Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm

Acute myeloid leukemia (AML) may follow a JAK2-positive myeloproliferative neoplasm (MPN), although the mechanisms of disease evolution, often involving loss of mutant JAK2, remain obscure. We studied 16 patients with JAK2-mutant (7 of 16) or JAK2 wild-type (9 of 16) AML after a JAK2-mutant MPN. Primary myelofibrosis or myelofibrotic transformation preceded all 7 JAK2-mutant but only 1 of 9 JAK2 wild-type AMLs (P = .001), implying that JAK2-mutant AML is preceded by mutation(s) that give rise to a "myelofibrosis" phenotype. Loss of the JAK2 mutation by mitotic recombination, gene conversion, or deletion was excluded in all wild-type AMLs. A search for additional mutations identified alterations of RUNX1, WT1, TP53, CBL, NRAS, and TET2, without significant differences between JAK2-mutant and wild-type leukemias. In 4 patients, mutations in TP53, CBL, or TET2 were present in JAK2 wild-type leukemic blasts but absent from the JAK2-mutant MPN. By contrast in a chronic-phase patient, clones harboring mutations in JAK2 or MPL represented the progeny of a shared TET2-mutant ancestral clone. These results indicate that different pathogenetic mechanisms underlie transformation to JAK2 wild-type and JAK2-mutant AML, show that TET2 mutations may be present in a clone distinct from that harboring a JAK2 mutation, and emphasize the clonal heterogeneity of the MPNs.

Comprehensive genomic screens identify a role for PLZF-RAR alpha as a positive regulator of cell proliferation via direct regulation of c-MYC

The t(11; 17)(q23;q21) translocation is associated with a retinoic acid (RA)-insensitive form of acute promyelocytic leukemia (APL), involving the production of reciprocal fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor alpha (PLZF-RAR alpha) and RAR alpha-PLZF. Using a combination of chromatin immuno-precipitation promotor arrays (ChIP-chip) and gene expression profiling, we identify novel, direct target genes of PLZF-RAR alpha that tend to be repressed in APL compared with other myeloid leukemias, supporting the role of PLZF-RAR alpha as an aberrant repressor in APL. In primary murine hematopoietic progenitors, PLZF-RAR alpha promotes cell growth, and represses Dusp6 and Cdkn2d, while inducing c-Myc expression, consistent with its role in leukemogenesis. PLZF-RAR alpha binds to a region of the c-MYC promoter overlapping a functional PLZF site and antagonizes PLZF-mediated repression, suggesting that PLZF-RAR alpha may act as a dominant-negative version of PLZF by affecting the regulation of shared targets. RA induced the differentiation of PLZF-RAR alpha-transformed murine hematopoietic cells and reduced the frequency of clonogenic progenitors, concomitant with c-Myc down-regulation. Surviving RA-treated cells retained the ability to be replated and this was associated with sustained c-Myc expression and repression of Dusp6, suggesting a role for these genes in maintaining a self-renewal pathway triggered by PLZF-RAR alpha. (Blood. 2009; 114: 5499-5511)

Synthesis and SAR of centrally active mGlu(5) positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold

This Letter describes the hit-to-lead progression and SAR of a series of biphenyl acetylene compounds derived from an HTS screening campaign targeting the mGlu(5) receptor. 'Molecular switches' were identified that modulated modes of pharmacology, and several compounds within this series were shown to be efficacious in reversal of amphetamine induced hyperlocomotion in rats after ip dosing, a preclinical model that shows similar positive effects with known antipsychotic agents. Published by Elsevier Ltd.

Realising political equality: the European Court of Human Rights and positive obligations in a democracy'

The European Convention on Human Rights (ECHR) speaks of the importance of an “effective political democracy” in its Preamble, though it is only in Article 3 of Protocol 1 (P1-3) that we find a right to free elections. This paper discusses the role of “positive obligations” under P1-3. This paper outlines the positive obligations in P1-3 focusing on obligations where the state is required to do more than just change the law. This may mean providing resources or facilities, adopting regulatory frameworks or creating new institutions. The paper highlights specific positive obligations that need to be further developed in the jurisprudence of the European Court of Human Rights (ECtHR). Sometimes these can be developed by analogy with positive obligations recognised in other areas of ECtHR jurisprudence. However, beyond these cases, states should ensure that members of vulnerable and disadvantaged minorities are able to participate in the electoral process and should ensure that dominant political groups cannot abuse their political power to exclude other parties unfairly. This is necessary to realise equal political rights. The second section of this paper sketches some preliminary points about the Strasbourg institutions’ approach to P1-3. After that, the third section identifies circumstances where the ECtHR should apply a more intense scrutiny in P1-3 cases. The fourth, fifth and sixth sections look at positive obligations relating to the right to vote, the right to run for election and the regulation of political parties.

