（6.17-6.23/2012）
恒峰g22国际集团:陶国新 

　　重要内容：细胞周期同步滞碍于G1期推进癌细胞匹敌癌药物的敏感性和细胞凋亡; 大脑的信息高速路; 发现Foxo3a助长癌症扭转目前的医治模式; 基质刚性节造了内皮分化和心脏前体的状态发生; 用于生物工程肾脏的“脚手架”; 加强Thbd-aPC通路的作用可能缓解电离辐射危险。

　　焦点动态：细胞周期同步滞碍于G1期推进癌细胞匹敌癌药物的敏感性和细胞凋亡。

1. 细胞周期同步滞碍于G1期推进癌细胞匹敌癌药物的敏感性和细胞凋亡

【动态】美国科学家最近发现了一种提高多发性骨髓瘤医治效能的战术. 通过两种抗癌药物精确把握机遇的挨次使用, 分两步使癌细胞先减弱抵抗力继而被杀死.  首先是用试验药物PD0332991,继而是已被核准用于骨髓瘤和淋巴瘤的药物硼替佐米(bortezomib),一种蛋白酶抑造剂, 以低于正常的剂量，诱导从同步的细胞周期G1期刚刚开释出来的癌细胞自杀。底子上讲癌症是一种细胞增殖失控的疾病，相对的，健全个别内细胞割裂受细胞周期的调控，一系列有序的法式性基因表白产生的高度节造的蛋白网络驱动细胞通过各个查抄站。 依赖细胞周期蛋白的激酶（CDKs）推动细胞经历其周期性的四个阶段。其中CDK4和CDK6推动细胞通过G1期进入后面阶段进行细胞割裂，而PD0332991是一个对CDK4和CDK6有高度选择性的幼分子，可能可逆的抑造这两个酶，陆续使用PD0332991可能将所有癌细胞同步于G1期，在G1期的持久滞碍侵扰了癌细胞的基因表白，增大了其代谢负荷和复造DNA的能量需要，减弱并使癌细胞对传统抗癌药物更为敏感，大大增长了硼替佐米诱导的癌细胞自杀。进一步的钻研发此刻PD0332991造成的G1期滞碍期间，骨髓瘤细胞失去了必须的存活因子IRF4蛋白，但出现了几种促凋亡蛋白。

【点评】 这些发现初次批注癌细胞细胞周期调控关键的存活和凋亡基因，也代表了细胞周期的生物学基础钻研与直接医学利用的无缝整合。该医治癌症的战术能否治愈或大大改善多发性骨髓瘤还需期待人体临床尝试的了局。

【参考论文】   
Blood, 2012; DOI: 10.1182/blood-2012-03-415984
Prolonged early G1 arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4
X. Huang, M. Di Liberto, D. Jayabalan, et al.   
Dysregulation of cyclin-dependent kinase (CDK)4 and CDK6 by gain of function or loss of inhibition is common in human cancer including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G1 arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G1 and prevents expression of genes programmed for other cell cycle phases. Removal of the early-G1 block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents such as the proteasome inhibitor bortezomib. The coordinated loss of IRF-4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.

 2.  大脑的信息高速路

【动态】荷兰和美国科学家对人体大脑结构神经网络衔接的钻研最近发现了一类特殊的大脑区域，它们高度互联和处于中心职位，这些枢纽区域相互亲昵衔接，在人脑中形成一个“富人俱乐部”，衔接这些枢纽区域的那些通路形成了大脑通讯的一个中心的高破费（能量和空间上）高容量的主干网，占据了总体通讯破费的40%。并且，神经节点之间69%的通讯最短通路要路过“富人俱乐部”，大部门这类通讯蹊径由井然有序的路段组成，先进入再穿越，后脱离“富人俱乐部”。这种有序的最短途通讯线路的普遍存在意味着中枢通讯利用分歧脑区之间信息传递的动态线路铺排，其中高度中心职位的“富人俱乐部”其重要作用。这些钻研了局批注“富人俱乐部”的骨干网在大脑区域间信号交通上起重要作用，形成了中枢职位的高破费高容量的大脑通讯主干网，在几十亿脑细胞间提供了急剧有效的通讯，吸纳，转换和传递信息。

