Novel therapies for children with acute myeloid leukaemia

Significant improvements in survival for children with acute myeloid leukaemia (AML) have been made over the past three decades, with overall survival rates now approximately 60-70%. However, these gains can be largely attributed to more intensive use of conventional cytotoxics made possible by advances in supportive care, and although over 90% of children achieve remission with frontline therapy, approximately one third in current protocols relapse. Furthermore, late effects of therapy cause significant morbidity for many survivors. Novel therapies are therefore desperately needed. Early-phase paediatric trials of several new agents such as clofarabine, sorafenib and gemtuzumab ozogamicin have shown encouraging results in recent years. Due to the relatively low incidence of AML in childhood, the success of paediatric early-phase clinical trials is largely dependent upon collaborative clinical trial design by international cooperative study groups. Successfully incorporating novel therapies into frontline therapy remains a challenge, but the potential for significant improvement in the duration and quality of survival for children with AML is high

10-Year Resource Utilization and Costs for Cardiovascular Care

Background: Cardiovascular disease (CVD) imparts a heavy economic burden on the U.S. health care system. Evidence regarding the long-term costs after comprehensive CVD screening is limited. Objectives: This study calculated 10-year health care costs for 6,814 asymptomatic participants enrolled in MESA (Multi-Ethnic Study of Atherosclerosis), a registry sponsored by the National Heart, Lung, and Blood Institute, National Institutes of Health. Methods: Cumulative 10-year costs for CVD medications, office visits, diagnostic procedures, coronary revascularization, and hospitalizations were calculated from detailed follow-up data. Costs were derived by using Medicare nationwide and zip code–specific costs, inflation corrected, discounted at 3% per year, and presented in 2014 U.S. dollars. Results: Risk factor prevalence increased dramatically and, by 10 years, diabetes, hypertension, and dyslipidemia was reported in 19%, 57%, and 53%, respectively. Self-reported symptoms (i.e., chest pain or shortness of breath) were common (approximately 40% of enrollees). At 10 years, approximately one-third of enrollees reported having an echocardiogram or exercise test, whereas 7% underwent invasive coronary angiography. These utilization patterns resulted in 10-year health care costs of $23,142. The largest proportion of costs was associated with CVD medication use (78$2 of every $10 were spent for outpatient visits and diagnostic testing among the elderly, obese, those with a high-sensitivity C-reactive protein level \u3e3 mg/l, or coronary artery calcium score (CACS) ≥400. Costs varied widely from \u3c$7,700 for low-risk (Framingham risk score \u3c6%, 0 CACS, and normal glucose measurements at baseline) to \u3e$35,800 for high-risk (persons with diabetes, Framingham risk score ≥20$74 million of the $155 million consumed by MESA participants. Conclusions: Longitudinal patterns of health care resource use after screening revealed new evidence on the economic burden of treatment and testing patterns not previously reported. Maintenance of a healthy population has the potential to markedly reduce the economic burden of CVD among asymptomatic individuals

Learning is Like a Lava Lamp: The Student Journey to Critical Thinking

This paper explores the ways in which a university Foundation Degree programme supports undergraduate early years students to develop critical thinking, mindfulness and self-actualisation through their lived personal and professional experiences. It considers the impact of this on graduates employed within the Early Years sector. Findings inform future design of a University Foundation Degree programme situated within Early Childhood Education and Care (ECEC). As undergraduates, students engage in higher-level learning aligned to their practice within the workplace. An interpretive Participatory Qualitative Research methodology is used to gather the views of 6 alumni who completed their studies in 2014. They participated in the research freely within ethical parameters approved by a university ethics committee. Findings revealed that the development of critical thinking is empowered by having a personal or professional impetus, which in the case of Early Years is the child as being at the heart of values based practice. This, with the inclusion of mindfulness, drives students to a sustainable deeper layer of thinking to achieve self-actualisation. Through the acquisition of critical thinking students have been subsequently able to take up positions of authority within the early years workforce

Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton's tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML

Mapping Forbidden Emission to Structure in Self-Assembled Organic Nanoparticles

© 2018 American Chemical Society. The interplay between micromorphology and electronic properties is an important theme in organic electronic materials. Here, we show that a spirofluorene-functionalized boron-dipyrromethene (BODIPY) with an alkyl norbornyl tail self-assembles into nanoparticles with qualitatively different properties as compared to the polymerized species. Further, the nanoparticles exhibit a host of unique emissive properties, including photobrightening, a blue satellite peak, and spectral diffusion. Extensive photophysical characterization, including single-particle imaging and spectroscopy, and time-resolved fluorescence, coupled with electronic structure calculations based on an experimentally determined crystal structure, allow a mechanism to be developed. Specifically, BODIPY chromophores are observed to form quasi-two-dimensional layers, where stacking of unit cells adds either J-aggregate character or H-aggregate character depending on the direction of the stacking. Particularly strongly H-coupled domains show the rare process of emission from an upper exciton state, in violation of Kasha's rule, and result in the blue satellite peak. The spatial heterogeneity of structure thus maps onto a gradient of photophysical behavior as seen in single-particle imaging, and the temporal evolution of structure maps onto fluctuating emissive behavior, as seen in single-particle spectroscopy. Taken together, this system provides a striking example of how physical structure and electronic properties are intertwined, and a rare opportunity to use one to chart the other

