Genomic landscapes and clonality of de novo AML

No abstract available

Genetic profiling in acute myeloid leukemia

No abstract available

BRD4 associates with p53 in DNMT3A-mutated leukemia cells and is implicated in apoptosis by the bromodomain inhibitor JQ1

The bromodomain and extra terminal (BET) family protein bromodomain containing protein 4 (BRD4) is an epigenetic regulator recently identified as a therapeutic target for several hematological cancers, notably mixed lineage leukemia-fusion acute myeloid leukemia (MLL-AML). Here, we show that the BRD4 bromodomain inhibitor JQ1 is highly active against the p53-wild-type Ontario Cancer Institute (OCI)-AML3 cell line which carries mutations in nucleophosmin (NPM1) and DNA methyltransferase 3 (DNMT3A) genes commonly associated with poor prognostic disease. We find that JQ1 causes caspase 3/7-mediated apoptosis and DNA damage response in these cells. In combination studies, we show that histone deacetylase (HDAC) inhibitors, the HDM2 inhibitor Nutlin-3, and the anthracycline daunorubicin all enhance the apoptotic response of JQ1. These compounds all induce activation of p53 suggesting that JQ1 might sensitize AML cells to p53-mediated cell death. In further experiments, we show that BRD4 associates with acetylated p53 but that this association is not inhibited by JQ1 indicating that the protein-protein interaction does not involve bromodomain binding of acetylated lysines. Instead, we propose that JQ1 acts to prevent BRD4-mediated recruitment of p53 to chromatin targets following its activation in OCI-AML3 cells resulting in cell cycle arrest and apoptosis in a c-MYC-independent manner. Our data suggest that BET bromodomain inhibition might enhance current chemotherapy strategies in AML, notably in poor-risk DNMT3A/NPM1-mutated disease

Understanding the progression of CML through the regulation of self-renewal and cell surface markers

No abstract available

Maintaining integrity in the face of death: the views and experiences of people affected by lung cancer in discussing preferences and wishes for end of life care

This thesis explores the views and experiences of people with lung cancer, and family members, of discussing preferences and wishes for end of life treatment and care. It presents an interpretive analysis based on the application of a constructivist grounded theory approach. Study participants included: eighteen men and seven women with lung cancer and nineteen family members. Participants were mainly from lower socio-economic groups living in the north of England. Single, joint and group interviews were used to gather data. Interview transcripts were analysed using a constant comparative method and conceptual models were drawn to aid the development of the theoretical interpretation. The study found that preferences and wishes for future care and treatment were not the main concern of people with cancer; rather, any concerns for the future were about the social aspects of death. Participants talked about their experiences of facing death whilst striving to live in the present. Planning for one’s own dying and eventual death was not something that people with lung cancer reported having discussed, except when, out of concern for their families, practical arrangements needed to be made following death. The disclosure of a poor prognosis had a huge emotional effect on participants, who ascribed a variety of meanings to this news. Participants’ reported that clinicians usually focused on their disease; they did not recall being offered any ‘options’ or ‘choices’ for future care. They commented that their preferences and wishes for future treatment and care were influenced by their clinician, spouse, other family members and their knowledge of others affected by cancer. The theory ‘maintaining integrity in the face of death’ is proposed. This theory purports that patients with advanced lung cancer and their families focus on acting and talking as ‘normal’ to help them balance living in the present whilst facing death. This thesis makes several contributions to knowledge. First, it provides the views of people from an underrepresented group of cancer patients from lower socioeconomic classes who are rarely included in research. Secondly, it shows how people facing the end of their life place little importance on choice. They focus instead on living in the present and carrying on as normal, which challenges current UK policy that seeks to promote individual patient choice at the end of life through advance care planning. The study findings suggest that policy makers and health and social care professionals need to develop ways of helping people prepare for a ‘social’ rather than a physical or ‘medicalised’ death: a focus on developing advance care planning that provides information to support people’s practical needs at the end of life, delivered as a family intervention, thereby helping people living with lung cancer to maintain their integrity in the face of death

Understanding the progression of CML through the regulation of self-renewal and cell surface markers

No abstract available

Maintaining integrity in the face of death: the views and experiences of people affected by lung cancer in discussing preferences and wishes for end of life care

