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天下生命科学前沿动态周报（十）
（05.24--05.30 / 2010）
一竞技国际集团:陶国新
本周动态包括以下内容：新型DNA抗癌疫苗; 首次发明可发育成卵的干细胞; 脂肪干细胞分解为心肌细胞; CD95 增进肿瘤生长 ；核糖核酸滋扰可抑制癌症活跃基因 ；人体干细胞乐成造出人工牙齿。
1. 新型DNA抗癌疫苗
【摘要】新华网 宣布时间：2010-5-25 16:44:42
瑞典卡罗林斯卡医学院日前揭晓通告说 ，该机构研究职员研制出一种可抑制恶性肿瘤生长的新型DNA（脱氧核糖核酸）疫苗 ，实验显示这种疫苗无副作用。当恶性肿瘤凌驾几个毫米时 ，需要形成新的血管为肿瘤提供营养和氧气。因此 ，阻止血管的生长是治疗恶性肿瘤的思绪之一。卵白质DLL4是形成血管的须要因素 ，若是能抑制肿瘤细胞中的DLL4卵白质 ，将使新血管失去功效 ，从而大大减缓肿瘤的生长速率。
研究职员据此研制出了这种DNA疫苗。经对患有乳腺癌的小白鼠举行试验 ，证实接种疫苗的小白鼠体内爆发了可抑制DLL4卵白质的抗体 ，阻止了体内乳腺肿瘤的生长 ，并且没有引起任何不良反应 ，也未影响小白鼠的伤口愈合。研究职员皮耶特拉斯称 ，选择乳腺癌作为试验目的是由于乳腺肿瘤带有大宗的DLL4卵白质。研究职员希望能将这种疫苗用于乳腺癌的术后治疗 ，避免肿瘤复发。
【点评】 点评：小鼠通过接种DNA疫苗 ，爆发抗体抑制恶性肿瘤新生血管必需的DLL4卵白质 ，从而阻止肿瘤生长。该疫苗关于减缓肿瘤生长和避免肿瘤复发可能有作用 ，可是由于不可直接作用于肿瘤细胞 ，还不可能根除癌症。
【原文摘录】Oncogene , (24 May 2010) | doi:10.1038/onc.2010.176
Therapeutic efficacy of a DNA vaccine targeting the endothelial tip cell antigen delta-like 4 in mammary carcinoma
BK Haller, A Bråve, E Wallgard, P Roswall, VG Sunkari, U Mattson, D Hallengärd, S-B Catrina, M Hellström och K Pietras
The Notch ligand delta-like ligand 4 (DLL4) is an essential component expressed by endothelial tip cells during angiogenic sprouting. We have described a conceptually novel therapeutic strategy for targeting tumor angiogenesis and endothelial tip cells based on DNA vaccination against DLL4. Immunization with DLL4-encoding plasmid DNA by in vivo electroporation severely retarded the growth of orthotopically implanted mammary carcinomas in mice by induction of a nonproductive angiogenic response. Mechanistically, vaccination brought about a break in tolerance against the self-antigen, DLL4, as evidenced by the production of inhibitory and inherently therapeutic antibodies against mouse DLL4. Importantly, no evidence for a delayed wound healing response, or for toxicity associated with pharmacological blockade of DLL4 signaling, was noted in mice immunized with the DLL4 vaccine. We have thus developed a well-tolerated DNA vaccination strategy targeting the endothelial tip cells and the antigen DLL4 with proven therapeutic efficacy in mouse models of mammary carcinoma; a disease that has been reported to dramatically induce the expression of DLL4. Conceivably, induction of immunity toward principal mediators of pathological angiogenesis could provide protection against recurrent malignant disease in the adjuvant setting.
