BACKGROUND & AIMS: :Growth hormone deficiency (GHD) related to standard dose chemotherapy has rarely been described. We report on a case of localized ganglioneuroblastoma treated by carboplatin/etoposide for 2 courses and surgery, which developed a serious GHD after 56 months. At present, the child is growing on by GH replacement therapy. We discuss about the hypothesis that GHD may be related to chemotherapy and we report a review of previous published cases.

背景与目标： ：很少有人描述与标准剂量化疗有关的生长激素缺乏症（GHD）。我们报告了一例通过卡铂/依托泊苷治疗的局部神经节神经母细胞瘤的疗程为2个疗程和手术，该病例在56个月后出现了严重的GHD。目前，孩子正在通过GH替代疗法长大。我们讨论了GHD可能与化学疗法有关的假说，并且我们报告了以前发表过的病例的综述。

BACKGROUND & AIMS: :The 6-h plasma profiles of adrenocorticotropic hormone (ACTH), cortisol, alpha-melanocyte-stimulating hormone (alpha-MSH), and GH were studied in 17 dogs with pituitary-dependent hyperadrenocorticism (PDH) before and after hypophysectomy. The aim of the study was to investigate the relation between the hormone profile characteristics and recurrence of PDH after surgery. The hormones were secreted in a pulsatile fashion. The basal plasma cortisol concentration and area under the curve (AUC) for cortisol were significantly higher in the PDH cases than in eight controls. The characteristics of the plasma profiles of ACTH and alpha-MSH were not significantly different between the PDH cases and the controls. In the PDH cases, less GH was secreted in pulses than in the controls, but the difference was not significant. The basal plasma cortisol concentration, the AUC for ACTH and cortisol, and the pulse frequency of ACTH and cortisol decreased significantly after hypophysectomy for the group of PDH cases. The basal plasma concentrations of ACTH and alpha-MSH, the AUC for alpha-MSH, and the characteristics of the plasma GH profiles of the PDH cases remained unchanged after hypophysectomy. No pulses of alpha-MSH were observed after hypophysectomy. The co-occurrence between the ACTH and cortisol pulses decreased significantly with hypophysectomy. The postoperative pulse frequency of ACTH was the only characteristic with predictive value for the recurrence of PDH after hypophysectomy. The results of this study demonstrate that ACTH, cortisol, alpha-MSH, and GH are secreted in a pulsatile fashion in dogs with PDH. Hypophysectomy effectively reduces the secretion of ACTH and cortisol. The presence of ACTH pulses after hypophysectomy is a risk factor for the recurrence of hyperadrenocorticism.

背景与目标： ：在垂体切除术前后垂体依赖性肾上腺皮质激素过多（PDH）的17只狗中研究了促肾上腺皮质激素（ACTH），皮质醇，α-黑素细胞刺激激素（α-MSH）和GH的6小时血浆分布。该研究的目的是研究激素谱特征与PDH术后复发之间的关系。激素以搏动的方式分泌。 PDH患者的基础血浆皮质醇浓度和皮质醇曲线下面积（AUC）显着高于八个对照组。在PDH病例和对照之间，ACTH和α-MSH的血浆分布特征没有显着差异。在PDH病例中，与对照相比，脉冲中分泌的GH少，但差异不显着。对于PDH组，在进行了植体切除后，基础血浆皮质醇浓度，ACTH和皮质醇的AUC以及ACTH和皮质醇的脉冲频率均显着降低。垂体切除后，PDH病例的ACTH和α-MSH的基础血浆浓度，α-MSH的AUC以及血浆GH谱的特征保持不变。垂体切除术后未观察到α-MSH脉冲。垂体后叶切除术使ACTH和皮质醇脉冲之间的同时发生显着降低。 ACTH的术后脉冲频率是对垂体切除术后PDH复发的唯一具有预测价值的特征。这项研究的结果表明，PDH犬的搏动性分泌ACTH，皮质醇，α-MSH和GH。垂体切除术可有效减少ACTH和皮质醇的分泌。垂体切除术后ACTH脉冲的存在是肾上腺皮质功能亢进复发的危险因素。

