BACKGROUND & AIMS: :Monomeric G-proteins, also referred to as small GTPases, function as biological hubs being activated by extracellular stimuli and regulate downstream signalling events, which result in different cellular responses. The importance of these mechanisms is mirrored by the fact that several pathological conditions, including allergic asthma, are associated with derailed GTPases signalling. For this reason attention has been focused on the role of monomeric G-proteins and their effectors in airway (patho)physiology. In this article we review our current knowledge on the regulation and functions of Ras and Rho GTPase signalling under physiological and pathophysiological conditions in the pulmonary system. Based on recent findings concerning novel regulatory proteins for Ras family members, we further discuss potential future directions for therapeutical interventions in asthma.

背景与目标： : 单体g蛋白，也称为小gtp酶，充当被细胞外刺激激活的生物枢纽，并调节下游信号传导事件，从而导致不同的细胞反应。这些机制的重要性反映在以下事实中: 包括过敏性哮喘在内的几种病理状况与脱轨的GTPases信号有关。由于这个原因，人们的注意力集中在单体g蛋白及其效应子在气道 (病理) 生理学中的作用。在这篇文章中，我们回顾了我们目前关于Ras和Rho GTPase信号在肺系统的生理和病理生理条件下的调节和功能的知识。基于有关新颖的最新发现ras家族成员的调节蛋白，我们进一步讨论了哮喘治疗干预的潜在未来方向。

BACKGROUND & AIMS: :p53 protein is a well-known tumor suppressor factor that regulates cellular homeostasis. As it has several and key functions exerted, p53 is known as "the guardian of the genome" and either loss of function or gain of function mutations in the TP53 coding protein sequence are involved in cancer onset and progression. The Hippo pathway is a key regulator of developmental and regenerative physiological processes but if deregulated can induce cell transformation and cancer progression. The p53 and Hippo pathways exert a plethora of fine-tuned functions that can apparently be in contrast with each other. In this review, we propose that the p53 status can affect the Hippo pathway function by switching its outputs from tumor suppressor to oncogenic activities. In detail, we discuss: (a) the oncogenic role of the protein complex mutant p53/YAP; (b) TAZ oncogenic activation mediated by mutant p53;

背景与目标： : p53蛋白是一种众所周知的肿瘤抑制因子，可调节细胞内稳态。由于p53具有多种关键功能，因此被称为 “基因组的守护者”，TP53编码蛋白序列中的功能丧失或功能突变的获得都与癌症的发生和发展有关。Hippo途径是发育和再生生理过程的关键调节剂，但如果放松管制，则可以诱导细胞转化和癌症进展。p53和Hippo途径发挥了许多微调功能，显然可以相互对比。在这篇综述中，我们提出p53状态可以通过将其输出从肿瘤抑制因子转换为致癌活性来影响Hippo途径的功能。详细地，我们讨论了 :( a) 蛋白质复合物突变体p53/YAP的致癌作用; (b) 突变p53介导的TAZ致癌激活;

BACKGROUND & AIMS: UNLABELLED:Most neurological diseases are associated with chronic inflammation initiated by the activation of microglia, which produce cytotoxic and inflammatory factors. Signal transducers and activators of transcription (STATs) are potent regulators of gene expression but contribution of particular STAT to inflammatory gene expression and STAT-dependent transcriptional networks underlying brain inflammation need to be identified. In the present study, we investigated the genomic distribution of Stat binding sites and the role of Stats in the gene expression in lipopolysaccharide (LPS)-activated primary microglial cultures. Integration of chromatin immunoprecipitation-promoter microarray data and transcriptome data revealed novel Stat-target genes including Jmjd3, Ccl5, Ezr, Ifih1, Irf7, Uba7, and Pim1. While knockdown of individual Stat had little effect on the expression of tested genes, knockdown of both Stat1 and Stat3 inhibited the expression of Jmjd3 and inflammatory genes. Transcriptional regulation of Jmjd3 by Stat1 and Stat3 is a novel mechanism crucial for launching inflammatory responses in microglia. The effects of Jmjd3 on inflammatory gene expression were independent of its H3K27me3 demethylase activity. Forced expression of constitutively activated Stat1 and Stat3 induced the expression of Jmjd3, inflammation-related genes, and the production of pro-inflammatory cytokines as potently as lipopolysacharide. Gene set enrichment and gene function analysis revealed categories linked to the inflammatory response in LPS and Stat1C + Stat3C groups. We defined upstream pathways that activate STATs in response to LPS and demonstrated contribution of Tlr4 and Il-6 and interferon-γ signaling. Our findings define novel direct transcriptional targets of Stat1 and Stat3 and highlight their contribution to inflammatory gene expression. KEY MESSAGE:Combined analysis of genomic Stat occupancy and transcriptome revealed novel Stat target genes in LPS-induced microglia. Jmjd3 transcription factor is a novel transcriptional target of Stat1 and Stat3. Stat1 and Stat3 cooperate with Jmjd3 to induce the expression of pro-inflammatory genes. Constitutively active Stat1 and Stat3 fully mimic the LPS-induced upregulation of inflammatory genes and secretion of cytokines.

