Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32)

The BCR-ABL1 fusion kinase is frequently associated with chronic myeloid leukemia and B-cell acute lymphoblastic leukemia but is rare in T-cell acute lymphoblastic leukemia (T-ALL). We recently identified NUP214-ABL1 as a variant ABL1 fusion gene in 6% of T-ALL patients. Here we describe the identification of another ABL1 fusion, EML1-ABL1, in a T-ALL patient with a cryptic t(9;14)(q34;q32) associated with deletion of CDKN2A (p16) and expression of TLX1 (HOX11). Echinoderm microtubule-associated protein-like 1-Abelson 1 (EML1-ABL1) is a constitutively phosphorylated tyrosine kinase that transforms Ba/F3 cells to growth factor-independent growth through activation of survival and proliferation pathways, including extracellular signal-related kinase 1/2 (Erk1/2), signal transducers and activators of transcription 5 (Stat5), and Lyn kinase. Deletion of the coiled-coil domain of EML1 abrogated the transforming properties of the fusion kinase. EML1-ABL1 and breakpoint cluster region (BCR)-ABL1 were equally sensitive to the tyrosine kinase inhibitor imatinib. These data further demonstrate the involvement of ABL1 fusions in the pathogenesis of T-ALL and identify EML1-ABL1 as a novel therapeutic target of imatinib

Short communication:Identifying key parameters for modelling the impacts of livestock health conditions on greenhouse gas emissions

Improved animal health can reduce greenhouse gas (GHG) emissions intensity in livestock systems while increasing productivity. Integrated modelling of disease impacts on farm-scale emissions is important in identifying effective health strategies to reduce emissions. However, it requires that modellers understand the pathways linking animal health to emissions and how these might be incorporated into models. A key barrier to meeting this need has been the lack of a framework to facilitate effective exchange of knowledge and data between animal health experts and emissions modellers. Here, these two communities engaged in workshops, online exchanges and a survey to i) identify a comprehensive list of disease-related model parameters and ii) test its application to evaluating models. Fifty-six parameters were identified and proved effective in assessing the potential of farm-scale models to characterise livestock disease impacts on GHG emissions. Easy wins for the emissions models surveyed include characterising disease impacts related to feeding

To what extent is climate change adaptation a novel challenge for agricultural modellers?

Modelling is key to adapting agriculture to climate change (CC), facilitating evaluation of the impacts and efficacy of adaptation measures, and the design of optimal strategies. Although there are many challenges to modelling agricultural CC adaptation, it is unclear whether these are novel or, whether adaptation merely adds new motivations to old challenges. Here, qualitative analysis of modellers’ views revealed three categories of challenge: Content, Use, and Capacity. Triangulation of findings with reviews of agricultural modelling and Climate Change Risk Assessment was then used to highlight challenges specific to modelling adaptation. These were refined through literature review, focussing attention on how the progressive nature of CC affects the role and impact of modelling. Specific challenges identified were: Scope of adaptations modelled, Information on future adaptation, Collaboration to tackle novel challenges, Optimisation under progressive change with thresholds, and Responsibility given the sensitivity of future outcomes to initial choices under progressive change

The effects of stimulus complexity on the preattentive processing of self-generated and nonself voices: an ERP study

The ability to differentiate one's own voice from the voice of somebody else plays a critical role in successful verbal self-monitoring processes and in communication. However, most of the existing studies have only focused on the sensory correlates of self-generated voice processing, whereas the effects of attentional demands and stimulus complexity on self-generated voice processing remain largely unknown. In this study, we investigated the effects of stimulus complexity on the preattentive processing of self and nonself voice stimuli. Event-related potentials (ERPs) were recorded from 17 healthy males who watched a silent movie while ignoring prerecorded self-generated (SGV) and nonself (NSV) voice stimuli, consisting of a vocalization (vocalization category condition: VCC) or of a disyllabic word (word category condition: WCC). All voice stimuli were presented as standard and deviant events in four distinct oddball sequences. The mismatch negativity (MMN) ERP component peaked earlier for NSV than for SGV stimuli. Moreover, when compared with SGV stimuli, the P3a amplitude was increased for NSV stimuli in the VCC only, whereas in the WCC no significant differences were found between the two voice types. These findings suggest differences in the time course of automatic detection of a change in voice identity. In addition, they suggest that stimulus complexity modulates the magnitude of the orienting response to SGV and NSV stimuli, extending previous findings on self-voice processing.This work was supported by Grant Numbers IF/00334/2012, PTDC/PSI-PCL/116626/2010, and PTDC/MHN-PCN/3606/2012, funded by the Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) and the Fundo Europeu de Desenvolvimento Regional through the European programs Quadro de Referencia Estrategico Nacional and Programa Operacional Factores de Competitividade, awarded to A.P.P., and by FCT Doctoral Grant Number SFRH/BD/77681/2011, awarded to T.C.info:eu-repo/semantics/publishedVersio