BACKGROUND & AIMS: :The growth of the pollen tube wall of Oenothera is effected by the expulsion of fibrillar material from the cytoplasm into the developing wall. This material may also be seen in the cytoplasm, contained in membrane-bound vesicles. It is not clear how the content of the vesicles is discharged, but it appears not to involve the participation of microtubules. The source of the cytoplasmic fibrillar bodies depends upon the stage of development of the pollen tube. The earilest growth is derived from the inclusion into the wall of vesicles containing pre-formed materials present in the grain on pollination. During the next stage of growth the wall is derived from the content of double-membraned inclusions also present in the pollen. The content of the former vesicles is not so similar to the wall as the latter, but intermediates between the 2 types of vesicle may be seen in the cytoplasm, indicating that the former are formed from the latter. Most of the tube wall is derived from the products of dictyosomes in the pollen grain or tube. These dicytosomes are few in number and they must be exceedingly active. This, and the observation that dictyosome vesicles are frequently associated with banked complexes of mitochondria, indicates that some steps in the metabolism of the vesicular content, perhaps phosphorylation, take place distant from the dicytosomes. These different sources of fibrillar material presumably permit the rapid starting of tube growth, without any attendant metabolism. However, it would be impossible to include enough pre-formed wall material in the grain to enable the full growth of the tube, so once started, it seems that the tube then relies on the elaboration of simple reserves for the contruction of its wall. These reserves are likely to be held in the pollen, and may be the large numbers of starch grains characteristic of the pollen cytoplasm.

背景与目标： ：月见草的花粉管壁的生长受到纤维状物质从细胞质中排入发育壁的影响。在膜结合的囊泡中所含的细胞质中也可以看到这种物质。目前尚不清楚囊泡中的内容物如何释放，但似乎不涉及微管的参与。细胞质原纤维体的来源取决于花粉管的发育阶段。最早的生长来自授粉时谷物中含有预先形成的物质的囊泡壁。在生长的下一阶段，壁是从花粉中也存在的双膜夹杂物的含量中获得的。前者囊泡的含量与后者的壁不太相似，但是在细胞质中可以看到两种类型囊泡之间的中间产物，这表明前者是由后者形成的。大多数管壁都来自花粉粒或管中的双核小体产物。这些双核小体的数量很少，它们必须具有超强的活性。这以及单核小泡囊泡经常与线粒体堆积的复合物相关的观察结果表明，泡囊内容物代谢的某些步骤（可能是磷酸化）发生在远离双核小体的地方。这些不同的纤维状物质来源大概可以使管的生长迅速开始，而没有任何新陈代谢。但是，不可能在晶粒中包含足够的预成型壁材料以使管完全生长，因此一旦启动，似乎管就依赖于简单的储备来构造其壁。这些储备可能保留在花粉中，并且可能是花粉细胞质特有的大量淀粉粒。

BACKGROUND & AIMS: :Neurons within each layer of cerebral cortex express multiple members of the neurotrophin family and their corresponding receptors. This multiplicity could provide functional redundancy; alternatively, different neurotrophins may direct distinct aspects of cortical neuronal growth and differentiation. By neutralizing endogenous neurotrophins in organotypic slices of developing cortex with Trk receptor bodies (Trk-IgGs), we found that BDNF and NT-3 oppose one another in regulating the dendritic growth of pyramidal neurons. In layer 4, both endogenous and exogenous NT-3 inhibited the dendritic growth stimulated by BDNF. In contrast, in layer 6 both endogenous and exogenous BDNF inhibited dendritic growth stimulated by NT-3. These antagonistic actions of endogenous BDNF and NT-3 provide a mechanism by which dendritic growth and retraction can be dynamically regulated during cortical development, and suggest that the multiple neurotrophins expressed in developing cortex represent distinct components of an extracellular signaling system for regulating dendritic growth.

背景与目标： 大脑皮层每一层中的神经元表达神经营养蛋白家族的多个成员及其相应的受体。这种多样性可以提供功能冗余。或者，不同的神经营养蛋白可指导皮质神经元生长和分化的不同方面。通过用Trk受体体（Trk-IgG）中和发育中的皮质器官的典型切片中的内源性神经营养蛋白，我们发现BDNF和NT-3在调节锥体神经元的树突状生长中彼此相对。在第4层中，内源性NT-3和外源性NT-3均抑制BDNF刺激的树突状生长。相反，在第6层中，内源性和外源性BDNF均抑制NT-3刺激的树突状生长。内源性BDNF和NT-3的这些拮抗作用提供了一种机制，通过该机制可以在皮质发育过程中动态调节树突状细胞的生长和收缩，并表明在发育中的皮质中表达的多种神经营养蛋白代表了调节树突状细胞生长的细胞外信号系统的不同组成部分。

