Coordinate Hyperactivation of Notch1 and Ras/MAPK Pathways Correlates with Poor Patient Survival: Novel Therapeutic Strategy for Aggressive Breast Cancers

Aberrant activation of Notch and Ras pathways has been detected in breast cancers. A synergy between these two pathways has also been shown in breast cell transformation in culture. Yet, the clinical relevance of Notch-Ras cooperation in breast cancer progression remains unexplored. In this study, we show that coordinate hyperactivation of Notch1 and Ras/MAPK pathways in breast cancer patient specimens, as assessed by IHC for cleaved Notch1 and pErk1/2, respectively, correlated with early relapse to vital organs and poor overall survival. Interestingly, majority of such Notch1 (high)Erk(high) cases encompassed the highly aggressive triple-negative breast cancers (TNBC), and were enriched in stem cell markers. We further show that combinatorial inhibition of Notch1 and Ras/MAPK pathways, using a novel mAb against Notch1 and a MEK inhibitor, respectively, led to a significant reduction in proliferation and survival of breast cancer cells compared with individual inhibition. Combined inhibition also abrogated sphere-forming potential, and depleted the putative cancer stem-like cell subpopulation. Most importantly, combinatorial inhibition of Notch1 and Ras/MAPK pathways completely blocked tumor growth in a panel of breast cancer xenografts, including the TNBCs. Thus, our study identifies coordinate hyperactivation of Notch1 and Ras/MAPK pathways as novel biomarkers for poor breast cancer outcome. Furthermore, based on our preclinical data, we propose combinatorial targeting of these two pathways as a treatment strategy for highly aggressive breast cancers, particularly the TNBCs that currently lack any targeted therapeutic module. (C) 2014 AACR.

A Gaussian network model study suggests that structural fluctuations are higher for inactive states than active states of protein kinases

We performed Gaussian network model based normal mode analysis of 3-dimensional structures of multiple active and inactive forms of protein kinases. In 14 different kinases, a more number of residues (1095) show higher structural fluctuations in inactive states than those in active states (525), suggesting that, in general, mobility of inactive states is higher than active states. This statistically significant difference is consistent with higher crystallographic B-factors and conformational energies for inactive than active states, suggesting lower stability of inactive forms. Only a small number of inactive conformations with the DFG motif in the ``in'' state were found to have fluctuation magnitudes comparable to the active conformation. Therefore our study reports for the first time, intrinsic higher structural fluctuation for almost all inactive conformations compared to the active forms. Regions with higher fluctuations in the inactive states are often localized to the aC-helix, aG-helix and activation loop which are involved in the regulation and/or in structural transitions between active and inactive states. Further analysis of 476 kinase structures involved in interactions with another domain/protein showed that many of the regions with higher inactive-state fluctuation correspond to contact interfaces. We also performed extensive GNM analysis of (i) insulin receptor kinase bound to another protein and (ii) holo and apo forms of active and inactive conformations followed by multi-factor analysis of variance. We conclude that binding of small molecules or other domains/proteins reduce the extent of fluctuation irrespective of active or inactive forms. Finally, we show that the perceived fluctuations serve as a useful input to predict the functional state of a kinase.

Antiangiogenic VEGF-Ax: A New Participant in Tumor Angiogenesis

The transcript of the angiogenic factor vascular endothelial growth factor A (VEGF-A) is subject to a multitude of stimulus-dependent, posttranscriptional regulatory events, consistent with its unusually long 30 untranslated region. We have recently reported translational readthrough of VEGFA mRNA whereby translating ribosomes traverse the canonical stop codon to a conserved, downstream stop codon, generating VEGF-Ax (''x'' for extended), a novel, extended isoform with an additional 22 amino acids appended at the C-terminus. This event is the first vertebrate example of protein-regulated, programmed translational readthrough that generates a protein with a known function. Remarkably, VEGF-Ax exhibits potent antiangiogenic activity, both in vitro and in vivo, thus raising profound clinical implications, particularly with respect to cancer treatment. In this review, we discuss the potential of VEGF-Ax as a therapeutic agent and drug target, as well as its possible role in the failure of, or resistance to, conventional anti-VEGF therapies in many types of cancers. (C) 2015 AACR.

Corrosion behaviour of creep-resistant AE42 magnesium alloy-based hybrid composites developed for powertrain applications

The corrosion behaviour of AE42 magnesium alloy and its composites reinforced with Saffil short fibres and SiC particles in various combinations was investigated. The corrosion rate of the unreinforced alloy was the lowest. The composite reinforced with Saffil short fibre alone exhibited slightly lower corrosion rate than the hybrid composites containing both Saffil short fibres and SiC particles. However, there was no specific trend observed in the corrosion rate of the hybrid composites with respect to the SiC particle content. The degradation of corrosion resistance of the composites was mainly attributed to the irregular and loose surface films.