2. 首次发明可发育成卵的干细胞
【摘要】新华网 2010-5-25 9:39:40
日本一个研究小组日前发明 ，在雌鳉鱼的卵巢内保存可发育成鳉鱼卵的干细胞。有关效果已经刊登在最新一期的美国《科学》杂志网络版上。这一效果是日本自然科学研究机构基础生物学研究所的研究职员获得的� ；∩镅а芯克涨敖蚁ǜ嫠� ，在脊椎动物中 ，已经发明雄性的精巢中保存发育成精子的干细胞 ，可是在卵巢中发明会发育成卵的干细胞则属天下首次。研究小组对雌性鳉鱼举行基因操作 ，使其卵巢内的卵发出红光 ，效果发明了许多即将发育为卵的细胞。使用绿色荧光卵白质给这些细胞做上标记以后 ，研究职员发明许多新形成的卵也会发出绿色荧光 ，这说明这些细胞简直发育成了卵 ，因此这些细胞就是干细胞。
【点评】 点评：天下首次在脊椎动物卵巢中发明会发育成卵的干细胞。由于没有直接证据显示成体脊椎动物卵巢中有生殖干细胞 ，这些发育成卵的干细胞很可能是从卵巢中的体细胞原位转变的。
【原文摘录】Science DOI: 10.1126/science.1185473
Identification of Germline Stem Cells in the Ovary of the Teleost Medaka
Shuhei Nakamura,1 Kayo Kobayashi,1 Toshiya Nishimura,1,2 Shin-ichi Higashijima,3,4 Minoru Tanaka1,2,*
Germline stem cells continually produce sperm in vertebrate testes, whereas there is no direct evidence showing that germline stem cells are present in adult vertebrate ovaries. Using transgenic methods and clonal analysis, we identified germline stem cells that supported oogenesis and the production of offspring in the ovaries of adult medaka fish. Early-stage germ cells were localized in clusters along interwoven threadlike cords of sox9b-expressing somatic cells (termed "germinal cradles") where the germ cells developed. Germline stem cells gave rise to germ cells that divided to produce cysts, which then underwent cell death or separated to form follicles. Our results provide insight into germline stem cell biology of medaka and provide a model system for studying vertebrate stem cell niches.
3. 脂肪干细胞分解为心肌细胞
【摘要】西班牙研究职员首次从人类脂肪组织中疏散出成熟的干细胞 ，让这些细胞暂时袒露于人类的心房细胞中 ，随后再对这些细胞重新举行作育。经由12天的作育 ，这些细胞向着心肌细胞的表型偏向分解 ，这可以通过以下方面获得证实：这些细胞从形态上爆发了改变 ，体现为带有纤维纹和分枝的双核细胞 ；免疫荧光检查发明 ，它们带有心脏特有的标记 ；RT - PCR检测证实 ，这些细胞保存心肌基因 ；它们有逆转录表达。这样 ，这些干细胞获得了一个心脏的表型。未来可通过这项手艺从患者身上直接提取细胞来再生心肌细胞。可是医生们体现 ，现在这项研究还处于初期阶段 ，要用于治疗尚有很长一段时间。
【点评】 点评：干细胞分解的决议受到其所处心理情形的调控 ，这类调控也决议了其在体外作育时的分解偏向。
【原文摘录】Cytotherapy DOI: 10.3109/14653240903548202
Human cardiac tissue induces transdifferentiation of adult stem cells towards cardiomyocytes
Background aims. The goal was to induce the transdifferentiation (or conversion) of human adipose-derived stem cells to cardiomyocytes using an intracellular extract obtained from adult human heart tissue. Methods. Human adult stem cells from lipoaspirates were transiently permeabilized, exposed to human atrial extracts and allowed to recover in culture. Results. After 21 days, the cells acquired a cardiomyocyte phenotype, as demonstrated by morphologic changes (appearance of binucleate, striated cells and branching fibers), immunofluorescence detection of cardiac-specific markers (connexin-43, sarcomeric α-actinin, cardiac troponin I and T, and desmin) and the presence of cardiomyocyte-related genes analyzed by reverse transcription–polymerase chain reaction (cardiac myosin light chain 1, α-cardiac actin, cardiac troponin T and cardiac β-myosin). Conclusions. We have demonstrated for the first time that adult cardiomyocytes obtained from human donors retain the capacity to induce cardiomyocyte differentiation of mesenchymal stromal cells. The use of autologous extracts for reprogramming adult stem cells may have potential therapeutic implications for treating heart disease.