BACKGROUND & AIMS: :The hypoxic environment in tumor is reported to play an important role in pancreatic cancer progression. The interaction between stromal and cancer cells also contributes to the malignant behavior of pancreatic cancer. In the present study, we investigated whether hypoxic stimulation affects stromal as well as pancreatic cancer cells. Our findings demonstrated that hypoxia remarkably elevated the HIF-1alpha expression in both pancreatic cancer (PK8) and fibroblast cells (MRC5). Hypoxic stimulation accelerated the invasive activity of PK8 cells, and invasiveness was thus further accelerated when the hypoxic PK8 cells were cultured with conditioned medium prepared from hypoxic MRC5 cells (hypoxic conditioned medium). MMP-2, MMP-7, MT1-MMP and c-Met expressions were increased in PK8 cells under hypoxia. Hypoxic stimulation also increased the hepatocyte growth factor (HGF) secretion from MRC5 cells, which led to an elevation of c-Met phosphorylation in PK8 cells. Conversely, the elevated cancer invasion, MMP activity and c-Met phosphorylation of PK8 cells were reduced by the removal of HGF from hypoxic conditioned medium. In immunohistochemical study, the HIF-1alpha expression was observed in surrounding stromal as well as pancreatic cancer cells, thus indicating hypoxia exists in both of cancer and stromal cells. Moreover, the stromal HGF expression was found to significantly correlate with not only the stromal HIF-1alpha expression but also the c-Met expression in cancer cells. These results indicate that the hypoxic environment within stromal as well as cancer cells activates the HGF/c-Met system, thereby contributing to the aggressive invasive features of pancreatic cancer.

背景与目标： ：据报道肿瘤中的低氧环境在胰腺癌的进展中起重要作用。基质细胞与癌细胞之间的相互作用也有助于胰腺癌的恶性行为。在本研究中，我们调查了低氧刺激是否影响基质以及胰腺癌细胞。我们的发现表明，低氧显着提高了胰腺癌（PK8）和成纤维细胞（MRC5）中HIF-1alpha的表达。低氧刺激加速了PK8细胞的侵袭活性，因此，当用由低氧MRC5细胞制备的条件培养基（低氧条件培养基）培养低氧PK8细胞时，侵袭性进一步加快。在缺氧条件下，PK8细胞中的MMP-2，MMP-7，MT1-MMP和c-Met表达增加。缺氧刺激还增加了MRC5细胞的肝细胞生长因子（HGF）分泌，从而导致PK8细胞中c-Met磷酸化的升高。相反，通过从低氧条件培养基中去除HGF，可以降低PK8细胞的癌浸润，MMP活性和c-Met磷酸化水平的升高。在免疫组织化学研究中，在周围的基质细胞和胰腺癌细胞中均观察到了HIF-1alpha的表达，因此表明在癌细胞和基质细胞中均存在缺氧。此外，发现基质HGF表达不仅与癌细胞中的基质HIF-1α表达而且与c-Met表达显着相关。这些结果表明基质以及癌细胞内的低氧环境激活了HGF / c-Met系统，从而促进了胰腺癌的侵袭性侵袭性。

BACKGROUND & AIMS: Genetic studies have recently revealed a role for transforming growth factor-beta-1 (TGF-beta 1) and its receptors (TGF-beta Rs I and II as well as endoglin) in embryonic vascular assembly and in the establishment and maintenance of vessel wall integrity. The purpose of this review is threefoldfirst, to reassess previous studies on TGF-beta and endothelium in the light of these recent findings; second, to describe some of the well-established as well as controversial issues concerning TGF-beta and its regulatory role in angiogenesis; and third, to explore the notion of "context' with respect to TGF-beta and endothelial cell function. Although the focus of this review will be on the endothelium, other vascular wall cells are also likely to be important in the pathogenesis of the vascular lesions revealed by genetic studies.

