Traversing probe Patent

Flow meter for measuring stagnation pressure in boundary layer around high speed flight vehicl

AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells

Chronic myeloid leukemia (CML) represents the first human malignancy successfully treated with a tyrosine kinase inhibitor (TKI; imatinib). However, early relapses and the emergence of imatinib-resistant disease are problematic. Evidence suggests that imatinib and other inhibitors may not effectively eradicate leukemic stem/progenitor cells, and that combination therapy directed to complimentary targets may improve treatment. Abelson helper integration site 1 (Ahi-1)/AHI-1 is a novel oncogene that is highly deregulated in CML stem/progenitor cells where levels of BCR-ABL transcripts are also elevated. Here, we demonstrate that overexpression of Ahi-1/AHI-1 in murine and human hematopoietic cells confer growth advantages in vitro and induce leukemia in vivo, enhancing effects of BCR-ABL. Conversely, RNAi-mediated suppression of AHI-1 in BCR-ABL–transduced lin−CD34+ human cord blood cells and primary CML stem/progenitor cells reduces their growth autonomy in vitro. Interestingly, coexpression of Ahi-1 in BCR-ABL–inducible cells reverses growth deficiencies exhibited by BCR-ABL down-regulation and is associated with sustained phosphorylation of BCR-ABL and enhanced activation of JAK2–STAT5. Moreover, we identified an AHI-1–BCR-ABL–JAK2 interaction complex and found that modulation of AHI-1 expression regulates phosphorylation of BCR-ABL and JAK2–STAT5 in CML cells. Importantly, this complex mediates TKI response/resistance of CML stem/progenitor cells. These studies implicate AHI-1 as a potential therapeutic target downstream of BCR-ABL in CML

Targeting Primitive Chronic Myeloid Leukemia Cells by Effective Inhibition of a New AHI-1BCR-ABL-JAK2 Complex

This is a pre-copyedited, author-produced version of an article accepted for publication in JNCI: Journal of the National Cancer Institute following peer review. The version of record Chen, M., et al. (2013). "Targeting Primitive Chronic Myeloid Leukemia Cells by Effective Inhibition of a New AHI-1–BCR-ABL–JAK2 Complex." JNCI: Journal of the National Cancer Institute 105(6): 405-423. is available online at: https://doi.org/10.1093/jnci/djt006This work was funded by the Canadian Cancer Society (grant 700289), in part by the Canadian Institutes of Health Research, the Leukemia & Lymphoma Society of Canada, and the Cancer Research Society (XJ), the Canadian Cancer Society Research Institute (AE, XJ, CE), Cancer Research UK Programme grant C11074/A11008 (TLH), the Glasgow Experimental Cancer Medicine Centre, which is funded by Cancer Research UK and by the Chief Scientist’s Office (Scotland), and Cancer Research UK grant C973/A9894 (JP, JS). M. Chen was supported by a fellowship from Lymphoma Foundation Canada, and P. Gallipoli was supported by Medical Research Council grant G1000288. X. Jiang was a Michael Smith Foundation for Health Research Scholar

Rho GTPases as therapeutic targets in Alzheimer’s disease

The progress we have made in understanding Alzheimer’s disease (AD) pathogenesis has led to the identification of several novel pathways and potential therapeutic targets. Rho GTPases have been implicated as critical components in AD pathogenesis, but their various functions and interactions make understanding their complex signaling challenging to study. Recent advancements in both the field of AD and Rho GTPase drug development provide novel tools for the elucidation of Rho GTPases as a viable target for AD. Herein, we summarize the fluctuating activity of Rho GTPases in various stages of AD pathogenesis and in several in vitro and in vivo AD models. We also review the current pharmacological tools such as NSAIDs, RhoA/ROCK, Rac1, and Cdc42 inhibitors used to target Rho GTPases and their use in AD-related studies. Finally, we summarize the behavioral modifications following Rho GTPase modulation in several AD mouse models. As key regulators of several AD-related signals, Rho GTPases have been studied as targets in AD. However, a consensus has yet to be reached regarding the stage at which targeting Rho GTPases would be the most beneficial. The studies discussed herein emphasize the critical role of Rho GTPases and the benefits of their modulation in AD

Predicting Pipeline Collapse Resistance

Much research has been performed over the past twenty-five years to refine our basic understanding of tubular stability, which includes bifurcation, imperfect systems, factors influencing tubular stability and post-buckling behaviour. Tubular instability resulting from load combinations is not a trivial topic, particularly when inelastic material behaviour occurs. Many influencing factors must be considered when attempting to understand (and predict) the onset of instability."/jats:p" "jats:p"Many existing collapse predictive methods are either simplistic or involve advanced plasticity or finite element methods. Simplistic methods are typically semi-empirical, and contain a degree of uncertainty resulting in conservative collapse predictions. Nonetheless, they are generally considered satisfactory for design purposes. Advanced methods normally involve high-end calculations using specialized software programs that might not be available for general use. Therefore, a relatively easy-to-use method that accurately predicts the actual collapse resistance is, in many cases, the most desirable option."/jats:p" "jats:p"This paper presents a collapse predictive methodology, developed from a variety of research projects performed over the last fifteen years. The prediction method, which can easily be entered into a spreadsheet program, is applicable to most forms of tubular members, including pipelines. Applicable load combinations include external pressure, axial tension and bending. An overview of the parameters influencing collapse resistance is also provided, including manufacturing history, material modelling, and tubular geometry and imperfections. Also presented is a summary of accuracy of the method to predict some test results. The test database largely contains results of collapse tests on tubular members subject to only external pressure, and axial tension with external pressure. The adaptation of the method to include external pressure with bending is summarized, and the accuracy of the prediction method is demonstrated by predicting the results of the Oman-India and Blue Stream pipeline collapse test programs, and comparing these predictions with those of other well known methodologies

OMAE2007-29493 LOCAL BUCKLING ASSESSMENTS FOR THE MEDGAZ PIPELINE

ABSTRACT Medgaz is a consortium of leading international energy companies, with the aim of designing, building and operating an Algerian-European gas pipeline via Spain. The offshore section of this pipeline will be 210 km long, traversing the Mediterranean Sea floor at a maximum depth of 2160 metres. The 24-inch diameter, grade X70 line will provide up to 8 billion cubic metres of natural gas per year, with first gas flow expected in 2009