This thesis explores the views and experiences of people with lung cancer, and family members, of discussing preferences and wishes for end of life treatment and care. It presents an interpretive analysis based on the application of a constructivist grounded theory approach. Study participants included: eighteen men and seven women with lung cancer and nineteen family members. Participants were mainly from lower socio-economic groups living in the north of England. Single, joint and group interviews were used to gather data. Interview transcripts were analysed using a constant comparative method and conceptual models were drawn to aid the development of the theoretical interpretation. The study found that preferences and wishes for future care and treatment were not the main concern of people with cancer; rather, any concerns for the future were about the social aspects of death. Participants talked about their experiences of facing death whilst striving to live in the present. Planning for one’s own dying and eventual death was not something that people with lung cancer reported having discussed, except when, out of concern for their families, practical arrangements needed to be made following death. The disclosure of a poor prognosis had a huge emotional effect on participants, who ascribed a variety of meanings to this news. Participants’ reported that clinicians usually focused on their disease; they did not recall being offered any ‘options’ or ‘choices’ for future care. They commented that their preferences and wishes for future treatment and care were influenced by their clinician, spouse, other family members and their knowledge of others affected by cancer. The theory ‘maintaining integrity in the face of death’ is proposed. This theory purports that patients with advanced lung cancer and their families focus on acting and talking as ‘normal’ to help them balance living in the present whilst facing death. This thesis makes several contributions to knowledge. First, it provides the views of people from an underrepresented group of cancer patients from lower socioeconomic classes who are rarely included in research. Secondly, it shows how people facing the end of their life place little importance on choice. They focus instead on living in the present and carrying on as normal, which challenges current UK policy that seeks to promote individual patient choice at the end of life through advance care planning. The study findings suggest that policy makers and health and social care professionals need to develop ways of helping people prepare for a ‘social’ rather than a physical or ‘medicalised’ death: a focus on developing advance care planning that provides information to support people’s practical needs at the end of life, delivered as a family intervention, thereby helping people living with lung cancer to maintain their integrity in the face of death

The psychological impact of COVID19 on a shielding high-risk cohort

No abstract available

Modelling the effect of beliefs about asthma medication and treatment intrusiveness on adherence and preference for once-daily vs. twice-daily medication

We thank the study participants whose data were used in this analysis. Medical writing support in the form of development of a draft outline and manuscript drafts in consultation with the authors, assembling tables and figures, collating author comments, copyediting, referencing and graphic services was provided by Jennifer Lawton, PhD, of Gardiner-Caldwell Communications, Macclesfield, UK, and was funded by GlaxoSmithKline. Study GHO-10-4705 is sponsored by GSK. These analyses were funded by GlaxoSmithKline (study GHO-10-4705) and supported by Spoonful of Sugar Ltd (A UCL Business spin out company). Sarah Chapman and Peter Dale were Employed by UCL School of Pharmacy at the time of involvement in this study. Gillian Stynes was employed by GSK at the time of involvement in this study. Previous presentations: These data were presented by S.C. in a poster at the European Respiratory Society 2016 Congress, and the abstract has been published: Chapman et al. Eur Respir J. 2016; 48 (Suppl 60): PA5018.Peer reviewedPublisher PD

Pilot trials in physical activity journals:a review of reporting and editorial policy

Background: Since the early 2000s, a number of publications in the medical literature have highlighted inadequacies in the design, conduct and reporting of pilot trials. This work led to two notable publications in 2016: a conceptual framework for defining feasibility studies and an extension to the CONSORT 2010 statement to include pilot trials. It was hoped that these publications would educate researchers, leading to better use of pilot trials and thus more rigorously planned and informed randomised controlled trials. The aim of the present work is to evaluate the impact of these publications in the field of physical activity by reviewing the literature pre- and post-2016. This first article presents the pre-2016 review of the reporting and the current editorial policy applied to pilot trials published in physical activity journals. Methods: Fourteen physical activity journals were screened for pilot and feasibility studies published between 2012 and 2015. The CONSORT 2010 extension to pilot and feasibility studies was used as a framework to assess the reporting quality of the studies. Editors of the eligible physical activity journals were canvassed regarding their editorial policy for pilot and feasibility studies. Results: Thirty-one articles across five journals met the eligibility criteria. These articles fell into three distinct categories: trials that were carried out in preparation for a future definitive trial (23%), trials that evaluated the feasibility of a novel intervention but did not explicitly address a future definitive trial (23%) and trials that did not have any clear objectives to address feasibility (55%). Editors from all five journals stated that they generally do not accept pilot trials, and none gave reference to the CONSORT 2010 extension as a guideline for submissions. Conclusion: The result that over half of the studies did not have feasibility objectives is in line with previous research findings, demonstrating that these findings are not being disseminated effectively to researchers in the field of physical activity. The low standard of reporting across most reviewed articles and the neglect of the extended CONSORT 2010 statement by the journal editors highlight the need to actively disseminate these guidelines to ensure their impact