背景与目标： 遗传研究最近揭示了在胚胎血管组装以及血管壁的建立和维持中转化生长因子-β-1（TGF-β1）及其受体（TGF-βRs I和II以及内皮糖蛋白）的作用。正直。这篇综述的目的是三重的，以根据这些最新发现重新评估先前对TGF-β和内皮的研究。其次，描述有关TGF-beta及其在血管生成中的调控作用的一些公认的和有争议的问题；第三，探讨有关TGF-β和内皮细胞功能的“背景”概念，尽管本综述的重点是内皮，但其他血管壁细胞也可能在血管的发病机理中起重要作用。通过遗传学研究发现病变。

BACKGROUND & AIMS: The expression and localization of hepatocyte growth factor/scatter factor (HGF/SF) were examined immunohistochemically in 59 human coronary artery lesions retrieved by directional coronary atherectomy and compared with the localization of transforming growth factor beta isoforms (TGF-beta 1, -beta 2, and -beta 3). In 21 of the 59 specimens (35.6%) HGF-like immunoreactivity (HGF-IR) was revealed. The HGF immunopositivity rate of 45% (14/31) in thrombotic tissue was significantly (P < 0.05) higher than the rates of 7.3% (4/55), 7.1% (3/42), and 0% (0/14) in fibrous tissue, neointimal hyperplasia and atheromatous gruel, respectively. Immunoreactivity for HGF was much weaker than that for TGF-beta isoforms in these components except in thrombotic tissue. These cells exhibiting strong HGF-IR were inflammatory cells such as monocytes/macrophages in thrombotic tissue, in tissue lesions adjacent to a thrombus, and outside the capillary walls in a portion of the neovascularized lesions. Smooth muscle cells (SMCs) hardly demonstrated HGF-IR. In contrast, in control coronary arteries obtained at autopsy, the HGF-IR was strongly expressed in SMCs. These findings suggest that HGF produced by macrophages play a part in the process of coronary plaque formation attributable to thrombus in man.

背景与目标： 免疫组织化学方法检测了定向冠状动脉粥样斑块切除术取回的59例人类冠状动脉病变中肝细胞生长因子/分散因子（HGF / SF）的表达和定位，并与转化生长因子β同工型（TGF-beta 1，-beta 2和-beta 3）。在59个样本中的21个（35.6％）中发现了类似HGF的免疫反应性（HGF-IR）。血栓形成组织中HGF免疫阳性率为45％（14/31）显着（P <0.05）分别高于7.3％（4/55），7.1％（3/42）和0％（0/14） ）分别在纤维组织，新内膜增生和粥样粥样硬化中。除了血栓形成组织外，在这些组件中，HGF的免疫反应性比TGF-β亚型的免疫反应性弱得多。这些表现出强HGF-IR的细胞是炎性细胞，例如血栓形成组织中，与血栓相邻的组织病变中，以及在部分新血管形成的病变中的毛细血管壁之外的单核细胞/巨噬细胞。平滑肌细胞（SMCs）几乎没有表现出HGF-IR。相反，在尸检时获得的对照冠状动脉中，HGF-IR在SMC中强烈表达。这些发现表明，巨噬细胞产生的HGF在可归因于人类血栓的冠状斑块形成过程中起作用。

BACKGROUND & AIMS: :Go/Gi coupled G-protein receptor mediated transactivation is critical in the activation of receptor tyrosine kinases (RTK). Here we show that mu opioid receptor (MOR) transactivates Flk1 and platelet-derived growth factor-beta (PDGF-beta) receptors and its agonist morphine stimulates pro-angiogenic and survival-promoting signaling in mouse retinal endothelial cells (mREC). Morphine stimulates mREC proliferation in a dose dependent fashion and promotes survival to the same extent as vascular endothelial growth factor164 (VEGF164). Morphine stimulates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and Akt phosphorylation in a time dependent manner like VEGF in mREC. Moreover, analogous to VEGF, morphine stimulates oncogenic signal transducer and activator of transcription 3 (STAT3) signaling. Morphine as well as VEGF-induced phospho-STAT3 and phospho-Flk1 immunoprecipitated with MOR-associated proteins. In addition morphine also stimulated MOR associated PDGF-beta receptor phosphorylation. Consistent with the relationship between VEGF and MOR we found that VEGF upregulates MOR protein and RNA expression in mREC. These data suggest that MOR associates and transactivates RTKs for Flk1 and PDGF-beta, which may have a compounding effect on angiogenic signaling in endothelium. Therefore, G-Protein coupled receptors including MOR provide novel targets to develop anti-angiogenic agents.