【点评】 该钻研对于大脑若何高效处置繁重的信息传递有了更深刻的理解。

【参考论文】   
Proceedings of the National Academy of Sciences, 2012 DOI:10.1073/pnas.1203593109
High-cost, high-capacity backbone for global brain communication
Martijn P. van den Heuvel, René S. Kahn, Joaquín Goñi and Olaf Sporns. 
Network studies of human brain structural connectivity have identified a specific set of brain regions that are both highly connected and highly central. Recent analyses have shown that these putative hub regions are mutually and densely interconnected, forming a “rich club” within the human brain. Here we show that the set of pathways linking rich club regions forms a central high-cost, high-capacity backbone for global brain communication. Diffusion tensor imaging (DTI) data of two sets of 40 healthy subjects were used to map structural brain networks. The contributions to network cost and communication capacity of global cortico-cortical connections were assessed through measures of their topology and spatial embedding. Rich club connections were found to be more costly than predicted by their density alone and accounted for 40% of the total communication cost. Furthermore, 69% of all minimally short paths between node pairs were found to travel through the rich club and a large proportion of these communication paths consisted of ordered sequences of edges (“path motifs”) that first fed into, then traversed, and finally exited the rich club, while passing through nodes of increasing and then decreasing degree. The prevalence of short paths that follow such ordered degree sequences suggests that neural communication might take advantage of strategies for dynamic routing of information between brain regions, with an important role for a highly central rich club. Taken together, our results show that rich club connections make an important contribution to interregional signal traffic, forming a central high-cost, high-capacity backbone for global brain communication.

 3. 发现Foxo3a助长癌症扭转目前的医治模式

【动态】最近美国科学家发现一种被宽泛以为能够匹敌多种癌症的分子Foxo3a 现实上援手了致命的甲状腺癌成长，而目前在人体试验中的癌症疗法可能助长这一作用。他们在未分化的甲状腺癌中叉头转录因子Foxo3a不是原以为的肿瘤抑造因子，相反是致命的肿瘤推进因子。在试验室此种肿瘤模型中将Foxo3a关关，癌细胞成长缓慢，但铺开Foxo3a后癌细胞成长就快的多了。以前的意识是：Foxo3a应对各类细胞蕴含癌细胞中产生的压力，打开细胞核里的触发细胞殒命的基因，而癌细胞通过Akt蛋白将Foxo3a从细胞核转移到细胞质中分化掉而关关其职能。该钻研利用Akt抑造剂将癌细胞的Foxo3a留在细胞核里,  本想它援手杀死癌细胞，却观察到它加快了癌细胞的成长。这使得我们必要重新思考Akt抑造剂在癌症医治中的使用，因其机理之一是使Foxo3a在细胞核中维持活性。该钻研还发现Foxo3a打开了细胞周期蛋白A1的基因表白，而细胞周期蛋白A1是推进癌细胞成长的。

【点评】 该钻研发现了Foxo3a对癌细胞的正反双重作用，可能扭转目前癌症医治的一些寂仔模式。

【参考论文】   
Journal of Cell Science, June 20, 2012 DOI: 10.1242/jcs.097428
Foxo3a drives proliferation in anaplastic thyroid carcinoma via transcriptional regulation of cyclin A1: A paradigm shift that impacts current therapeutic strategies
Laura A. Marlow, Christina A. von Roemeling, Simon J. Cooper, et al.
The Forkhead transcription factor, FoxO3a, is a known suppressor of primary tumor growth via transcriptional regulation of key genes regulating cell cycle arrest and apoptosis. In many types of cancer, in response to growth factor signaling, FoxO3a is phosphorylated by Akt, resulting in its exclusion from the nucleus. Here we show that FoxO3a remains nuclear in anaplastic thyroid carcinoma (ATC). This correlates with lack of Akt phosphorylation at S473 in ATC cell lines and patient ATC tissues, providing a potential explanation for nuclear FoxO3a. Mechanistically, nuclear FoxO3a promotes cell cycle progression by transcriptional upregulation of cyclin A1, promoting proliferation of human ATC cells. Silencing FoxO3a with a reverse genetics approach leads to down-regulation of CCNA1 mRNA and protein. This combined data implicates an entirely novel function for FoxO3a in ATC promotion by enhancing cell cycle progression and tumor growth via transcriptional upregulation of cyclin A1. This is clinically relevant since we detected highly elevated CCNA1 mRNA and protein levels in ATC patient tumor tissues. Our data indicate therapeutic inactivation of FoxO3a may lead to attenuation of tumor expansion in ATC. This new paradigm also suggests caution related to current dogma focused upon reactivation of FoxO3a as a therapeutic strategy against cancers harboring active PI3-K and Akt signaling pathways.

