Targeting quiescent leukemic stem cells using second generation autophagy inhibitors

In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically approved autophagy inhibitor, does not consistently inhibit autophagy in cancer patients, so more potent autophagy inhibitors are needed. We generated a murine model of CML in which autophagic flux can be measured in bone marrow-located LSCs. In parallel, we use cell division tracing, phenotyping of primary CML cells, and a robust xenotransplantation model of human CML, to investigate the effect of Lys05, a highly potent lysosomotropic agent, and PIK-III, a selective inhibitor of VPS34, on the survival and function of LSCs. We demonstrate that long-term haematopoietic stem cells (LT-HSCs: Lin−Sca-1+c-kit+CD48−CD150+) isolated from leukemic mice have higher basal autophagy levels compared with non-leukemic LT-HSCs and more mature leukemic cells. Additionally, we present that while HCQ is ineffective, Lys05-mediated autophagy inhibition reduces LSCs quiescence and drives myeloid cell expansion. Furthermore, Lys05 and PIK-III reduced the number of primary CML LSCs and target xenografted LSCs when used in combination with TKI treatment, providing a strong rationale for clinical use of second generation autophagy inhibitors as a novel treatment for CML patients with LSC persistence

A study of patent thickets

Report analysing whether entry of UK enterprises into patenting in a technology area is affected by patent thickets in the technology area

Understanding individual experiences of cyberbullying encountered through work

This paper was accepted for publication in the journal International Journal of Organizational Theory and Behavior and the definitive published version is available at http://pracademics.com/attachments/article/17/Article%202_Heatherington%20Coyne.pdfLittle research has explored individual experiences of cyberbullying in working contexts. To start bridging the gap in our current understanding, we used Interpretative Phenomenological Analysis (IPA) to explore individuals’ shared experiences of cyberbullying encountered through work. In-depth interviews, conducted with five cyberbullied workers from the pharmaceutical, charity and university sectors, resulted in five superordinate themes: attributions of causality; crossing of boundaries; influence of communication media richness on relationship development; influence of communication explicitness and openness; and strategies for coping. Overall, some similarities emerged between cyberbullying experiences and traditional bullying research, yet the complexities associated with managing relationships, both virtually and physically, were central to individuals’ subjective experiences. Practical implications in developing effective leadership and business policies to support virtual groups and manage behaviours are discussed

C–H Functionalization Reactivity of a Nickel–Imide

This article discusses C-H functionalization reactivity of a Nickel-Imide

ICAR: endoscopic skull‐base surgery

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Obelix vs. Asterix : size of US commercial banks and its regulatory challenge

Big banks pose substantial costs to society in the form of increased systemic risk and government bailouts during crises. So the question is: Should regulators limit the size of banks? To answer this question, regulators need to assess the potential costs of such regulations. If big banks enjoy substantial scale economies (i.e., average costs get lower as bank size increases), limiting the size of banks through regulations may be inefficient and likely to reduce social welfare. However, the literature offers conflicting results regarding the existence of economies of scale for the biggest US banks. We contribute to this literature using a novel approach to estimating nonparametric measures of scale economies and total factor productivity (TFP) growth. For US commercial banks, we find that around 73 % of the top one hundred banks, 98 % of medium and small banks, and seven of the top ten biggest banks by asset size exhibit substantial economies of scale. Likewise, we find that scale economies contribute positively and significantly to their TFP growth. The existence of substantial scale economies raises an important challenge for regulators to pursue size limit regulations

Big Data Analytics for Wireless and Wired Network Design: A Survey

Currently, the world is witnessing a mounting avalanche of data due to the increasing number of mobile network subscribers, Internet websites, and online services. This trend is continuing to develop in a quick and diverse manner in the form of big data. Big data analytics can process large amounts of raw data and extract useful, smaller-sized information, which can be used by different parties to make reliable decisions. In this paper, we conduct a survey on the role that big data analytics can play in the design of data communication networks. Integrating the latest advances that employ big data analytics with the networks’ control/traffic layers might be the best way to build robust data communication networks with refined performance and intelligent features. First, the survey starts with the introduction of the big data basic concepts, framework, and characteristics. Second, we illustrate the main network design cycle employing big data analytics. This cycle represents the umbrella concept that unifies the surveyed topics. Third, there is a detailed review of the current academic and industrial efforts toward network design using big data analytics. Forth, we identify the challenges confronting the utilization of big data analytics in network design. Finally, we highlight several future research directions. To the best of our knowledge, this is the first survey that addresses the use of big data analytics techniques for the design of a broad range of networks