背景与目标： ：Go / Gi偶联的G蛋白受体介导的反式激活在受体酪氨酸激酶（RTK）的激活中至关重要。在这里，我们显示mu阿片类受体（MOR）激活Flk1和血小板衍生的生长因子-β（PDGF-β）受体，其激动剂吗啡刺激小鼠视网膜内皮细胞（mREC）促血管生成和促进生存的信号传导。吗啡以剂量依赖性方式刺激mREC增殖，并以与血管内皮生长因子164（VEGF164）相同的程度促进存活。吗啡像mREC中的VEGF一样，以时间依赖性方式刺激促分裂原活化的蛋白激酶/细胞外信号调节激酶（MAPK / ERK）和Akt磷酸化。此外，类似于VEGF，吗啡刺激致癌信号转导子和转录激活子3（STAT3）信号转导。吗啡以及VEGF诱导的磷酸化STAT3和磷酸化Flk1被MOR相关蛋白免疫沉淀。此外，吗啡还刺激了MOR相关的PDGF-β受体的磷酸化。与VEGF和MOR之间的关系一致，我们发现VEGF上调mREC中的MOR蛋白和RNA表达。这些数据表明，MOR与Flk1和PDGF-beta的RTK缔合并反激活，这可能对内皮中的血管生成信号具有复合作用。因此，包括MOR在内的G蛋白偶联受体为开发抗血管生成剂提供了新的靶标。

BACKGROUND & AIMS: :In the last few years, our knowledge of genetically determined causes of short stature has greatly increased by reports of challenging patients, who offered the opportunity to study genes that play a role in growth. Since the first paper that showed the etiology of Laron syndrome [Godowski PJ, et al: Proc Natl Acad Sci USA 1989;86:8083-8087], many mutations in the growth hormone (GH) receptor have been identified. Recently, new mutations or deletions have been found in several components of the GH-insulin-like growth factor-I (IGF-I) axis: a homozygous mutation of the GH1 gene, resulting in a bio-inactive GH; mutations in the STAT5b gene, which plays a major role in the GH signal transduction; a homozygous missense mutation in the IGF-I gene; heterozygous mutations in the IGF-I receptor gene and a homozygous deletion of the acid-labile subunit gene. In this mini review, we describe the clinical and biochemical features of these genetic defects. Genetic analysis has become essential in the diagnostic workup of a patient with short stature. However, regarding the time consuming nature of molecular analysis, it is important to carefully select the patient for specific genetic evaluation. To help in this selection process, we developed flowcharts, based on the recently described patients, that can be used as guidelines in the diagnostic process of patients with severe short stature of unknown origin.

背景与目标： ：在过去的几年中，由于挑战性患者的报道，我们对遗传决定的矮小身高原因的了解大大增加了，这些患者为研究在生长中起作用的基因提供了机会。自从第一篇显示Laron综合征病因的论文以来[Godowski PJ等人：Proc Natl Acad Sci USA 1989; 86：8083-8087]，已经确定了生长激素（GH）受体的许多突变。最近，在GH-胰岛素样生长因子-I（IGF-I）轴的几个组成部分中发现了新的突变或缺失：GH1基因的纯合突变，导致了生物失活的GH； STAT5b基因的突变，在GH信号转导中起主要作用； IGF-I基因的纯合错义突变； IGF-1受体基因中的杂合突变和对酸不稳定的亚基基因的纯合缺失。在这个小型综述中，我们描述了这些遗传缺陷的临床和生化特征。遗传分析已成为身材矮小的患者的诊断检查中必不可少的。但是，考虑到分子分析的耗时性质，重要的是要仔细选择患者进行特定的基因评估。为了帮助选择过程，我们根据最近描述的患者制定了流程图，可以将其用作诊断患有严重身材矮小，来源不明的患者的诊断过程中的指导原则。

BACKGROUND & AIMS: Poly(1-vinyl-2-pyrrolidinone) (PVP) and copolymers of 1-vinyl-2-pyrrolidinone are insoluble in water when crosslinked but they can absorb very large amounts of water to become syringe-injectable hydrogels. Such gels have been investigated recently as potential substitutes for the vitreous humour in the eye. In this study, during the cytotoxic evaluation by sulforhodamine B colorimetric assay of variously crosslinked PVP gels, it was found that many of them showed protective/growth promoting effects on 3T3 mouse fibroblasts in static cultures, a phenomenon encountered previously only with aqueous solutions of a limited number of natural or synthetic polymers. Particularly, the gels crosslinked with diethylene glycol dimethacrylate (DEGDMA) induced a significant enhancement of cell proliferation, especially in serum-free cultures. No correlation between this effect and the essential gel properties (chemical composition, viscoelasticity and equilibrium water content) could be established. The study demonstrated that crosslinked PVP hydrogels showed a serum-like growth promoting effect on an anchorage-dependent cell line, which may be due to physical protection, inability of the insoluble gels to penetrate cell membranes, and their ability to mimic the extracellular matrix.

