The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia

The oncogenic transcription factor TAL1/SCL is aberrantly expressed in 60% of cases of human T cell acute lymphoblastic leukemia (T-ALL) and initiates T-ALL in mouse models. By performing global microRNA (miRNA) expression profiling after depletion of TAL1, together with genome-wide analysis of TAL1 occupancy by chromatin immunoprecipitation coupled to massively parallel DNA sequencing, we identified the miRNA genes directly controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. The most dynamically regulated miRNA was miR-223, which is bound at its promoter and up-regulated by the TAL1 complex. miR-223 expression mirrors TAL1 levels during thymic development, with high expression in early thymocytes and marked down-regulation after the double-negative-2 stage of maturation. We demonstrate that aberrant miR-223 up-regulation by TAL1 is important for optimal growth of TAL1-positive T-ALL cells and that sustained expression of miR-223 partially rescues T-ALL cells after TAL1 knockdown. Overexpression of miR-223 also leads to marked down-regulation of FBXW7 protein expression, whereas knockdown of TAL1 leads to up-regulation of FBXW7 protein levels, with a marked reduction of its substrates MYC, MYB, NOTCH1, and CYCLIN E. We conclude that TAL1-mediated up-regulation of miR-223 promotes the malignant phenotype in T-ALL through repression of the FBXW7 tumor suppressor

The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia

The oncogenic transcription factor TAL1/SCL is aberrantly expressed in 60% of cases of human T cell acute lymphoblastic leukemia (T-ALL) and initiates T-ALL in mouse models. By performing global microRNA (miRNA) expression profiling after depletion of TAL1, together with genome-wide analysis of TAL1 occupancy by chromatin immunoprecipitation coupled to massively parallel DNA sequencing, we identified the miRNA genes directly controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. The most dynamically regulated miRNA was miR-223, which is bound at its promoter and up-regulated by the TAL1 complex. miR-223 expression mirrors TAL1 levels during thymic development, with high expression in early thymocytes and marked down-regulation after the double-negative-2 stage of maturation. We demonstrate that aberrant miR-223 up-regulation by TAL1 is important for optimal growth of TAL1-positive T-ALL cells and that sustained expression of miR-223 partially rescues T-ALL cells after TAL1 knockdown. Overexpression of miR-223 also leads to marked down-regulation of FBXW7 protein expression, whereas knockdown of TAL1 leads to up-regulation of FBXW7 protein levels, with a marked reduction of its substrates MYC, MYB, NOTCH1, and CYCLIN E. We conclude that TAL1-mediated up-regulation of miR-223 promotes the malignant phenotype in T-ALL through repression of the FBXW7 tumor suppressor.National Cancer Institute (U.S.) (5P01CA109901)National Cancer Institute (U.S.) (5P01CA68484)National Cancer Institute (U.S.) (1K99CA157951)National Institutes of Health (U.S.). Intramural Research ProgramCenter for Cancer Research (National Cancer Institute (U.S.)

Local men local communities : a rural placed-based approach to increase men's engagement with mental health training and events

Issue Addressed: Suicide is the leading cause of death for Australians aged 15–49 (Department of Health and Aged Care Suicide in Australia, https://www.health.gov.au/health-topics/mental-health-and-suicide-prevention/suicide-in-australia, 2021). With the loss of one community member impacting the individual's family, friends, and wider community. The aim of the article is to showcase a process evaluation of a place-based approach to suicide prevention, exploring the elements of mental health training and events that can be tailored to increase engagement with the men living in a rural Local Government Area in Gippsland, Victoria, Australia. Methods: Participation records and promotional material for the Local Men Local Communities project was utilised to explore similarities and differences between the training and events offered. Results: Results indicated that men living in rural areas engaged best with events that included a social element such as food or an activity, highlighting that men may find it easier to talk and connect when they have something to do. Conclusion: Mental health training and events need to be tailored to meet the needs of the target population. Key details to consider include location, time, promotional material, content, and inclusion of a social element. So What?: When rural men were provided ownership of their conversations, they were more likely to have them. This challenges the stereotype that men do not talk and creates the opportunity for social connection within the community. © 2024 The Authors. Health Promotion Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of Australian Health Promotion Association

Implications of differing attitudes and experiences between providers and persons with obesity: results of the national ACTION study