背景与目标：

BACKGROUND & AIMS: :Haem-containing proteins such as haemoglobin and myoglobin play an essential role in oxygen transport and storage. Comparison of the amino-acid sequences of globins from Bacteria and Eukarya suggests that they share an early common ancestor, even though the proteins perform different functions in these two kingdoms. Until now, no members of the globin family have been found in the third kingdom, Archaea. Recent studies of biological signalling in the Bacteria and Eukarya have revealed a new class of haem-containing proteins that serve as sensors. Until now, no haem-based sensor has been described in the Archaea. Here we report the first myoglobin-like, haem-containing protein in the Archaea, and the first haem-based aerotactic transducer in the Bacteria (termed HemAT-Hs for the archaeon Halobacterium salinarum, and HemAT-Bs for Bacillus subtilis). These proteins exhibit spectral properties similar to those of myoglobin and trigger aerotactic responses.

背景与目标： 含血红素的蛋白质，如血红蛋白和肌红蛋白，在氧气运输和储存中起着至关重要的作用。来自细菌和真核生物的球蛋白的氨基酸序列的比较表明，即使蛋白质在这两个王国中具有不同的功能，它们也具有早期的共同祖先。直到现在，在第三王国古菌 (Archaea) 中还没有发现珠蛋白家族的成员。最近对细菌和真核生物中的生物信号传导的研究揭示了一类新的含血红素的蛋白质作为传感器。到目前为止，古细菌中还没有描述过基于血红素的传感器。在这里，我们报告了古细菌中第一个类似肌红蛋白的含血红素的蛋白质，以及细菌中第一个基于血红素的航空趋化换能器 (古细菌盐藻称为HemAT-Hs，枯草芽孢杆菌称为HemAT-Bs)。这些蛋白质表现出与肌红蛋白相似的光谱特性，并触发了航空反应。

BACKGROUND & AIMS: :Male breast cancer (MBC) is a rare hormone-driven disease often associated with obesity. HMG-CoAR is the central enzyme of the mevalonate pathway, a molecular route deputed to produce cholesterol and steroid-based hormones. HMG-CoAR regulates the oncogenic Hippo transducers TAZ/YAP whose expression was previously associated with shorter survival in MBC. 225 MBC samples were immunostained for HMG-CoAR and 124 were considered eligible for exploring its relationship with hormone receptors (ER, PgR, AR), Hippo transducers and survival outcomes. HMG-CoAR was positively associated with the expression of hormone receptors (ER, PgR, AR) and Hippo transducers. Overall survival was longer in patients with HMG-CoAR-positive tumors compared with their negative counterparts (p = 0.031). Five- and 10-year survival outcomes were better in patients whose tumors expressed HMG-CoAR (p = 0.044 and p = 0.043). Uni- and multivariate analyses for 10-year survival suggested that HMG-CoAR expression is a protective factor (HR 0.50, 95% CI: 0.25-0.99, p = 0.048 and HR 0.53, 95% CI: 0.26-1.07, p = 0.078). Results were confirmed in a sensitivity analysis by excluding uncommon histotypes (multivariate Cox: HR 0.45, 95% CI: 0.21-0.97, p = 0.043). A positive relationship emerged between HMG-CoAR, hormone receptors and TAZ/YAP, suggesting a connection between the mevalonate pathway, the hormonal milieu and Hippo in MBC. Moreover, HMG-CoAR expression may be a favorable prognostic indicator.