背景与目标： 聚（1-乙烯基-2-吡咯烷酮）（PVP）和1-乙烯基-2-吡咯烷酮的共聚物在交联时不溶于水，但它们可以吸收大量的水，成为可注射注射器的水凝胶。最近已经研究了这种凝胶作为眼睛中玻璃体液的潜在替代物。在这项研究中，在通过磺基若丹明B比色法对各种交联的PVP凝胶进行细胞毒性评估时，发现它们中的许多在静态培养物中对3T3小鼠成纤维细胞均显示出保护性/促生长作用，这种现象以前仅在A的水溶液中会遇到。数量有限的天然或合成聚合物。特别是，用二甘醇二甲基丙烯酸二甲酯（DEGDMA）交联的凝胶可显着增强细胞增殖，特别是在无血清培养物中。在这种作用与基本的凝胶性质（化学组成，粘弹性和平衡水含量）之间没有相关性。该研究表明，交联的PVP水凝胶对锚定依赖性细胞系显示出类似血清的生长促进作用，这可能是由于物理保护，不溶性凝胶无法穿透细胞膜以及它们模仿细胞外基质的能力所致。

BACKGROUND & AIMS: :Receptor tyrosine kinases (RTKs) are critical for normal cell growth, differentiation, and development, but they contribute to various pathological conditions when disrupted. Activation of RTKs stimulates a plethora of pathways, including the ubiquitylation and endocytosis of the receptor itself. Although endocytosis terminates RTK signaling, it has emerged as a requisite step in RTK activation of signaling pathways. We have discovered that the endocytic scaffolding protein intersectin (ITSN) cooperated with epidermal growth factor receptor (EGFR) in the regulation of cell growth and signaling. However, a biochemical link between ITSN and EGFR was not defined. In this study, we demonstrate that ITSN is a scaffold for the E3 ubiquitin ligase Cbl. ITSN forms a complex with Cbl in vivo mediated by the Src homology (SH) 3 domains binding to the Pro-rich COOH terminus of Cbl. This interaction stimulates the ubiquitylation and degradation of the activated EGFR. Furthermore, silencing ITSN by RNA interference attenuated EGFR internalization as well as activation of the extracellular signal-regulated kinasemitogen-activated protein kinase pathway, thereby demonstrating the importance of ITSN in EGFR function. Given the cooperativity between ITSN and additional RTKs, these results point to an important evolutionarily conserved, regulatory role for ITSN in RTK function that is necessary for both signaling from receptors as well as the ultimate termination of receptor signaling.

背景与目标： 受体酪氨酸激酶（RTKs）对于正常细胞的生长，分化和发育至关重要，但是当它们被破坏时，它们会导致各种病理状况。 RTK的激活刺激了许多途径，包括受体自身的泛素化和内吞作用。尽管内吞作用终止了RTK信号传导，但它已成为RTK激活信号通路的必要步骤。我们已经发现，内吞支架蛋白intersectin（ITSN）与表皮生长因子受体（EGFR）协同调节细胞生长和信号传导。但是，尚未定义ITSN和EGFR之间的生化联系。在这项研究中，我们证明了ITSN是E3泛素连接酶Cbl的支架。 ITSN在体内与Cbl形成复合物，该复合物是通过与Cbl富含Pro的COOH末端结合的Src同源性（SH）3结构域介导的。这种相互作用刺激了活化的EGFR的泛素化和降解。此外，通过RNA干扰使ITSN沉默可以减弱EGFR的内在化以及细胞外信号调节激酶有丝分裂原激活的蛋白激酶途径的激活，从而证明了ITSN在EGFR功能中的重要性。考虑到ITSN和其他RTK之间的协作性，这些结果表明ITSN在RTK功能中具有重要的进化保守的调节作用，这对于受体的信号传导以及受体信号传导的最终终止都是必需的。