Large acoustic solitons and double layers in plasmas with two positive ion species

Large nonlinear acoustic waves are discussed in a plasma made up of cold supersonic and adiabatic subsonic positive ions, in the presence of hot isothermal electrons, with the help of Sagdeev pseudopotential theory. In this model, no solitons are found at the acoustic speed, and no compositional parameter ranges exist where solutions of opposite polarities can coexist. All nonlinear modes are thus super-acoustic, but polarity changes are possible. The upper limits on admissible structure velocities come from different physical arguments, in a strict order when the fractional cool ion density is increased: infinite cold ion compression, warm ion sonic point, positive double layers, negative double layers, and finally, positive double layers again. However, not all ranges exist for all mass and temperature ratios. Whereas the cold and warm ion sonic point limitations are always present over a wide range of mass and temperature ratios, and thus positive polarity solutions can easily be obtained, double layers have a more restricted existence range, specially if polarity changes are sought. (C) 2011 American Institute of Physics. [doi:10.1063/1.3579397]

The Evolution of European Identity: Using biographical methods to study the development of European identity

Based upon the original application to the European Commission, this article gives insights into the thinking of the Euroidentities team at the point that the project began. The question: “Is the European ‘identity project’ failing?” is posed in the sense that the political and economic attainments of the European Union have not been translated into a sense of identity with or commitment to Europe from the populaces that have benefited from them. The urgency of European ‘identity work’ is asserted with a number of levels for the construction of European identity being hypothesized. Euroidentities is intended to break conceptual ground by bringing together on an equal footing two apparently antagonistic views of identity -- the collective and institutional and the individual and biographical – to give a more anchored and nuanced view of identity formation and transformation than either can provide on its own. Rather than following the dominant approaches to research on European identity that have been macro-theoretical and ‘top-down’, retrospective in-depth qualitative biographical interviews are planned since they provide the ideal means of gaining insight into the formation of a European identity or multiple identities from the ‘bottom up’ perspective of non-elite groups. The reliability of analysis will be buttressed by the use of contrastive comparison between cases, culminating in contrastive comparison across the national project teams between cases drawn from different ‘sensitized groups’ that provide the fieldwork structure of the project. The paper concludes with a summary of some of the more significant findings.

Associations between Mothers' Experiences with the Troubles in Northern Ireland and Mothers' and Childrens' Psychological Functioning: The Moderating Role of Social Identity.

Relatively little research has examined the relations between growing up in a community with a history of protracted violent political conflict and subsequent generations' well-being. The current article examines relations between mothers' self-report of the impact that the historical political violence in Northern Ireland (known, as the Troubles) has on her and her child's current mental health. These relations are framed within the social identity model of stress, which provides a framework for understanding coping responses within societies that have experienced intergroup conflict. Mother-child dyads (N = 695) living in Belfast completed interviews. Results suggest that the mother-reported impact of the Troubles continue to be associated with mothers' mental health, which, in, turn, is associated with her child's adjustment. The strength of mothers' social identity moderated pathways between the impact of the Troubles and her mental health, consistent with the social identity model of stress. (C) 2010 Wiley Periodicals, Inc.

The Battle of the Somme in Ulster memory and identity

One of the enduring illusions about Northern Ireland is that its society can be conceptualized through a binary distinction between protestant and catholic. unionist and nationalist. It is increasingly apparent that these broad domains are themselves fractured and diverse and that otherness is often conceived from within rather than without. Northern Ireland can also be viewed as a laboratory for identity formation as unionists and loyalists strive to reconcile themselves with the fundamental political changes that have followed in the wake of the Peace Process. This paper considers one aspect of the contestation of belonging that increasingly characterizes unionism. It examines the competition for the ownership of the mythology of the Battle of the Somme ( 1916), long a key event in the unionist narrative. In particular, the paper addresses the ways in which paramilitary organizations are using the Somme to legitimate their own activities but also to distance the loyalist working classes from the former hegemonic Britishness of official unionism and the sectarianism of the Orange Order. The analysis concludes that loyalist identity is being conceptualized thorough a narrative of betrayal from within and at an intensely localized scale.