背景与目标： 男性乳腺癌 (MBC) 是一种罕见的激素驱动疾病，通常与肥胖相关。HMG-CoAR是甲羟戊酸途径的中心酶，甲羟戊酸途径是一种产生胆固醇和类固醇激素的分子途径。HMG-CoAR调节致癌Hippo换能器TAZ/YAP，其表达先前与MBC的较短生存期相关。225 MBC样品对HMG-CoAR进行免疫染色，124被认为有资格探索其与激素受体 (ER，PgR，AR)，Hippo换能器和生存结果的关系。HMG-CoAR与激素受体 (ER，PgR，AR) 和Hippo换能器的表达呈正相关。与阴性患者相比，HMG-CoAR阳性患者的总生存期更长 (p   =   0.031)。肿瘤表达HMG-CoAR的患者 (p   =   0.044，p   =   0.043) 5年和10年的生存结局较好。10年生存率的单因素和多因素分析表明，HMG-CoAR表达是一种保护因子 (HR 0.50，95% ci ci: 0.25-0.99，p   =   0.048和HR 0.53，95%  CI: 0.26-1.07，p   =   0.078)。通过排除不常见的组织类型 (多变量Cox: HR 0.45，95%  CI: 0.21-0.97，p   =   0.043)，在敏感性分析中证实了结果。HMG-CoAR，激素受体和TAZ/YAP之间出现正相关关系，表明MBC中的甲羟戊酸途径，激素环境和河马之间存在联系。此外，HMG-CoAR表达可能是有利的预后指标。

BACKGROUND & AIMS: :Diaphragm pressure transducers are designed to measure pressures in fluids, but have also been applied to measuring pressures on soft materials, such as at the interface between the residual limb of a lower-limb amputee and the supporting surface defined by the prosthetic socket. The reliability and accuracy of Kulite XTM-190 transducer as a pressure monitor on soft materials, such as silicone and Pelite was evaluated in three physical model set-ups. The evaluations included the uniform loading of solid disks of silicone and Pelite, the application of air pressure to the core of a contained thick-walled cylinder made of silicone, and the dynamic indentation of a contained solid silicone cylinder. Sensor measurements in all situations were similar to analytical, iterative or finite element solutions when certain conditions were met. These conditions include: (i) lubricating the interface between the soft material and the supporting structure; (ii) calibrating the transducers under surface and material conditions used during measurements; and (iii) using compatible soft materials (e.g. silicone but not Pelite).

背景与目标： : 隔膜压力传感器被设计用于测量流体中的压力，但也已应用于测量软材料上的压力，例如在下肢截肢者的残肢与由假肢窝限定的支撑表面之间的界面处。在三个物理模型设置中评估了Kulite XTM-190传感器作为软材料 (例如硅树脂和Pelite) 上的压力监测器的可靠性和准确性。评估包括均匀加载硅树脂和Pelite的实心圆盘，将气压施加到由硅树脂制成的内置厚壁圆柱体的核心以及内置的实心硅树脂圆柱体的动态压痕。当满足某些条件时，所有情况下的传感器测量都类似于解析，迭代或有限元解决方案。这些条件包括 :( i) 润滑软材料和支撑结构之间的界面; (ii) 在测量过程中使用的表面和材料条件下校准换能器; 以及 (iii) 使用兼容的软材料 (例如硅树脂而不是Pelite)。

BACKGROUND & AIMS: :Ultrasound speckle is a consequence of the stochastic nature of the reflectivity of scattering media (e.g., biological tissue) and of the coherent nature of piezoelectric transducers. This speckle noise can be reduced by the use of incoherent processing techniques (e.g., spatial compounding, incoherent summation, random phase and phase insensitive transducers). We present a unified framework that explains the limitations of incoherent processing in terms of the information grain theory. This theory predicts the gains in SNR as well as the losses in directivity. We also present the random phase transducer approach to incoherence to total coherence. We present applications to speckle reduction, detection of specular reflectors, attenuation estimation and ultrasound imaging. We show that totally incoherent transducers completely remove diffraction effects. They might be used in attenuation estimation, in which case, correction for diffraction is no longer required, in order to obtain unbiased estimates. Partially coherent transducers might also be useful in imaging to reduce speckle noise.

