EWS-FLI1 Utilizes Divergent Chromatin Remodeling Mechanisms to Directly Activate or Repress Enhancer Elements in Ewing Sarcoma

SummaryThe aberrant transcription factor EWS-FLI1 drives Ewing sarcoma, but its molecular function is not completely understood. We find that EWS-FLI1 reprograms gene regulatory circuits in Ewing sarcoma by directly inducing or repressing enhancers. At GGAA repeat elements, which lack evolutionary conservation and regulatory potential in other cell types, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors. These divergent chromatin-remodeling patterns repress tumor suppressors and mesenchymal lineage regulators while activating oncogenes and potential therapeutic targets, such as the kinase VRK1. Our findings demonstrate how EWS-FLI1 establishes an oncogenic regulatory program governing both tumor survival and differentiation

The ‘vicious cycle’ of personalised asthma action plan implementation in primary care: a qualitative study of patients and health professionals’ views

Background: Personal asthma action plans (PAAPs) have been guideline recommended for years, but consistentlyunder-issued by health professionals and under-utilised by patients. Previous studies have investigated sub-optimalPAAP implementation but more insight is needed into barriers to their use from the perspective of professionals,patients and primary care teams.Methods: A maximum variation sample of professional and patient participants were recruited from five demographicallydiverse general practices and another group of primary care professionals in one Scottish region. Interviews were digitallyrecorded and data thematically analysed using NVivo.Results: Twenty-nine semi-structured interviews were conducted (11 adults with asthma, seven general practitioners, tenpractice nurses, one hospital respiratory nurse). Three over-arching themes emerged: 1) patients generally do not valuePAAPs, 2) professionals do not fully value PAAPs and, 3) multiple barriers reduce the value of PAAPs in primary care. Sixpatients had a PAAP but these were outdated, not reflecting their needs and not used. Patients reported not wanting orneeding PAAPs, yet identified circumstances when these could be useful. Fifteen professionals had selectively issuedPAAPs with eight having reviewed one. Many professionals did not value PAAPs as they did not see patients using theseand lacked awareness of times when patients could have benefited from one. Multi-level compounding barriers emerged.Individual barriers included poor patient awareness and professionals not reinforcing PAAP use. Organisational barriersincluded professionals having difficulty accessing PAAP templates and fragmented processes including patients not beingasked to bring PAAPs to their asthma appointments.Conclusions: Primary care PAAP implementation is in a vicious cycle. Professionals infrequently review/update PAAPswith patients; patients with out-dated PAAPs do not value or use these; professionals observing patients’ lack of interestin PAAPs do not discuss these. Patients observing this do not refer to their plans and perceive them to be of little valuein asthma self-management. Twenty-five years after PAAPs were first recommended, primary care practices are still notready to support their implementation. Breaking this vicious cycle to create a healthcare context more conducive to PAAPimplementation requires a whole systems approach with multi-faceted interventions addressing patient, professional andorganisational barriers

Vitamin d status predicts 30 day mortality in hospitalised cats

Vitamin D insufficiency, defined as low serum concentrations of the major circulating form of vitamin D, 25 hydroxyvitamin D (25(OH)D), has been associated with the development of numerous infectious, inflammatory, and neoplastic disorders in humans. In addition, vitamin D insufficiency has been found to be predictive of mortality for many disorders. However, interpretation of human studies is difficult since vitamin D status is influenced by many factors, including diet, season, latitude, and exposure to UV radiation. In contrast, domesticated cats do not produce vitamin D cutaneously, and most cats are fed a commercial diet containing a relatively standard amount of vitamin D. Consequently, domesticated cats are an attractive model system in which to examine the relationship between serum 25(OH)D and health outcomes. The hypothesis of this study was that vitamin D status would predict short term, all-cause mortality in domesticated cats. Serum concentrations of 25(OH)D, together with a wide range of other clinical, hematological, and biochemical parameters, were measured in 99 consecutively hospitalised cats. Cats which died within 30 days of initial assessment had significantly lower serum 25(OH)D concentrations than cats which survived. In a linear regression model including 12 clinical variables, serum 25(OH)D concentration in the lower tertile was significantly predictive of mortality. The odds ratio of mortality within 30 days was 8.27 (95% confidence interval 2.54-31.52) for cats with a serum 25(OH)D concentration in the lower tertile. In conclusion, this study demonstrates that low serum 25(OH)D concentration status is an independent predictor of short term mortality in cats