激光熔覆层陶瓷颗粒界面力学行为的数值分析

研究了激光涂覆时因陶瓷颗粒与金属之间物理性能差异而在其界面处形成的残余应力特征。在一定假设条件下，通过有限元计算和界面应力场分析，得出熔覆层由陶瓷颗垃的数量及其形状对陶瓷／金属界面应力状态的影响。

Convergence of attractors

The system of coupled oscillators and its time-discretization (with constant stepsize h) are considered in this paper. Under some conditions, it is showed that the discrete systems have one-dimensional global attractors l(h) converging to l which is the global attractor of continuous system.

PICES Press, Vol. 14, No. 1, January 2006

The state of PICES science - 2005 (pdf, 0.2 Mb) 2005 Wooster Award (pdf, 0.4 Mb) Korea and U.S. federate metadata collection (pdf, 0.3 Mb) PICES Interns (pdf, 0.3 Mb) Studies on long-term variation of ocean ecosystem / climate interactions based on the Odate collection (pdf, 0.2 Mb) Hokkaido University Fisheries & Oceanographic Database CD-ROM (pdf, 0.2 Mb) Workshop on sardine and anchovy fluctuations (pdf, 0.1 Mb) Photo highlights of PICES XIV (pdf, 0.4 Mb) Workshop on SEEDS-II (pdf, 0.2 Mb) NPAFC-PICES joint symposium "The status of Pacific salmon and their role in North Pacific marine ecosystems" (pdf, 0.2 Mb) PICES Calendar (pdf, 0.2 Mb) New Chairman of the PICES Fishery Science Committee (pdf, 0.1 Mb) The state of the western North Pacific in the first half of 2005 (pdf, 0.4 Mb) Latest and upcoming PICES publications (pdf, 0.4 Mb) Recent trends in waters of the subarctic NE Pacific (pdf, 0.2 Mb) The Bering Sea: Current status and recent events (pdf, 0.1 Mb) PICES and GLOBEC to sponsor workshop on sub-arctic seas (pdf, 0.1 Mb) Professor Mikhail N. Koshlyakov - 75 (pdf, 0.1 Mb) Obituary - Dr. Al Tyler (pdf, 0.1 Mb)

Collecção das Leis da Republica dos Estados Unidos do Brazil de 1899

Parte 1 - Atos do Poder Legislativo

A snapshot of digitisation and OCR Developments

One of the goals of Knowledge Exchange (www.knowledge-exchange.info) is to help partners to share knowledge and expertise and facilitate the build of expert networks. In the area of digitisation, including non-textual and 3-D-digitisation, a first step is to provide a snapshot of current activities and challenges in the KE partner countries. This paper is a synthesis of the information gathered in a questionnaire that was sent to 15 infrastructure institutions, e.g. libraries and also funders, within the five partner countries of Knowledge Exchange: Denmark (DK), Finland (FIN), Germany (GER), the Netherlands (NL) and the United Kingdom (UK). The paper is based on the answers provided by 6 respondents from four countries:  DK o Danish Agency of Culture (Henrik Jarl Hansen) o State and University Library (Tonny Skovgård Jensen)  GER o German research foundation, DFG (Franziska Regner)  NL o Royal Library (Hildelies Balk) o Leiden University Library (Saskia van Bergen)  UK o Jisc (Paola Marchionni, Peter Findlay) The absence of Finnish responses may be due to Finland participating in the recent Enumerate Core Survey II that also addressed digitisation. We have included some of the outcomes of this survey to present a richer picture.

两个光纤激光器的相位锁定及高相干功率输出

研究了两个光纤激光器的相位锁定及其相干输出。将两个光纤激光器的输出耦合进一个自成像共振腔，然后利用一个空间滤波器进行模式选择。自成像共振腔由两个焦距为8mm的准直透镜、一个焦距为500mm的傅里叶透镜和一个耦合输出镜组成。滤波器由两根20μm的铂金线组成，并放置在耦合输出镜面上。实验中，观测到光束截面图样具有高对比度的干涉条纹。输出镜反射率在50％和30％情况下，分析了单个激光器和激光器阵列的斜率效率。在总抽运功率为60W时，获得了18．3W的高相干功率输出。稳定的相位锁定是由于激光器阵列具有能适应光程长

Effect of PbO on precipitation of laser-induced gold nanoparticles inside silicate glasses

We report on three-dimensional precipitation of Au nanoparticles in gold ions-doped silicate glasses by a femtosecond laser irradiation and further annealing. Experimental results show that PbO addition plays the double roles of inhibiting hole-trapped centers generation and promoting formation and growth of gold nanoparticles. Additionally, glass containing PbO shows an increased non-linear absorption after femtosecond laser irradiation and annealing. The observed phenomena are significant for applications such as fabrications of three-dimensional multi-colored images inside transparent materials and three-dimensional optical memory, and integrated micro-optical switches. (c) 2007 Elsevier B.V. All rights reserved.