BACKGROUND & AIMS: :Several molecular-targeted therapeutics have been tested in clinical trials for the treatment of head and neck squamous cell carcinoma (HNSCC). Of these, therapeutics targeting the epidermal growth factor receptor (EGFR) have been studied most extensively and some agents have demonstrated measurable clinical effectiveness. However, molecular studies designed to define HNSCC patient subcohorts of likely responders to EGFR-targeted therapy have not identified molecular signatures that correlate with clinical response. Here, the authors summarise the relevant clinical findings and highlight reported molecular correlative studies for EGFR-targeted therapeutics for HNSCC. The authors focus especially on molecular markers evaluated for association with clinical response and include data from EGFR-targeted clinical studies in other cancer sites that they anticipate will be of interest to the head and neck cancer research and treatment communities.

背景与目标： ：几种针对分子的疗法已在临床试验中用于治疗头颈部鳞状细胞癌（HNSCC）。其中，针对表皮生长因子受体（EGFR）的疗法已得到最广泛的研究，某些药物已证明可测量的临床有效性。然而，旨在定义可能对EGFR靶向治疗有反应的HNSCC患者亚组的分子研究尚未发现与临床反应相关的分子标志。在这里，作者总结了相关的临床发现，并着重报道了针对HNSCC的EGFR靶向治疗药物的分子相关研究。作者尤其关注评估与临床反应相关的分子标志物，并包括来自其他癌症部位针对EGFR的临床研究的数据，他们预期这将是头颈癌研究和治疗界感兴趣的数据。

BACKGROUND & AIMS: CONTEXT:Concern has been raised about the safety of assisted reproduction techniques for the offspring. OBJECTIVES:The objective of the study was to investigate postnatal growth and growth factors in children born after intra-cytoplasmatic sperm injection (ICSI) and in vitro fertilization (IVF). DESIGN:The study had two cohorts: a population-based longitudinal infant cohort 0-36 months [236 ICSI, 173 IVF, 1530 naturally conceived (NC)], and a cross-sectional child cohort at 5 yr (68 ICSI, 67 IVF, 70 NC). INTERVENTION:Anthropometrical measurements were made at birth, 3, 18, 36 (infant cohort), and 60 months (child cohort), and blood samples were collected at 3 or 60 months. MAIN OUTCOME MEASURES:Serum IGF-I, IGFBP-3, height, weight, head and abdominal circumference, body mass index, and fat folds were the main outcome measures. RESULTS:Anthropometrical measurements showed no significant differences between ICSI and IVF children and controls in either cohort. However, singleton ICSI girls [3.4 (0.6) kg, P = 0.008] had a slightly lower birth weight than IVF [3.5 (0.5) kg] and NC girls [3.5 (0.5) kg]. Birth weights of singleton boys [3.6 (0.5) kg], twin boys [2.6 (0.6) kg], and twin girls [2.4 (0.5) kg] did not differ between types of conception. In the infant cohort in 3-month-old singletons, serum IGF-I was lower in ICSI [78 (26) ng/ml] than NC boys [94 (27) ng/ml, P < 0.001] and IVF [74 (34) ng/ml], compared with NC girls [93 (43) ng/ml, P = 0.011]. ICSI children were also smaller than their target height (sd score) at 3 yr of age [mean -0.91 (1.2)], compared with NC children [-0.61 (0.9), P = 0.033]. In the child cohort, target height attainment (sd score) and growth factors did not differ among the three groups. CONCLUSIONS:The overall growth pattern of ICSI and IVF children in both cohorts was normal. Our findings of subtle differences in target height attainment and serum IGF-I levels between infants born after assisted reproduction techniques and controls may not be clinically significant. However, these observations indicate that further systematic follow-up of growth and puberty in these children is needed.