Objective: Our aim was to explore how differing attitudes, expectations, and experiences among people with obesity (PwO) and healthcare providers (HCPs) might have an impact on effectively implementing current obesity treatment guidelines. Methods: Online surveys were conducted among 3,008 adult PwO (BMI≥30 by self-reported height and weight) and 606 HCPs. Results: PwO with weight loss ≥ 10% during the previous three years were more likely to have been diagnosed with obesity and to have discussed a weight loss plan with an HCP. However, only 21% believe HCPs have a responsibility to actively contribute to their obesity treatment. Further, HCPs tend not to effectively communicate the diagnosis of obesity, its nature as a serious and chronic disease, the full range of treatment options, and obesity’s implications for health and quality of life. Regarding treatment goals, HCPs more often focus on BMI reduction, while PwO’s goals focus on improved functioning, energy, and appearance. HCPs also tend to underestimate their patients’ motivation to address their obesity. Twenty-eight percent of HCPs ‘completely agreed’ that losing weight was a high priority for PwO, whereas more than half of PwO ‘completely agreed’ that losing weight was a high priority for them. When asked how their HCP could better support them, PwO most often expressed a desire for helpful resources, as well as assistance with specific and realistic goal-setting to improve health. Conclusions: HCPs can more effectively implement obesity treatment guidelines by more clearly and proactively communicating with PwO about their diagnosis, health implications of obesity, desired treatment goals, and the full range of treatment options. HCPs should understand that most PwO believe that managing their disease is solely their own responsibility. HCPs can also encourage more effective conversations by better appreciating their patients’ motivation and treatment goals.publishedVersio

Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study123

Background: Obesity is a serious chronic disease. Controlled-release phentermine/topiramate (PHEN/TPM CR), as an adjunct to lifestyle modification, has previously shown significant weight loss compared with placebo in a 56-wk study in overweight and obese subjects with ≥2 weight-related comorbidities

Growing from Our Roots: Strategies for Developing Culturally Grounded Health Promotion Interventions in American Indian, Alaska Native, and Native Hawaiian Communities

Given the paucity of empirically based health promotion interventions designed by and for American Indian, Alaska Native, and Native Hawaiian (i.e., Native) communities, researchers and partnering communities have had to rely on the adaptation of evidence-based interventions (EBIs) designed for non-Native populations, a decidedly sub-optimal approach. Native communities have called for development of Indigenous health promotion programs in which their cultural worldviews and protocols are prioritized in the design, development, testing, and implementation. There is limited information regarding how Native communities and scholars have successfully collaborated to design and implement culturally based prevention efforts “from the ground up.” Drawing on five diverse community-based Native health intervention studies, we describe strategies for designing and implementing culturally grounded models of health promotion developed in partnership with Native communities. Additionally, we highlight indigenist worldviews and protocols that undergird Native health interventions with an emphasis on the incorporation of (1) original instructions, (2) relational restoration, (3) narrative-[em]bodied transformation, and (4) indigenist community-based participatory research (ICBPR) processes. Finally, we demonstrate how culturally grounded interventions can improve population health when they prioritize local Indigenous knowledge and health-positive messages for individual to multi-level community interventions

The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease

Operationalizing Occupational Fatigue in Pharmacists: An Exploratory Factor Analysis

IntroductionThe Quadruple Aim recognizes that caring for the healthcare employee is necessary to optimize patient outcomes and health system performance. Although previous research has assessed pharmacists’ workload, this study is the first to describe pharmacist occupational fatigue – a characteristic of excessive workload that inhibits workers’ abilities to function at normal capacity. The purpose of this study was to describe occupational fatigue in pharmacists using exploratory factor analysis (EFA) – assessing whether dimensional structures used to describe occupational fatigue in other health professions fit pharmacist perceptions.MethodsA model was created to conceptualize ‘fatigue’ domains found in the literature. A priori, the two domains identified were physical fatigue (ex. physical discomfort), and mental fatigue (ex. trouble thinking clearly). These domains were operationalized and used to create a paper survey that was distributed to licensed pharmacists at a pharmacy conference. An EFA was conducted to identify the key domains underlying pharmacist perceptions of fatigue.ResultsA total of 283 surveys were distributed and 115 were returned and usable. Respondents were primarily white, female, worked 9.52 hours-per-day on average, and mean age of 39-years-old. The EFA suggested a statistically significant two-factor model (χ2 9.73, p=0.28; TLI 0.998, RMSEA 0.048), which included physical fatigue (α = 0.87) and mental fatigue (α = 0.82).DiscussionThe EFA yielded a structure similar to what was anticipated from the literature with physical and mental fatigue dimensions. This is just the first step in promoting systematic interventions to prevent or cope with fatigue and prevent the downstream patient, pharmacist, and institutional outcomes. By addressing fatigue and caring for employees, health care systems can take steps to work toward the Quadruple Aim.</jats:sec