 4.  基质刚性节造了内皮分化和心脏前体的状态发生

【动态】组织发育和再生牵扯到缜密协和谐整合的多种过程：常驻干细胞和前体细胞的选择性增殖，分化为指标体细胞，空间状态的组织。美国科学家对这一过程中机械环境的最新钻研显示源自本地心脏组织的多能细胞持续监测细胞基质的刚度并显示当刚度极度靠近心肌细胞时会加强增殖，内皮分化和状态发生。这些过程的机械调控必要p190RhoGAP，一种针对RhoA的鸟苷三磷酸酶激活蛋白，通过依赖和不依赖RhoA的机造起作用。这一发现可能引出更好的医治心脏病的步骤。心肌组织经历心脏病发生后通常会形成虚弱的疤痕，而最近有一些报路可用干细胞出产健全组织阻止疤痕的产生。

【点评】 p190RhoGAP的发现及其机械调控作用会有助于干细胞顺利造成特定健全组织。该钻研加强了我们对干细胞生物学的理解并提醒了新方式来节造心肌干细胞在移植入心脏前后的行为。

【参考论文】   
Science Signaling, 2012; 5 (227): ra41 DOI: 10.1126/scisignal.2003002
Matrix Rigidity Controls Endothelial Differentiation and Morphogenesis of Cardiac Precursors
Kshitiz, M. E. Hubbi, E. H. Ahn, et al.  
Tissue development and regeneration involve tightly coordinated and integrated processes: selective proliferation of resident stem and precursor cells, differentiation into target somatic cell type, and spatial morphological organization. The role of the mechanical environment in the coordination of these processes is poorly understood. We show that multipotent cells derived from native cardiac tissue continually monitored cell substratum rigidity and showed enhanced proliferation, endothelial differentiation, and morphogenesis when the cell substratum rigidity closely matched that of myocardium. Mechanoregulation of these diverse processes required p190RhoGAP, a guanosine triphosphatase–activating protein for RhoA, acting through RhoA-dependent and -independent mechanisms. Natural or induced decreases in the abundance of p190RhoGAP triggered a series of developmental events by coupling cell-cell and cell-substratum interactions to genetic circuits controlling differentiation.

 5.  用于生物工程肾脏的“脚手架”

【动态】美国科学家在尝试室中造作代替肾脏的持久项目最近达到了一个早期里程碑，他们用猪的肾脏去除所有动物细胞，只留器官骨架，造作出了支持结构“脚手架”，病人自己的细胞能够在上面成长形成的器官理论上不会被病人自身所倾轧。再生医学已经成功地造作了生物工程皮肤，软骨，膀胱，输尿管，气管和血管植入患者体内。这些结构在发育出自身的血管之前可能邻近的血管组织获取氧气和养料。但是，再生医学的“圣杯”是造作出更复杂的器官如肾，肝，心脏和胰腺。这些器官含有大量细胞必须有自己的氧气供给能力存活，这种生物工程就必要有齐全脉管系统的“脚手架”。