背景与目标： : 超声斑点是散射介质 (例如生物组织) 的反射率的随机性质和压电换能器的相干性质的结果。可以通过使用非相干处理技术 (例如，空间复合，非相干求和，随机相位和相位不敏感的换能器) 来降低斑点噪声。我们提出了一个统一的框架，该框架根据信息谷物理论解释了不连贯处理的局限性。该理论预测了SNR的收益以及方向性的损失。我们还介绍了随机相位换能器方法，以使其与总相干性不一致。我们介绍了在散斑减少，镜面反射器的检测，衰减估计和超声成像方面的应用。我们证明了完全不相干的换能器完全消除了衍射效应。它们可以用于衰减估计，在这种情况下，不再需要衍射校正，以便获得无偏估计。部分相干换能器也可能在成像中以减少斑点噪声中有用。

BACKGROUND & AIMS: OBJECTIVE:This safety study was designed to investigate tissue heating close to the surface of transvaginal ultrasound transducers, with the objective of assessing the validity of manufacturing safety standards set by the International Electrotechnical Commission (IEC). METHODS:The transducers investigated in this study were held in contact with a layered soft-tissue mimicking material (TMM), and the temperature increase was measured at various depths using a miniature thermocouple. The temperature rise at 200 s was recorded, and the measured profiles of temperature rise with depth were compared with profiles predicted from both analytical and numeric models. Two transvaginal transducers of different manufacturers were investigated, operating in B-mode imaging, color-flow imaging and pulsed Doppler modes, using scanner settings giving acoustic output power towards the upper end of that available. RESULTS:The greatest heating always occurred at the interface between the transducer and the TMM, and it reduced to about 0.1 times the surface temperature rise at a depth of 1 cm. A local maximum was observed in pulsed Doppler mode. A three-dimensional finite-element model which accounted for transducer dimensions gave a better prediction of temperature increase than a simple analytical model. The temperature profiles were compared with the depth of fetal tissue measured from a small survey of clinical scans. CONCLUSIONS:It is provisionally concluded that the transducer surface temperature rise of 6 degrees C allowed to manufacturers by the IEC may give rise to an associated worst-case contribution to temperature rise due to the transducer, in fetal tissue, of between 0.5 and 1 degrees C at 1-cm depth. The contribution to tissue heating at 2 cm and deeper is negligible. Published by John Wiley & Sons, Ltd.

背景与目标：

BACKGROUND & AIMS: :The transcription factors signal transducers and activators of transcription (STAT)5a and STAT5b (STAT5) are essential mediators of many actions of GH, including transcription of the IGF-I gene. Here, we present evidence that skeletal muscle STAT5 is important for postnatal growth and suggest that this is conveyed by the production of localized IGF-I. To investigate the role of STAT5 signaling in skeletal muscle, mice with a skeletal-muscle-specific deletion of the Stat5a and Stat5b genes (Stat5MKO mice) were used. IGF-I mRNA levels were reduced by 60% in muscle tissue of these mice. Despite only a 15% decrease in circulating IGF-I, 8-wk-old male Stat5MKO mice displayed approximately 20% reduction in body weight that was accounted for by a reduction in lean mass. The skeletons of Stat5MKO mice were found to be smaller than controls, indicating the growth defect was not restricted to skeletal muscle. These results demonstrate an as yet unreported critical role for STAT5 in skeletal muscle for local IGF-I production and postnatal growth and suggest the skeletal muscle as a major site of GH action.

背景与目标： : 转录因子信号转导子和转录激活子 (STAT)5a和STAT5b (STAT5) 是GH许多作用的重要介质，包括igf-i基因的转录。在这里，我们提供证据表明骨骼肌STAT5对出生后的生长很重要，并表明这是通过局部igf-i的产生来传达的。为了研究STAT5信号在骨骼肌中的作用，使用了骨骼肌特异性缺失Stat5a和Stat5b基因的小鼠 (Stat5MKO小鼠)。这些小鼠的肌肉组织中的60% 降低了igf-i mRNA水平。尽管只有循环igf-i的15% 降低，8周龄的雄性Stat5MKO小鼠表现出约20% 的体重减少，这是由于瘦体重的减少所致。发现Stat5MKO小鼠的骨骼小于对照组，表明生长缺陷不仅限于骨骼肌。这些结果表明STAT5在骨骼肌中对于局部igf-i的产生和产后生长起着尚未报道的关键作用，并表明骨骼肌是GH作用的主要部位。

BACKGROUND & AIMS: :Two possible methods to determine the spatial average temporal average intensity I(sata) and ultrasonic power W in composite ltrasonic transducers for medical application are described. Results showed that integrals using one method will yield accurate results but a vast amount of computational effort is required. On the other hand, using an alternative method these integrals may readily be solved at the expense of the accuracy of the results deduced.

