gonzalez C.
Model organisms such as the fruit fly Drosophila melanogaster can help to elucidate the molecular basis of complex diseases such as cancer. Mutations in the Drosophila gene lethal (3) malignant brain tumor cause malignant growth in the larval brain. Here we show that l(3)mbt tumors exhibited a soma-to-germline transformation through the ectopic expression of genes normally required for germline stemness, fitness, or longevity. Orthologs of some of these genes were also expressed in human somatic tumors. In addition, inactivation of any of the germline genes nanos, vasa, piwi, or aubergine suppressed l(3)mbt malignant growth. Our results demonstrate that germline traits are necessary for tumor growth in this Drosophila model and suggest that inactivation of germline genes might have tumor-suppressing effects in other species.
5. 癌细胞自我杀绝与自我�；さ男藕欧肿�
【摘要】
斯坦福大学医学院的研究职员发明许多癌细胞自身带有自我杀绝的种子--细胞外貌一种名为钙网素的卵白—能召集循环系统的巨噬细胞来吞食消化他们 。而绝大大都癌细胞没有被杀绝是由于他们同时表达另一种信号卵白CD47对抗钙网素的作用 。
【点评】
CD47与钙网素的作用及二者平衡的调理会增进癌症免疫疗法的生长 。
【原文摘录】 Sci Transl Med 22 December 2010: Vol. 2, Issue 63, p. 63ra94
Calreticulin Is the Dominant Pro-Phagocytic Signal on Multiple Human Cancers and Is Counterbalanced by CD47
M. P. Chao, S. Jaiswal, R. Weissman-Tsukamoto, et al.
Under normal physiological conditions, cellular homeostasis is partly regulated by a balance of pro- and anti-phagocytic signals. CD47, which prevents cancer cell phagocytosis by the innate immune system, is highly expressed on several human cancers including acute myeloid leukemia, non-Hodgkin’s lymphoma, and bladder cancer. Blocking CD47 with a monoclonal antibody results in phagocytosis of cancer cells and leads to in vivo tumor elimination, yet normal cells remain mostly unaffected. Thus, we postulated that cancer cells must also display a potent pro-phagocytic signal. Here, we identified calreticulin as a pro-phagocytic signal that was highly expressed on the surface of several human cancers, but was minimally expressed on most normal cells. Increased CD47 expression correlated with high amounts of calreticulin on cancer cells and was necessary for protection from calreticulin-mediated phagocytosis. Blocking the interaction of target cell calreticulin with its receptor, low-density lipoprotein receptor–related protein, on phagocytic cells prevented anti-CD47 antibody–mediated phagocytosis. Furthermore, increased calreticulin expression was an adverse prognostic factor in diverse tumors including neuroblastoma, bladder cancer, and non-Hodgkin’s lymphoma. These findings identify calreticulin as the dominant pro-phagocytic signal on several human cancers, provide an explanation for the selective targeting of tumor cells by anti-CD47 antibody, and highlight the balance between pro- and anti-phagocytic signals in the immune evasion of cancer.
6. 细小RNA表达模式的整体图谱区分干细胞种别
【摘要】
干细胞生物学在全天下引发人们对其可以最终修复身体部位的重大期望 。只管许多科学家以为这是可行的，可是必需战胜许多障碍，包括令人担心的在修复器官时引发癌症的潜在危害 。而克日报道的加州大学的一项关于多能性干细胞的细小RNA表达模式的研究或许对此有所资助 。他们剖析许多种多能性干细胞的细小RNA表达模式，发明所有的多能性干细胞细小RNA表达模式并不相同，但不是因细胞泉源而异，而是具有差别的p53 系统状态 。细小RNA表达模式的整体图谱能够告诉你这是何种细胞，何种癌症，是否干细胞等信息 。
【点评】
细小RNA表达模式的整体图谱研究也许会有助于研究人体潜能再生细胞的定位和属性 。
【原文摘录】 Cell Stem Cell, Volume 7, Issue 6, 671-681, 3 December 2010
MicroRNA Profiling Reveals Two Distinct p53-Related Human Pluripotent Stem Cell States
Pierre Neveu, Min Jeong Kye, Shuping Qi, et al.
Highlights
miRNA profiles distinguish two categories of human pluripotent stem cells
The p53 network status distinguishes pluripotent cells independently of their origin
p53-targeting miRNAs change the classification status of iPSCs
A 2D representation of miRNA profiles tracks differentiation and reprogramming
Summary
Reprogramming methodologies have provided multiple routes for achieving pluripotency. However, pluripotency is generally considered to be an almost singular state, with subtle differences described between induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs). We profiled miRNA expression levels across 49 human cell lines, including ESCs, iPSCs, differentiated cells, and cancer cell lines. We found that the resulting miRNA profiles divided the iPSCs and hESCs examined into two distinct categories irrespective of the cell line origin. The miRNAs that defined these two pluripotency categories also distinguished cancer cells from differentiated cells. Transcriptome analysis suggested that several gene sets related to p53 distinguished these categories, and overexpression of the p53-targeting miRNAs miR-92 and miR-141 in iPSCs was sufficient to change their classification status. Thus, our results suggest a subdivision of pluripotent stem cell states that is independent of their origin but related to p53 network status.
7. 2010再生科学年度希望
凭证与人体再生回复科学的相关水平，今年度刊登的以下动态作为2010再生科学年度希望：
1.人体多醒目细胞体外定向分解形成肠组织；
2.老鼠实验批注修复端�？梢阅孀嗦�；
3.蝾螈重生肢体和器官的奇异酶；
4.生长因子TGF-β2和BMP4可使成熟细胞转化为成人干细胞；
5.生命重大性的爆发可能必需先有线粒体泛起；
6.黄芩汤可减轻肠癌患者化疗损伤；
7.细胞生长调控依赖细胞质核传输；
8.洞螈长寿研究或解开朽迈之谜；
9.脂肪可用作细胞内在pH感受器；
10.发明上皮组织中神秘免疫细胞的功效和机理；
11.细胞归巢法使兔滑膜枢纽面再生；
12.控制细胞分解的力学因素；
13.要害基因控制哺乳动物组织再生；
14.细胞运动的整体调控控制胚胎的生长；
15.首次发明可发育成卵的干细胞;
16.精子形成历程中的细胞在一准时期内可以变回干细胞；
17.“活体生物反应器”“原位”作育再生新器官；
18.发明斑马鱼造血干细胞天生气理 。