背景与目标： 背景：人们对后代辅助生殖技术的安全性表示关注。
目的：本研究的目的是调查胞浆内精子注射（ICSI）和体外受精（IVF）后出生的儿童的出生后生长和生长因子。
设计：该研究有两个队列：基于人群的纵向婴儿队列0-36个月[236 ICSI，173 IVF，1530自然受孕（NC）]和5岁时的横断面儿童队列（68 ICSI，67 IVF ，70 NC）。
干预措施：分别在出生时，3、18、36（婴儿队列）和60个月（儿童队列）进行人体测量，并在3或60个月时采集血样。
主要观察指标：血清IGF-I，IGFBP-3，身高，体重，头围和腹围，体重指数和脂肪褶皱是主要的观察指标。
结果：人体测量结果显示，ICSI和IVF儿童与对照组之间均无显着差异。但是，单身ICSI女孩[3.4（0.6）千克，P = 0.008]的出生体重略低于IVF [3.5（0.5）千克]和NC女孩[3.5（0.5）千克]。单胎男孩[3.6（0.5）千克]，双胞胎男孩[2.6（0.6）千克]和双胞胎女孩[2.4（0.5）千克]的出生体重在不同的受孕类型之间没有差异。在3个月大的单胎婴儿队列中，ICSI的血清IGF-I低于NC男孩[94（27）ng / ml，P <0.001]和IVF [74（ 34）ng / ml]，而NC女生则为[93（43）ng / ml，P = 0.011]。与3岁儿童相比，ICSI儿童在3岁时也小于其目标身高（sd评分）[平均-0.91（1.2）]，而NC儿童则为[-0.61（0.9），P = 0.033]。在儿童队列中，三组之间的目标身高获得（sd得分）和生长因子没有差异。
结论：两组人群ICSI和IVF儿童的总体生长方式均正常。我们在辅助生殖技术和对照后出生的婴儿之间的目标身高获得和血清IGF-I水平细微差异的发现可能在临床上并不重要。但是，这些观察结果表明，需要对这些儿童的生长和青春期进行进一步的系统随访。

BACKGROUND & AIMS: :Cytoplasmic dynein transports short microtubules down the axon in part by pushing against the actin cytoskeleton. Recent studies have suggested that comparable dynein-driven forces may impinge upon the longer microtubules within the axon. Here, we examined a potential role for these forces on axonal retraction and growth cone turning in neurons partially depleted of dynein heavy chain (DHC) by small interfering RNA. While DHC-depleted axons grew at normal rates, they retracted far more robustly in response to donors of nitric oxide than control axons, and their growth cones failed to efficiently turn in response to substrate borders. Live cell imaging of dynamic microtubule tips showed that microtubules in DHC-depleted growth cones were largely confined to the central zone, with very few extending into filopodia. Even under conditions of suppressed microtubule dynamics, DHC depletion impaired the capacity of microtubules to advance into the peripheral zone of the growth cone, indicating a direct role for dynein-driven forces on the distribution of the microtubules. These effects were all reversed by inhibition of myosin-II forces, which are known to underlie the retrograde flow of actin in the growth cone and the contractility of the cortical actin during axonal retraction. Our results are consistent with a model whereby dynein-driven forces enable microtubules to overcome myosin-II-driven forces, both in the axonal shaft and within the growth cone. These dynein-driven forces oppose the tendency of the axon to retract and permit microtubules to advance into the peripheral zone of the growth cone so that they can invade filopodia.

背景与目标： 细胞质的动力蛋白部分是通过推动肌动蛋白的细胞骨架，将短的微管沿轴突向下运输。最近的研究表明，类似的动力蛋白驱动力可能会作用于轴突内更长的微管上。在这里，我们检查了这些力在小干扰RNA导致部分消除了动力蛋白重链（DHC）的神经元中对轴突回缩和生长锥转向的潜在作用。尽管DHC耗尽的轴突以正常速度生长，但它们对一氧化氮供体的反应比对对照轴突的撤回作用要强得多，并且它们的生长锥无法响应底物边界而有效地转向。动态微管尖端的活细胞成像显示，DHC耗尽的生长锥中的微管主要局限在中心区域，很少延伸到丝状伪足。即使在微管动力学受到抑制的条件下，DHC的消耗也会削弱微管进入生长锥外围区域的能力，这表明动力蛋白驱动力对微管的分布起着直接作用。这些作用都通过抑制肌球蛋白II力而逆转，肌球蛋白II力是轴突收缩过程中肌动蛋白在生长锥中逆行流动和皮质肌动蛋白收缩力的基础。我们的结果与动力蛋白驱动力使微管克服轴突轴和生长锥内肌球蛋白II驱动力的模型相符。这些由达因蛋白驱动的力与轴突收缩的趋势相反，并允许微管前进到生长锥的外围区域，因此它们可以侵入丝状伪足。