背景与目标： : 描述了两种可能的方法来确定用于医学应用的复合超声换能器中的空间平均时间平均强度I(sata) 和超声功率W。结果表明，使用一种方法的积分将产生准确的结果，但需要大量的计算量。另一方面，使用另一种方法，可以很容易地解决这些积分，但要牺牲推导结果的准确性。

BACKGROUND & AIMS: :This paper presents novel micromachined two-dimensional array piezoelectrically actuated flextensional transducers that can be used to generate sound in air or water. Micromachining techniques to fabricate these devices are also presented. Individual unimorph array elements consist of a thin piezoelectric annular disk and a thin, fully clamped, circular plate. We manufacture the transducer in two-dimensional arrays using planar silicon micromachining and demonstrate ultrasound transmission in air at 2.85 MHz with 0.15 microm/V peak displacement. The devices have a range of operating resonance frequencies starting from 450 kHz up to 4.5 MHz. Such an array could be combined with on-board driving and addressing circuitry for different applications.

背景与目标： : 本文介绍了新型的微机械二维阵列压电驱动的挠曲张换能器，可用于在空气或水中产生声音。还介绍了制造这些设备的微加工技术。单个单压电晶片阵列元件由薄的压电环形盘和薄的，完全夹紧的圆板组成。我们使用平面硅微加工在二维阵列中制造换能器，并演示了在2.85 MHz的空气中具有0.15 microm/V峰值位移的超声传输。这些器件具有从450 kHz到4.5 MHz开始的一系列工作谐振频率。这样的阵列可以与用于不同应用的车载驱动和寻址电路结合使用。

BACKGROUND & AIMS: :Differences in tissue heating rates between ultrasound transducers have been well documented; however, comparative analysis between ultrasound fields to determine why tissue heating rates may differ is lacking. We selected three transducers from the same manufacturer with similar effective radiating area, output power, effective intensity and beam nonuniformity ratio [as defined by the FDA, 21 CFR Chap. 1, part 1,050 (10)], but markedly different Schlieren images. Each transducer was utilized to heat tissue with a standardized ultrasound application to determine whether Schlieren analysis may be useful in understanding variability in tissue heating rates. Thermocouples were inserted into the left triceps surae of 12 volunteers at a depth of 1.5 cm below one half the measured skin fold thickness (estimated average depth of the thermocouple was 1.99 +/- 0.27 cm). Each subject received one treatment from each transducer in a single session (n = 3); 3 MHz at 1.2 W/cm(2) for 8 min with a 100% duty cycle. Each transducer increased the IM temperature over time (p < 0.0001). IM temperatures were not significantly different between transducers from time zero to the fourth minute of treatment. After the fourth min, transducers B and C generated significantly higher tissue temperatures (p < 0.01). Transducer A, B and C increased IM temperature from 34.9 +/- 0.5 to 41.2 +/- 1.3 degrees C, 34.9 +/- 0.6 to 42.5 +/- 1.4 degrees C and 34.9 +/- 0.5 to 42.7 +/- 1.7 degrees C, respectively. Interestingly, transducer C emitted 22% lower output power but heated 24% higher than transducer A and our Schlieren images demonstrate that transducers B and C produced a more concentrated field compared with transducer A. The data we present here supports the general contention that a more concentrated field will heat to a higher temperature than a more disperse field, however, technical challenges in estimating output power, ERA and Schlieren analysis remain an issue.