Modelling Adaptation to climate change in agricultural systems

Modelling agricultural adaptation to climate change presents a range of challenges for modellers, but is vital to enabling decision makers to understand the potential costs and benefits of applying adaptation measures on-farm (or not) including risks and uncertainties associated with different actions. Here, the first stages of collaborative work undertaken at a workshop held in Braunschweig, Germany in autumn 2015, and subsequent analysis of findings, are reported. Subsequently, a second report will detail the development of these actions into a coherent overview of the state-of-the-art in modelling adaptation. Modellers and experimental researchers from a variety of disciplines (including biophysical and economic modellers from livestock, crop and grassland systems backgrounds) were asked to consider major climate impacts and associated adaptation options, and the challenges to modelling adaptations. Key modelling challenges fell into four main categories: information availability, accessibility of model outputs for stakeholders, technical challenges, and knowledge gaps. Within these categories, lists of specific challenges were compiled. The workshop revealed the diversity of approaches to modelling adaptation, and highlighted the different challenges associated with biophysical versus economic modelling. Understanding the state-of-the-art and key priorities for the modelling of climate change adaptation in agriculture is shown to be a complex and multi-faceted challenge. However, such an overview would provide a road map for stakeholder-driven improvement in modelling, with the potential to inform increased uptake of adaptation measures on-farm in Europe.(The main text will be published in a peer-reviewed journal

miR-15a-5p and miR-21-5p contribute to chemoresistance in cytogenetically normal acute myeloid leukaemia by targeting PDCD4, ARL2 and BTG2

Cytarabine and daunorubicin are old drugs commonly used in the treatment of acute myeloid leukaemia (AML). Refractory or relapsed disease because of chemotherapy resistance is a major issue. microRNAs (miRNAs) were incriminated in resistance. This study aimed to identify miRNAs involved in chemoresistance in AML patients and to define their target genes. We focused on cytogenetically normal AML patients with wild-type NPM1 without FLT3-ITD as the treatment of this subset of patients with intermediate-risk cytogenetics is not well established. We analysed baseline AML samples by small RNA sequencing and compared the profile of chemoresistant to chemosensitive AML patients. Among the miRNAs significantly overexpressed in chemoresistant patients, we revealed miR-15a-5p and miR-21-5p as miRNAs with a major role in chemoresistance in AML. We showed that miR-15a-5p and miR-21-5p overexpression decreased apoptosis induced by cytarabine and/or daunorubicin. PDCD4, ARL2 and BTG2 genes were found to be targeted by miR-15a-5p, as well as PDCD4 and BTG2 by miR-21-5p. Inhibition experiments of the three target genes reproduced the functional effect of both miRNAs on chemosensitivity. Our study demonstrates that miR-15a-5p and miR-21-5p are overexpressed in a subgroup of chemoresistant AML patients. Both miRNAs induce chemoresistance by targeting three pro-apoptotic genes PDCD4, ARL2 and BTG2

Transient Responses to NOTCH and TLX1/HOX11 Inhibition in T-Cell Acute Lymphoblastic Leukemia/Lymphoma