Reframing professional development through understanding authentic professional learning

Continuing to learn is universally accepted and expected by professionals and other stakeholders across all professions. However, despite changes in response to research findings about how professionals learn, many professional development practices still focus on delivering content rather than enhancing learning. In exploring reasons for the continuation of didactic practices in professional development, this article critiques the usual conceptualization of professional development through a review of recent literature across professions. An alternative conceptualization is proposed, based on philosophical assumptions congruent with evidence about professional learning from seminal educational research of the past two decades. An argument is presented for a shift in discourse and focus from delivering and evaluating professional development programs to understanding and supporting authentic professional learning

Integrated nuclear proteomics and transcriptomics identifies S100A4 as a therapeutic target in acute myeloid leukemia

Inappropriate localization of proteins can interfere with normal cellular function and drive tumor development. To understand how this contributes to the development of acute myeloid leukemia (AML), we compared the nuclear proteome and transcriptome of AML blasts with normal human CD34+ cells. Analysis of the proteome identified networks and processes that significantly affected transcription regulation including misexpression of 11 transcription factors with seven proteins not previously implicated in AML. Transcriptome analysis identified changes in 40 transcription factors but none of these were predictive of changes at the protein level. The highest differentially expressed protein in AML nuclei compared with normal CD34+ nuclei (not previously implicated in AML) was S100A4. In an extended cohort, we found that over-expression of nuclear S100A4 was highly prevalent in AML (83%; 20/24 AML patients). Knock down of S100A4 in AML cell lines strongly impacted their survival whilst normal hemopoietic stem progenitor cells were unaffected. These data are the first analysis of the nuclear proteome in AML and have identified changes in transcription factor expression or regulation of transcription that would not have been seen at the mRNA level. These data also suggest that S100A4 is essential for AML survival and could be a therapeutic target in AML

Survey of Activated FLT3 Signaling in Leukemia

Activating mutations of FMS-like tyrosine kinase-3 (FLT3) are found in approximately 30% of patients with acute myeloid leukemia (AML). FLT3 is therefore an attractive drug target. However, the molecular mechanisms by which FLT3 mutations lead to cell transformation in AML remain unclear. To develop a better understanding of FLT3 signaling as well as its downstream effectors, we performed detailed phosphoproteomic analysis of FLT3 signaling in human leukemia cells. We identified over 1000 tyrosine phosphorylation sites from about 750 proteins in both AML (wild type and mutant FLT3) and B cell acute lymphoblastic leukemia (normal and amplification of FLT3) cell lines. Furthermore, using stable isotope labeling by amino acids in cell culture (SILAC), we were able to quantified over 400 phosphorylation sites (pTyr, pSer, and pThr) that were responsive to FLT3 inhibition in FLT3 driven human leukemia cell lines. We also extended this phosphoproteomic analysis on bone marrow from primary AML patient samples, and identify over 200 tyrosine and 800 serine/threonine phosphorylation sites in vivo. This study showed that oncogenic FLT3 regulates proteins involving diverse cellular processes and affects multiple signaling pathways in human leukemia that we previously appreciated, such as Fc epsilon RI-mediated signaling, BCR, and CD40 signaling pathways. It provides a valuable resource for investigation of oncogenic FLT3 signaling in human leukemia

Between text and stage: the theatrical adaptations of J.M. Coetzee’s Foe

Several of J.M. Coetzee’s novels have been adapted successfully for the stage, both as theatrical and operatic versions, but these adaptations have not received much critical attention. This article examines the ways in which Peter Glazer and Mark Wheatley have adapted Coetzee’s novel Foe (1986), resulting in two different and distinct stage productions, performed in the US and the UK respectively. In order to explore the complex relationship between the published text and the play versions, the article will ground itself in theories of adaptation, drawing extensively on work by Linda Hutcheon and Robert Stam and Alessandra Raengo. One of the key ideas in adaptation theory is that adaptive fidelity to the source text is neither possible nor desirable, but that adaptation is a more complex, multi-layered intertextual and intermedial interplay of fictional material. The article discusses the two play scripts and analyses the adaptive choices which underpin them and how these structure their meaning-making. Finally, the article also suggests that these scripts can be used to throw more light on Coetzee’s enigmatic novel.DHE