背景与目标： : 超声换能器之间的组织加热速率差异已得到充分记录; 但是，缺乏超声场之间的比较分析以确定为什么组织加热速率可能不同。我们从同一制造商中选择了三个换能器，它们具有相似的有效辐射面积，输出功率，有效强度和光束不均匀性比 [由FDA，21 CFR第1章，第1,050 (10) 部分定义]，但明显不同的Schlieren图像。利用每个换能器通过标准化的超声应用来加热组织，以确定Schlieren分析是否有助于理解组织加热速率的变异性。将热电偶插入到12名志愿者的左肱三头肌中，深度1.5厘米低于测得的皮肤褶皱厚度的一半 (热电偶的估计平均深度为1.99 +/-0.27厘米)。每个受试者在单个会话 (n = 3) 中从每个换能器接受一次治疗; 在1.2 W/cm(2) 下3 MHz，持续8分钟，具有100% 的占空比。每个换能器随时间增加IM温度 (p <0.0001)。从零点到治疗的第四分钟，换能器之间的IM温度没有显着差异。在第四分钟后，换能器B和C产生明显更高的组织温度 (p <0.01)。换能器A、B和C分别将IM温度从34.9 +/- 0.5增加到41.2 +/- 1.3 ℃，34.9 +/- 0.6到42.5 +/- 1.4 ℃，34.9 +/- 0.5到42.7 +/- 1.7 ℃。有趣的是，与换能器A相比，换能器C发射22% 更低的输出功率，但加热的24% 更高，并且我们的Schlieren图像表明，与换能器a相比，换能器B和C产生了更集中的场。我们在这里提供的数据支持了一个普遍的论点，即更集中的场将比更分散的场加热到更高的温度，但是，估计输出功率，ERA和Schlieren分析的技术挑战仍然是一个问题。

BACKGROUND & AIMS: :Hippo signaling controls cellular processes that ultimately impact organogenesis and homeostasis. Consequently, disease states including cancer can emerge when signaling is deregulated. The major pathway transducers Yap and Taz require cofactors to impart transcriptional control over target genes. Research into Yap/Taz-mediated epigenetic modifications has revealed their association with chromatin-remodeling complex proteins as a means of altering chromatin structure, therefore affecting accessibility and activity of target genes. Specifically, Yap/Taz have been found to associate with factors of the GAGA, Ncoa6, Mediator, Switch/sucrose nonfermentable (SWI/SNF), and Nucleosome Remodeling and Deacetylase (NuRD) chromatin-remodeling complexes to alter the accessibility of target genes. This review highlights the different mechanisms by which Yap/Taz collaborate with other factors to modify DNA packing at specific loci to either activate or repress target gene transcription.

背景与目标： 河马信号控制最终影响器官发生和体内平衡的细胞过程。因此，当信号解除管制时，包括癌症在内的疾病状态可能会出现。主要途径转导子Yap和Taz需要辅因子来赋予靶基因转录控制。对Yap/Taz介导的表观遗传修饰的研究表明，它们与染色质重塑复合物蛋白的关联是改变染色质结构的一种手段，因此影响了靶基因的可及性和活性。具体而言，已发现Yap/Taz与GAGA，Ncoa6，介体，开关/蔗糖不可发酵 (SWI/SNF) 以及核小体重塑和脱乙酰酶 (NuRD) 染色质重塑复合物的因子相关，以改变目标基因的可及性。这篇综述强调了Yap/Taz与其他因素合作以修饰特定基因座处的DNA包装以激活或抑制靶基因转录的不同机制。

BACKGROUND & AIMS: :Suppressors of cytokine signaling (SOCS) family is constituted by cytokine-inducible proteins that modulate receptor signal transduction via tyrosine kinases, mainly the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway. Differential SOCS expression was noted in renal cells that were incubated with inflammatory stimuli, but the role of SOCS in the pathogenesis of renal diseases is not yet well defined. Because angiotensin II (Ang II) plays a key role in renal disease, SOCS proteins were studied as a novel mechanism involved in the negative regulation of Ang II-mediated processes. Systemic Ang II infusion for 3 d increased the renal mRNA expression of SOCS-3 and SOCS-1. SOCS protein synthesis was found in glomerular mesangial area and tubules. In cultured mesangial cells and tubular epithelial cells, Ang II induced a rapid and transient SOCS-3 and SOCS-1 expression in parallel with JAK2 and STAT1 activation. In both cell types, overexpression of SOCS proteins prevented the STAT activation in response to Ang II. SOCS expression observed in Ang II-infused rats and in Ang II-stimulated cells was significantly inhibited by treatment with AT(1) but not AT(2) receptor antagonist and was attenuated in mesangial cells from AT(1a)-deficient mice, demonstrating the implication of AT(1) in those responses. In SOCS-3 knockdown studies, antisense oligonucleotides inhibited the expression of SOCS-3 and increased the Ang II-induced STAT activation and c-Fos/c-Jun expression, then resulting in a more severe renal damage. These results suggest that SOCS proteins may act as negative regulators of Ang II signaling in renal cells and implicate SOCS as important modulators of renal damage.

