1,039 research outputs found
Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML
Pharmacological targeting of BTK using ibrutinib has recently shown encouraging clinical activity in a range of lymphoid malignancies. Recently we reported that ibrutinib inhibits human acute myeloid leukemia (AML) blast proliferation and leukemic cell adhesion to the surrounding bone marrow stroma cells. Here we report that in human AML ibrutinib, in addition, functions to inhibit SDF1/CXCR4-mediated AML migration at concentrations achievable in vivo. It has previously been shown that SDF1/CXCR4-induced migration is dependent on activation of downstream BTK in chronic lymphocytic leukaemia (CLL) and multiple myeloma. Here we show that SDF-1 induces BTK phosphorylation and downstream MAPK signalling in primary AML blast. Furthermore, we show that ibrutinib can inhibit SDF1-induced AKT and MAPK activation. These results reported here provide a molecular mechanistic rationale for clinically evaluating BTK inhibition in AML patients and suggests that in some AML patients the blasts count may initially rise in response to ibrutinib therapy, analgous to similar clinical observations in CLL
Ventromedial Prefrontal and Anterior Cingulate Cortex Adopt Choice and Default Reference Frames during Sequential Multi-Alternative Choice
Although damage to the medial frontal cortex causes profound decision-making impairments, it has been difficult to pinpoint the relative
contributions of key anatomical subdivisions. Here we use function magnetic resonance imaging to examine the contributions of human
ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (dACC) during sequential choices between multiple alternatives—
two key features of choices made in ecological settings. By carefully constructing options whose current value at any given
decision was dissociable from their longer term value, we were able to examine choices in current and long-term frames of reference. We
present evidence showing that activity at choice and feedback in vmPFC and dACC was tied to the current choice and the best long-term
option, respectively. vmPFC, mid-cingulate, and posterior cingulate cortex encoded the relative value between the chosen and next best
option at each sequential decision, whereas dACC encoded the relative value of adapting choices from the option with the highest value in
the longer term. Furthermore, at feedback we identify temporally dissociable effects that predict repetition of the current choice and
adaptation away from the long-term best option in vmPFC and dACC, respectively. These functional dissociations at choice and feedback
suggest that sequential choices are subject to competing cortical mechanisms
The bone marrow microenvironment – Home of the leukemic blasts
Acute Myeloid Leukaemia (AML) is a genetically, biologically and clinically heterogeneous set of diseases, which are characterised by an increased growth of abnormal myeloid progenitor cells within the bone marrow (BM). Ex-vivo AML exhibits a high level of spontaneous apoptosis. Furthermore, relapse for patients achieving remission occurs from minimal residual disease harboured within the BM microenvironment. Taken together, these observations illustrate the importance of the BM microenvironment in sustaining AML. While significant progress has been made elaborating the small-scale genetic mutations and larger-scale chromosomal translocations that contribute to the development of AML and its prognosis in response to treatment, less is understood about the complex microenvironment of the BM, which is known to be a key player in the pathogenesis of the disease. As we look towards future therapies, the consideration that the BM microenvironment is uniquely important as a niche for AML - coupled with the idea that leukaemic blasts are more likely to be genetically unstable and therefore evolve resistance to conventional chemotherapies - make the functions of the non-malignant cells of the BM attractive targets for therapy. In this review, we discuss the microanatomy of the BM and provide an overview of the evidence supporting the role of the BM microenvironment in creating conditions conducive to the survival and proliferation of AML blasts. Ultimately, we examine the therapeutic potential of uncoupling AML from the BM microenvironment
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-ÎşB 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
Access to medicines in remote and rural areas: a survey of residents in the Scottish Highlands and Western Isles.
Objectives: Sparsely populated areas are potentially predisposed to health inequalities due to limited access to services. This study aimed to explore and describe issues of access to medicines and related advice experienced by residents of the Scottish Highlands and Western Isles. Study design: Cross-sectional cohort study. Methods: Anonymized questionnaires were mailed to a random sample of 6000 residents aged ≥18 years identified from the electoral register. The questionnaire contained items on: access to medicines; interactions with health care services; and perceptions of the services. Results were analysed using descriptive, inferential and spatial statistics. Results: Adjusted response rate was 49.5% (2913/5889). Almost two thirds (63.4%, 1847) were prescribed medicines regularly, 88.5% (1634) of whom considered the source convenient. Pharmacy (73.8%, 1364) or dispensing GP (24.0%, 443) were the most accessed sources. Prescription medicine advice was mainly obtained from the GP (55.7%, 1029). Respondents ≥80 years old were significantly (P0.0001) more likely to live alone (45.3%, 92) compared with those 80 (15.8%, 424). Almost a fifth (16.5%, 31) of those 80 years living alone disagreed that they obtained prescribed medicines from a convenient source. The majority of respondents who felt they did not have a convenient medicines source, regardless of urban/rural classification, lived within five miles of a pharmacy or GP practice. Conclusions: Respondents accessed medicines and advice from a variety of sources. While most considered their access to medicines convenient, there were issues for those over 80 years and living alone. Perceived convenience would not appear to be solely based on geographical proximity to supply source. This requires further exploration given that these individuals are likely to have long-term conditions and be prescribed medicines on a chronic basis
NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival
Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics
Recurrent nocturnal hypoglycaemia as a cause of morning fatigue in treated Addison’s disease – Favourable response to dietary management: A case report
Background: Addison’s disease, or primary adrenal insufficiency, is often associated with reduced well-being and fatigue despite use of currently recommended adrenal hormone replacement. Hypoglycaemia is a known manifestation of glucocorticoid deficiency, but is generally considered rare in adults and not relevant to troubling ongoing symptoms in patients with Addison’s disease.
Case presentation: A 43 year old woman with a three year history of Addison’s disease complained of severe morning fatigue and headaches, despite standard glucocorticoid replacement therapy in the form of thrice daily hydrocortisone and mineralocorticoid replacement with fludrocortisone. Alternative glucocorticoid replacement regimens and the addition of dehydroepiandrosterone replacement therapy had no effect. Nocturnal hypoglycaemia was suspected and a 4-day continuous glucose monitor system (CGMS) revealed hypoglycaemia (interstitial glucose \u3c 2.2mmol/L) between 0200–0400 h on 3 of 4 days. The patient was counselled to take an evening snack designed to ensure slow absorption of ingested carbohydrates. Nocturnal hypoglycaemia was then absent on follow up CGMS assessment. The patient noted a marked symptomatic improvement in morning symptoms, but with persistent fatigue during the day.
Conclusion: Currently, the best strategy for control of non-specific symptoms in treated Addison’s disease is unknown, but it may be that investigation for hypoglycaemia and treatment, where necessary, could assist some sufferers to achieve improved wellbeing. A systematic study of this phenomenon in Addison’s disease is required
Causal role of a neural system for separating and selecting multidimensional social cognitive information
People are multi-faceted, typically good at some things but bad at others, and a critical aspect of social judgement is the ability to focus on those traits relevant for the task at hand. However, it remains unknown how the brain supports such context-dependent social judgement. Here, we examine how people represent multidimensional individuals, and how the brain extracts relevant information and filters out irrelevant information when comparing individuals within a specific dimension. Using human fMRI, we identify distinct neural representations in dorsomedial prefrontal cortex (dmPFC) and anterior insula (AI) supporting separation and selection of information for context-dependent social judgement. Causal evaluation using non-invasive brain stimulation shows that AI disruption alters the impact of relevant information on social comparison, whereas dmPFC disruption only affects the impact of irrelevant information. This neural circuit is distinct from the one supporting integration across, as opposed to separation of, different features of a multidimensional cognitive space
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