4. CD95 增进肿瘤生长
【摘要】CD95 原来一直被以为是凋亡受体卵白 ，通过诱导细胞凋亡来调理组织内稳态 ，是癌细胞杀手。现在发明 ，自相矛盾的是 ，癌细胞的正常生长也离不开它。没有它 ，小鼠的卵巢癌和肝癌发病率和肿瘤体积都降低了。
【点评】 点评：发明CD95 受体卵白在癌症生长中有增进作用 ，在癌症治疗中应该抑制其活性而非原来以为的增强其活性。
【原文摘录】Nature 465, 492–496 (27 May 2010) doi:10.1038/nature09075
CD95 promotes tumour growth
Lina Chen, Sun-Mi Park, Alexei V. Tumanov, Annika Hau, Kenjiro Sawada, Christine Feig, Jerrold R. Turner, Yang-Xin Fu, Iris L. Romero, Ernst Lengyel & Marcus E. Peter
CD95 (also called Fas and APO-1) is a prototypical death receptor that regulates tissue homeostasis mainly in the immune system through the induction of apoptosis1, 2, 3. During cancer progression CD95 is frequently downregulated or cells are rendered apoptosis resistant4, 5, raising the possibility that loss of CD95 is part of a mechanism for tumour evasion. However, complete loss of CD95 is rarely seen in human cancers4 and many cancer cells express large quantities of CD95 and are highly sensitive to CD95-mediated apoptosis in vitro. Furthermore, cancer patients frequently have elevated levels of the physiological ligand for CD95, CD95L6. These data raise the possibility that CD95 could actually promote the growth of tumours through its non-apoptotic activities7. Here we show that cancer cells in general, regardless of their CD95 apoptosis sensitivity, depend on constitutive activity of CD95, stimulated by cancer-produced CD95L, for optimal growth. Consistently, loss of CD95 in mouse models of ovarian cancer and liver cancer reduces cancer incidence as well as the size of the tumours. The tumorigenic activity of CD95 is mediated by a pathway involving JNK and Jun. These results demonstrate that CD95 has a growth-promoting role during tumorigenesis and indicate that efforts to inhibit its activity rather than to enhance it should be considered during cancer therapy.
5. 核糖核酸滋扰可抑制癌症活跃基因
【摘要】2010年05月29日 09:15:13 泉源： 科技日报
加拿大麦吉尔大学生物化学系研究职员发明 ，与核糖核酸相团结的一种卵白质片断能够控制基因的正常表达 ，其中包括那些在癌症中活跃的基因。专家以为 ，这是癌症研究事情的一项主要突破 ，可连忙将其应用到实验室的研究事情中 ，并且使现在各国科学家普遍开展的癌症个性化治疗事情向前推进了一大步。相关研究效果揭晓在5月26日《自然》杂志网络版上。人类细胞需要在合适的时间生产出适度数目的正常卵白以维持其康健。细胞对卵白生产举行有用控制时 ，所接纳的主要手段之一就是依赖“核糖核酸滋扰”。“核糖核酸滋扰”是基因静默的一种形式 ，即小片断核糖核酸（又称微核糖核酸）与它们的遗传密码团结 ，以阻断特殊卵白的生产。然而 ，不是核糖核酸的任何片断都能够按此方法行事。
麦吉尔大学的哈桑·拉贾尔博士与同事合作 ，使用结构生物学揭开了Argonaute卵白中的一小段 ，即“核糖核酸滋扰”的要害分子怎样能够选择准确的微核糖核酸的神秘。研究职员发明 ，“核糖核酸滋扰”可以促使Argonaute卵白增添基因静默。拉贾尔博士以为 ，“核糖核酸滋扰”可以作为可行的治疗要领 ，来抑制那些在癌症等疾病中显得特殊活跃的特殊基因。他体现现在已经掌握了修改微核糖核酸的要领 ，可以使其更具效力 ，并有希望基于此开发出治疗药物。研究职员以为 ，该发明要进入现实治疗还需时日 ，但它为有目的地控制那些非正常卵白的生产提供了有用要领。麦吉尔大学生化系主任汤姆斯博士以为 ，医学界一直期盼有朝一日可以竣事依赖化疗要领治疗癌症 ，而该项发明朝着癌症患者个性化基因治疗偏向迈出了主要的一步。（记者杜华斌）
【点评】 点评：核糖核酸滋扰（RNAi）是可行的抑制那些在癌症等疾病中特殊活跃的特殊基因的要领 ，但只是暂时关闭这类基因而不可消除导致其特殊活跃的因素 ，很难根除癌症。
【原文摘录】Nature advance online publication 26 May 2010 | doi:10.1038/nature09039
Structural basis for 5′-nucleotide base-specific recognition of guide RNA by human AGO2
Filipp Frank1,2,3, Nahum Sonenberg1,2 & Bhushan Nagar1,3