背景与目标： : 细胞因子信号传导抑制子 (SOCS) 家族由细胞因子诱导蛋白组成，这些蛋白通过酪氨酸激酶调节受体信号转导，主要是Janus激酶信号转导和转录激活子 (JAK-STAT) 途径。在与炎症刺激一起孵育的肾细胞中发现了不同的SOCS表达，但是SOCS在肾脏疾病发病机理中的作用尚未明确。由于血管紧张素II (Ang II) 在肾脏疾病中起关键作用，因此研究了SOCS蛋白作为参与Ang II介导过程负调节的新机制。全身Ang II输注3 d可增加SOCS-3和SOCS-1的肾脏mRNA表达。在肾小球系膜区和肾小管中发现了SOCS蛋白合成。在培养的系膜细胞和肾小管上皮细胞中，Ang II与JAK2和STAT1激活平行地诱导快速且短暂的SOCS-3和SOCS-1表达。在两种细胞类型中，SOCS蛋白的过表达均阻止了响应Ang II的STAT激活。在注入Ang II的大鼠和Ang II刺激的细胞中观察到的SOCS表达通过AT(1) 处理而显着抑制，但不抑制AT(2) 受体拮抗剂，并且在AT(1a) 缺陷小鼠的系膜细胞中减弱，证明AT(1) 在这些回应中的含义。在SOCS-3敲低研究中，反义寡核苷酸抑制SOCS-3的表达并增加Ang II诱导的STAT激活和c-Fos/c-6月表达，从而导致更严重的肾损伤。这些结果表明，SOCS蛋白可能充当肾细胞中Ang II信号传导的负调节剂，并暗示SOCS是肾损伤的重要调节剂。

BACKGROUND & AIMS: :Abstract: Previous studies have shown that total epidermal growth factor receptor (EGFR) protein is highly expressed in soft tissue sarcoma (STS). We aimed to investigate the significance of phosphorylated-EGFR (pEGFR) and its activated-downstream signal transducers in STS tissue samples. A tissue microarray comprising 87 STS samples was assessed for total EGFR, pEGFR and its phosphorylated signal transducers and expression was correlated with clinicopathlogical parameters including patient outcome. Although the expression of total EGFR was significantly associated with adverse STS histologic grade (p = 0.004) and clinical stage (p = 0.012) similar to pEGFR, phosphorylated protein kinase B (pAkt) and phosphorylated extracellular signal regulated kinase (pERK), it is not a prognostic factor for survival. By contrast, the expression of pEGFR is an independent factor for cancer specific survival, while pERK is an independent prognostic factor for both overall and cancer specific survival in STS (p < 0.05, Cox proportional hazard model and log-rank test) in addition to the recognised factors of tumour grade and clinical stage. pERK and pEGFR are new independent prognostic factors for overall and/or cancer specific survival in STS. The expression of EGFR/pEGFR, and their associated downstream signal transducers, was associated with STS progression, suggesting that EGFR downstream signalling pathways may jointly support STS cell survival.

背景与目标： 摘要: 已有研究表明，表皮生长因子受体 (EGFR) 蛋白在软组织肉瘤 (STS) 中高表达。我们旨在研究STS组织样品中磷酸化EGFR (pEGFR) 及其激活的下游信号换能器的意义。评估了包含87个STS样品的组织微阵列的总EGFR，pEGFR及其磷酸化信号换能器，并且表达与包括患者结果在内的临床病理参数相关。尽管总EGFR的表达与pEGFR、磷酸化蛋白激酶B (pAkt) 和磷酸化细胞外信号调节激酶 (pERK) 相似的不良STS组织学分级 (p = 0.004) 和临床分期 (p = 0.012) 显著相关，但它不是生存的预后因素。相比之下，除了肿瘤分级和临床分期的公认因素外，pEGFR的表达是癌症特异性生存的独立因素，而pERK是STS总体和癌症特异性生存的独立预后因素 (p <0.05，Cox比例风险模型和log-rank检验)。pERK和pEGFR是STS总体和/或癌症特异性生存的新的独立预后因素。EGFR/pEGFR及其相关下游信号转导子的表达与STS进展相关，提示EGFR下游信号通路可能共同支持STS细胞存活。