BCR-ABL1 tyrosine kinase sustained MECOM expression in chronic myeloid leukaemia

MECOM oncogene expression correlates with chronic myeloid leukaemia (CML) progression. Here we show that the knockdown of MECOM (E) and MECOM (ME) isoforms reduces cell division at low cell density, inhibits colony-forming cells by 34% and moderately reduces BCR-ABL1 mRNA and protein expression but not tyrosine kinase catalytic activity in K562 cells. We also show that both E and ME are expressed in CD34<sup>+</sup> selected cells of both CML chronic phase (CML-CP), and non-CML (normal) origin. Furthermore, MECOM mRNA and protein expression were repressed by imatinib mesylate treatment of CML-CP CD34<sup>+</sup> cells, K562 and KY01 cell lines whereas imatinib had no effect in non-CML BCR-ABL1 −ve CD34<sup>+</sup> cells. Together these results suggest that BCR-ABL1 tyrosine kinase catalytic activity regulates MECOM gene expression in CML-CP progenitor cells and that the BCR-ABL1 oncoprotein partially mediates its biological activity through MECOM. MECOM gene expression in CML-CP progenitor cells would provide an in vivo selective advantage, contributing to CML pathogenesis

Water security in times of climate change and intractability : Reconciling conflict by transforming security concerns into equity concerns

This paper considers how to achieve equitable water governance and the flow-on effects it has in terms of supporting sustainable development, drawing on case studies from the international climate change adaptation and governance project (CADWAGO). Water governance, like many other global issues, is becoming increasingly intractable (wicked) with climate change and is, by the international community, being linked to instances of threats to human security, thewar in the Sudanese Darfur and more recently the acts of terrorism perpetuated by ISIS. In this paper, we ask the question: how can situations characterized by water controversy (exacerbated by the uncertainties posed by climate change) be reconciled? The main argument is based on a critique of the way the water security discourse appropriates expert (normal) claims about human-biophysical relationships. When water challenges become increasingly securitized by the climate change discourse it becomes permissible to enact processes that legitimately transgress normative positions through post-normal actions. In contrast, the water equity discourse offers an alternative reading of wicked and post-normal water governance situations. We contend that by infusing norm critical considerations into the process of securitization, new sub-national constellations of agents will be empowered to enact changes; thereby bypassing vicious cycles of power brokering that characterize contemporary processes intended to address controversies

Local perceptions of climate change impacts and migration patterns in Malé, Maldives

For the last few decades, Maldives has been seen as being at the forefront of addressing climate change impacts. The low elevation of the islands makes them vulnerable to slow-onset hazards, such as coastal erosion, sea-level rise, salinity intrusion, and change in monsoon patterns and hence rainfall. Consequently, migration has long been discussed as an adaptation strategy for the population. This study covers outcomes from our field research conducted among islanders in Malé, the capital of Maldives, in 2013. It contributes empirical evidence toward understanding complex relations among environmental challenges, climate change, and migration. We set up two main research questions. The first question explored islanders' perceptions of impacts of climatic variability in recent years and possible impacts of future climate change. The second question probed whether out-migration from the islands might be considered to be an adaptation strategy and whether the islanders were willing to move outside Maldives due to projected climate change impacts. We conducted our field research in the capital Malé and nearby residential islands, using quantitative questionnaires with local respondents (N=347). Our results suggest that, besides a set of actually experienced environmental and climate challenges, slow-onset climate change impacts such as sea-level rise are perceived as being one of the key factors affecting Maldivian society and livelihoods. More than 50% of respondents perceive future sea-level rise to be a serious challenge at the national level and they accept that migration from islands to other countries might be a potential option. Conversely, from the individual perspective, sea-level rise is not perceived by the local population as being one of their own important challenges. The reason is that many other factors - cultural, religious, economic and social - play an important role in decisionmaking about migrating or not

Understanding the cancer stem cell

The last 15 years has seen an explosion of interest in the cancer stem cell (CSC). Although it was initially believed that only a rare population of stem cells are able to undergo self-renewing divisions and differentiate to form all populations within a malignancy, a recent work has shown that these cells may not be as rare as thought first, at least in some malignancies. Improved experimental models are beginning to uncover a less rigid structure to CSC biology, in which the concepts of functional plasticity and clonal evolution must be incorporated into the traditional models. Slowly the genetic programmes and biological processes underlying stem cell biology are being elucidated, opening the door to the development of drugs targeting the CSC. The aim of ongoing research to understand CSCs is to develop novel stem cell-directed treatments, which will reduce therapy resistance, relapse and the toxicity associated with current, non-selective agents

The Hemopoietic Stem Cell Niche Versus the Microenvironment of the Multiple Myeloma-Tumor Initiating Cell

Multiple myeloma cells are reminiscent of hemopoietic stem cells in their strict dependence upon the bone marrow microenvironment. However, from all other points of view, multiple myeloma cells differ markedly from stem cells. The cells possess a mature phenotype and secrete antibodies, and have thus made the whole journey to maturity, while maintaining a tumor phenotype. Not much credence was given to the possibility that the bulk of plasma-like multiple myeloma tumor cells is generated from tumor-initiating cells. Although interleukin-6 is a major contributor to the formation of the tumor’s microenvironment in multiple myeloma, it is not a major factor within hemopoietic stem cell niches. The bone marrow niche for myeloma cells includes the activity of inflammatory cytokines released through osteoclastogenesis. These permit maintenance of myeloma cells within the bone marrow. In contrast, osteoclastogenesis constitutes a signal that drives hemopoietic stem cells away from their bone marrow niches. The properties of the bone marrow microenvironment, which supports myeloma cell maintenance and proliferation, is therefore markedly different from the characteristics of the hemopoietic stem cell niche. Thus, multiple myeloma presents an example of a hemopoietic tumor microenvironment that does not resemble the corresponding stem cell renewal niche

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies

Beyond the ‘Migrant Network’? Exploring assistance received in the migration of brazilians to Portugal and the Netherlands

This paper explores the tenability of three important critiques to the ‘migrant network’ approach in migration studies: (1) the narrow focus on kin and community members, which connect prospective migrants in origin countries with immigrants in the destination areas, failing to take due account of sources of assistance beyond the ‘migrant network’ like institutional or online sources; (2) that it is misleading to assume a general pattern in the role of migrant networks in migration, regardless of contexts of arrival or departure, including the scale and history of migration or the immigration regime; and (3) that ‘migrant networks’ are not equally relevant to all migrants, and that important differences may exist between labour migrants and other types of migrants like family migrants or students. Drawing on survey data on the migration of Brazilians to Portugal and the Netherlands we find support for these critiques but also reaffirm the relevance of ‘migrant networks’.info:eu-repo/semantics/publishedVersio