【点评】 这种异种脚手架并不能齐全排除机体的倾轧，并且生物工程造作器官也不是再生医学的圣杯，真正的圣杯是无需任何移植的器官原位再生。

【参考论文】   
Annals of Surgery, 2012; : 1 DOI:10.1097/SLA.0b013e31825a02ab
Production and Implantation of Renal Extracellular Matrix Scaffolds From Porcine Kidneys as a Platform for Renal Bioengineering Investigations
Giuseppe Orlando, Alan C. Farney, Samy S. Iskandar, et al.
BACKGROUND:
It is important to identify new sources of transplantable organs because of the critical shortage of donor organs. Tissue engineering holds the potential to address this issue through the implementation of decellularization-recellularization technology.
OBJECTIVE:
To produce and examine acellular renal extracellular matrix (ECM) scaffolds as a platform for kidney bioengineering.
METHODS:
Porcine kidneys were decellularized with distilled water and sodium dodecyl sulfate-based solution. After rinsing with buffer solution to remove the sodium dodecyl sulfate, the so-obtained renal ECM scaffolds were processed for vascular imaging, histology, and cell seeding to investigate the vascular patency, degree of decellularization, and scaffold biocompatibility in vitro. Four whole renal scaffolds were implanted in pigs to assess whether these constructs would sustain normal blood pressure and to determine their biocompatibility in vivo. Pigs were sacrificed after 2 weeks and the explanted scaffolds were processed for histology.
RESULTS:
Renal ECM scaffolds were successfully produced from porcine kidneys. Scaffolds retained their essential ECM architecture and an intact vascular tree and allowed cell growth. On implantation, unseeded scaffolds were easily reperfused, sustained blood pressure, and were tolerated throughout the study period. No blood extravasation occurred. Pathology of explantedscaffolds showed maintenance of renal ultrastructure. Presence of inflammatory cells in the pericapsular region and complete thrombosis of the vascular tree were evident.
CONCLUSIONS:
Our investigations show that pig kidneys can be successfully decellularized to produce renal ECM scaffolds. These scaffolds maintain their basic components, are biocompatible, and show intact, though thrombosed, vasculature.

 6.  加强Thbd-aPC通路的作用可能缓解电离辐射危险

【动态】美国和德国科学家最近发现加强老鼠体内血液中的一种蛋白通路可能；だ鲜竺馐芊渲猩。他们发现通过重组的血栓调节蛋白或激活的蛋白C加强Thbd-aPC 通路的作用，可能缓解电离辐射引起的组织危险和致命性。该钻研揭示了前所未知的Thbd-aPC 通路在缓解辐射中伤方面的作用。通常该通路是预防血栓形成，援手机体抵抗习染，而该钻研发现这一通路援手骨髓血细胞从辐射危险中复原，但其；ぷ饔弥辉诒徽丈涞睦鲜竽Ｐ吞迥诜⑸，体表没有作用，意味着它必要体内其它细胞或物质的援手。

【点评】 该钻研证实动物体内有援手抵抗电离辐射的机造，也有步骤去加强这一机造。

【参考论文】   
Nature Medicine, 24 June 2012 DOI:10.1038/nm.2813
Pharmacological targeting of the thrombomodulin–activated protein C pathway mitigates radiation toxicity
Hartmut Geiger, Snehalata A Pawar, Edward J Kerschen, et al.
Tissue damage induced by ionizing radiation in the hematopoietic and gastrointestinal systems is the major cause of lethality in radiological emergency scenarios and underlies some deleterious side effects in patients undergoing radiation therapy. The identification of target-specific interventions that confer radiomitigating activity is an unmet challenge. Here we identify the thrombomodulin (Thbd)-activated protein C (aPC) pathway as a new mechanism for the mitigation of total body irradiation (TBI)-induced mortality. Although the effects of the endogenous Thbd-aPC pathway were largely confined to the local microenvironment of Thbd-expressing cells, systemic administration of soluble Thbd or aPC could reproduce and augment the radioprotective effect of the endogenous Thbd-aPC pathway. Therapeutic administration of recombinant, soluble Thbd or aPC to lethally irradiated wild-type mice resulted in an accelerated recovery of hematopoietic progenitor activity in bone marrow and a mitigation of lethal TBI. Starting infusion of aPC as late as 24 h after exposure to radiation was sufficient to mitigate radiation-induced mortality in these mice. These findings suggest that pharmacologic augmentation of the activity of the Thbd-aPC pathway by recombinant Thbd or aPC might offer a rational approach to the mitigation of tissue injury and lethality caused by ionizing radiation.