MicroRNAs (miRNAs) mediate post-transcriptional gene regulation through association with Argonaute proteins (AGOs)1. Crystal structures of archaeal and bacterial homologues of AGOs have shown that the MID (middle) domain mediates the interaction with the phosphorylated 5′ end of the miRNA guide strand and this interaction is thought to be independent of the identity of the 5′ nucleotide in these systems2,3. However, analysis of the known sequences of eukaryotic miRNAs and co-immunoprecipitation experiments indicate that there is a clear bias for U or A at the 5′ position4,5,6,7. Here we report the crystal structure of a MID domain from a eukaryotic AGO protein, human AGO2. The structure, in complex with nucleoside monophosphates (AMP, CMP, GMP, and UMP) mimicking the 5′ end of miRNAs, shows that there are specific contacts made between the base of UMP or AMP and a rigid loop in the MID domain. Notably, the structure of the loop discriminates against CMP and GMP and dissociation constants calculated from NMR titration experiments confirm these results, showing that AMP (0.26 mM) and UMP (0.12 mM) bind with up to 30-fold higher affinity than either CMP (3.6 mM) or GMP (3.3 mM). This study provides structural evidence for nucleotide-specific interactions in the MID domain of eukaryotic AGO proteins and explains the observed preference for U or A at the 5′ end of miRNAs.
6. 人体干细胞乐成造出人工牙齿
【摘要】网易探索2010-5-28 5:18:39
哥伦比亚大学医学中心5月25日宣布牙齿再外行艺获得新突破 ，研究职员乐成在动物口腔内举行了牙齿再生实验 ，这意味着未来人们就可将该手艺应用于临床实验领域。
杰瑞米·毛（Jeremy Mao）博士认真向导哥伦比亚大学医学中心组织工程学及再生药物实验室的研究职员从事该课题的研究 ，他们找到一种新的手艺 ，只需在患者口腔内植入一个托架 ，并将患者体内的干细胞指导至需要牙齿再生的地方 ，就可以实现真正意义上的“牙齿再生”。用于植入患者口腔的托架将所有接纳自然质料制成 ，并将被安排在失去牙齿的牙洞内。在生长的历程中 ，该托架将与其周围的牙洞组织逐渐融合 ，甚至还会令牙周韧带及齿槽骨再生。而这些正是古板种牙要领所无法带来的。
【点评】 点评：干细胞分解的决议受到其所处心理情形的调控 ，在没有移植细胞的情形下 ，在牙齿托架和再生诱导物的作用下 ，体内细胞迁徙过来再生新牙齿。
【原文摘录】Journal of Dental Research, May 2010; vol. 0: pp. 0022034510370803v1.
Anatomically Shaped Tooth and Periodontal Regeneration by Cell Homing
K. Kim, C.H. Lee, B.K. Kim, and J.J. Mao
Tooth regeneration by cell delivery encounters translational hurdles. We hypothesized that anatomically correct teeth can regenerate in scaffolds without cell transplantation. Novel, anatomically shaped human molar scaffolds and rat incisor scaffolds were fabricated by 3D bioprinting from a hybrid of poly--caprolactone and hydroxyapatite with 200-μm-diameter interconnecting microchannels. In each of 22 rats, an incisor scaffold was implanted orthotopically following mandibular incisor extraction, whereas a human molar scaffold was implanted ectopically into the dorsum. Stromal-derived factor-1 (SDF1) and bone morphogenetic protein-7 (BMP7) were delivered in scaffold microchannels. After 9 weeks, a putative periodontal ligament and new bone regenerated at the interface of rat incisor scaffold with native alveolar bone. SDF1 and BMP7 delivery not only recruited significantly more endogenous cells, but also elaborated greater angiogenesis than growthfactor-free control scaffolds. Regeneration of tooth-like structures and periodontal integration by cell homing provide an alternative to cell delivery, and may accelerate clinical applications.