To improve the treatment strategies of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), further efforts are needed to identify therapeutic targets. Dysregulated expression of HOX-type transcription factors occurs in 30–40% of cases of T-ALL. TLX1/HOX11 is the prototypical HOX-type transcription factor. TLX1 may be an attractive therapeutic target because mice that are deficient in TLX1 are healthy. To test this possibility, we developed a conditional doxycycline-regulated mouse model of TLX1-initiated T-ALL. TLX1 induced T-ALL after ∼5–7 months with penetrance of 15–60%. Similar to human TLX1-type T-ALLs, the TLX1-induced tumors were arrested at the cortical stage of T-cell development and acquired activating NOTCH1 mutations. Inhibition of NOTCH signaling abrogated growth of cell lines derived from the TLX1-induced tumors. NOTCH inhibition also transiently delayed leukemia progression in vivo. Suppression of TLX1 expression slowed the growth of TLX1 tumor cell lines. Suppression of TLX1 in vivo also transiently delayed leukemia progression. We have shown that TLX1 functions as a T-cell oncogene that is active during both the induction and the maintenance phases of leukemia. However, the effect of suppressing NOTCH or TLX1 was transient. The tumors eventually “escaped” from inhibition. These data imply that the biological pathways and gene sets impacted by TLX1 and NOTCH have largely lost their importance in the fully established tumor. They have been supplanted by stronger oncogenic pathways. Although TLX1 or NOTCH inhibitors may not be effective as single agents, they may still contribute to combination therapy for TLX1-driven acute leukemia

Effects of Electrical and Structural Remodeling on Atrial Fibrillation Maintenance: A Simulation Study

Atrial fibrillation, a common cardiac arrhythmia, often progresses unfavourably: in patients with long-term atrial fibrillation, fibrillatory episodes are typically of increased duration and frequency of occurrence relative to healthy controls. This is due to electrical, structural, and contractile remodeling processes. We investigated mechanisms of how electrical and structural remodeling contribute to perpetuation of simulated atrial fibrillation, using a mathematical model of the human atrial action potential incorporated into an anatomically realistic three-dimensional structural model of the human atria. Electrical and structural remodeling both shortened the atrial wavelength - electrical remodeling primarily through a decrease in action potential duration, while structural remodeling primarily slowed conduction. The decrease in wavelength correlates with an increase in the average duration of atrial fibrillation/flutter episodes. The dependence of reentry duration on wavelength was the same for electrical vs. structural remodeling. However, the dynamics during atrial reentry varied between electrical, structural, and combined electrical and structural remodeling in several ways, including: (i) with structural remodeling there were more occurrences of fragmented wavefronts and hence more filaments than during electrical remodeling; (ii) dominant waves anchored around different anatomical obstacles in electrical vs. structural remodeling; (iii) dominant waves were often not anchored in combined electrical and structural remodeling. We conclude that, in simulated atrial fibrillation, the wavelength dependence of reentry duration is similar for electrical and structural remodeling, despite major differences in overall dynamics, including maximal number of filaments, wave fragmentation, restitution properties, and whether dominant waves are anchored to anatomical obstacles or spiralling freely

In Vitro Transformation of Primary Human CD34+ Cells by AML Fusion Oncogenes: Early Gene Expression Profiling Reveals Possible Drug Target in AML

Different fusion oncogenes in acute myeloid leukemia (AML) have distinct clinical and laboratory features suggesting different modes of malignant transformation. Here we compare the in vitro effects of representatives of 4 major groups of AML fusion oncogenes on primary human CD34+ cells. As expected from their clinical similarities, MLL-AF9 and NUP98-HOXA9 had very similar effects in vitro. They both caused erythroid hyperplasia and a clear block in erythroid and myeloid maturation. On the other hand, AML1-ETO and PML-RARA had only modest effects on myeloid and erythroid differentiation. All oncogenes except PML-RARA caused a dramatic increase in long-term proliferation and self-renewal. Gene expression profiling revealed two distinct temporal patterns of gene deregulation. Gene deregulation by MLL-AF9 and NUP98-HOXA9 peaked 3 days after transduction. In contrast, the vast majority of gene deregulation by AML1-ETO and PML-RARA occurred within 6 hours, followed by a dramatic drop in the numbers of deregulated genes. Interestingly, the p53 inhibitor MDM2 was upregulated by AML1-ETO at 6 hours. Nutlin-3, an inhibitor of the interaction between MDM2 and p53, specifically inhibited the proliferation and self-renewal of primary human CD34+ cells transduced with AML1-ETO, suggesting that MDM2 upregulation plays a role in cell transformation by AML1-ETO. These data show that differences among AML fusion oncogenes can be recapitulated in vitro using primary human CD34+ cells and that early gene expression profiling in these cells can reveal potential drug targets in AML