Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies.

Extensive transcriptional and ontogenetic diversity exists among normal tissue-resident macrophages, with unique transcriptional profiles endowing the cells with tissue-specific functions. However, it is unknown whether the origins of different macrophage populations affect their roles in malignancy. Given potential artifacts associated with irradiation-based lineage tracing, it remains unclear if bone-marrow-derived macrophages (BMDMs) are present in tumors of the brain, a tissue with no homeostatic involvement of BMDMs. Here, we employed multiple models of murine brain malignancy and genetic lineage tracing to demonstrate that BMDMs are abundant in primary and metastatic brain tumors. Our data indicate that distinct transcriptional networks in brain-resident microglia and recruited BMDMs are associated with tumor-mediated education yet are also influenced by chromatin landscapes established before tumor initiation. Furthermore, we demonstrate that microglia specifically repress Itga4 (CD49D), enabling its utility as a discriminatory marker between microglia and BMDMs in primary and metastatic disease in mouse and human

Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells

Brain malignancies encompass a range of primary and metastatic cancers, including low-grade and high-grade gliomas and brain metastases (BrMs) originating from diverse extracranial tumors. Our understanding of the brain tumor microenvironment (TME) remains limited, and it is unknown whether it is sculpted differentially by primary versus metastatic disease. We therefore comprehensively analyzed the brain TME landscape via flow cytometry, RNA sequencing, protein arrays, culture assays, and spatial tissue characterization. This revealed disease-specific enrichment of immune cells with pronounced differences in proportional abundance of tissue-resident microglia, infiltrating monocyte-derived macrophages, neutrophils, and T cells. These integrated analyses also uncovered multifaceted immune cell activation within brain malignancies entailing converging transcriptional trajectories while maintaining disease- and cell-type-specific programs. Given the interest in developing TME-targeted therapies for brain malignancies, this comprehensive resource of the immune landscape offers insights into possible strategies to overcome tumor-supporting TME properties and instead harness the TME to fight cancer

ELM triggering conditions for the integrated modeling of H-mode plasmas

Recent advances in the integrated modeling of ELMy H-mode plasmas are presented. A model for the H-mode pedestal and for the triggering of ELMs predicts the height, width, and shape of the H-mode pedestal and the frequency and width of ELMs. Formation of the pedestal and the L-H transition is the direct result of ExB flow shear suppression of anomalous transport. The periodic ELM crashes are triggered by either the ballooning or peeling MHD instabilities. The BALOO, DCON, and ELITE ideal MHD stability codes are used to derive a new parametric expression for the peeling-ballooning threshold. The new dependence for the peeling-ballooning threshold is implemented in the ASTRA transport code. Results of integrated modeling of DIII-D like discharges are presented and compared with experimental observations. The results from the ideal MHD stability codes are compared with results from the resistive MHD stability code NIMROD.Comment: 12th International Congress on Plasma Physics, 25-29 October 2004, Nice (France

Implementing evidence-based recommended practices for the management of patients with mild traumatic brain injuries in Australian emergency care departments: study protocol for a cluster randomised controlled trial

Background: Mild head injuries commonly present to emergency departments. The challenges facing clinicians in emergency departments include identifying which patients have traumatic brain injury, and which patients can safely be sent home. Traumatic brain injuries may exist with subtle symptoms or signs, but can still lead to adverse outcomes. Despite the existence of several high quality clinical practice guidelines, internationally and in Australia, research shows inconsistent implementation of these recommendations. The aim of this trial is to test the effectiveness of a targeted, theory- and evidence-informed implementation intervention to increase the uptake of three key clinical recommendations regarding the emergency department management of adult patients (18 years of age or older) who present following mild head injuries (concussion), compared with passive dissemination of these recommendations. The primary objective is to establish whether the intervention is effective in increasing the percentage of patients for which appropriate post-traumatic amnesia screening is performed. Methods/design: The design of this study is a cluster randomised trial. We aim to include 34 Australian 24-hour emergency departments, which will be randomised to an intervention or control group. Control group departments will receive a copy of the most recent Australian evidence-based clinical practice guideline on the acute management of patients with mild head injuries. The intervention group will receive an implementation intervention based on an analysis of influencing factors, which include local stakeholder meetings, identification of nursing and medical opinion leaders in each site, a train-the-trainer day and standardised education and interactive workshops delivered by the opinion leaders during a 3 month period of time. Clinical practice outcomes will be collected retrospectively from medical records by independent chart auditors over the 2 month period following intervention delivery (patient level outcomes). In consenting hospitals, eligible patients will be recruited for a follow-up telephone interview conducted by trained researchers. A cost-effectiveness analysis and process evaluation using mixed-methods will be conducted. Sample size calculations are based on including 30 patients on average per department. Outcome assessors will be blinded to group allocation

Genetically engineered multicistronic allele of Pmel yielding highly specific CreERT2-mediated recombination in the melanocyte lineage

YesGenetic approaches that allow lineage tracing are essential to our future understanding of melanocytes and melanoma. To date, the approaches used to label melanocytes in mice have relied on random integration of transgenes driven by the promoters of the Tyrosinase and Dopachrome tautomerase genes, knock-in to the Dopachrome tautomerase locus or knock-in to the Mlana locus in a bacterial artificial chromosome. These strategies result in expression in other tissues such as telencephalon and other cell types such as nerves. Here we used homologous recombination in mouse embryonic stem cells to generate a targeted multicistronic allele of the Pmel locus that drives melanocyte-specific expression of CreERT2, nuclear localised H2B-Cerulean and membrane localised marcks-mKate2 allowing live imaging of melanocytes and activation of other conditional alleles. We combined this allele with R26R-EYFP mice allowing induction of EYFP expression on administration of tamoxifen or its metabolite 4-OHT. The fluorescent proteins H2B-Cerulean and marcks-mKate2 label the cell nucleus and plasma membrane respectively allowing live imaging and FACS isolation of melanoblasts and melanocytes as well as serving to provide an internal control allowing estimation of recombination efficiency after administration of tamoxifen. We demonstrate the utility of the transgene in embryonic and adult tissues.Cancer Research UK. Grant Number: A15673. Medical Research Council. Grant Number: MC_PC_U127527200. National Centre for the Replacement Refinement and Reduction of Animals in Research. Grant Number: NC/K001612/1. North West Cancer Research Fund. Grant Number: CR1132. Medical Research Scotland. Grant Number: 436FR

Health literacy and long-term health outcomes following myocardial infarction: protocol for a multicentre, prospective cohort study (ENHEARTEN study)

Introduction: Low health literacy is common in people with cardiovascular disease and may be one factor that affects an individual’s ability to maintain secondary prevention health behaviours following myocardial infarction (MI). However, little is known about the association between health literacy and longer-term health outcomes in people with MI. The ENhancing HEAlth literacy in secondary pRevenTion of cardiac evENts (ENHEARTEN) study aims to examine the relationship between health literacy and a number of health outcomes (including healthcare costs) in a cohort of patients following their first MI. Findings may provide evidence for the significance of health literacy as a predictor of long-term cardiac outcomes. Methods and analysis: ENHEARTEN is a multicentre, prospective observational study in a convenience sample of adults (aged >18 years) with their first MI. A total of 450 patients will be recruited over 2 years across two metropolitan health services and one rural/regional health service in Victoria, Australia. The primary outcome of this study will be all-cause, unplanned hospital admissions within 6 months of index admission. Secondary outcomes include cardiac-related hospital admissions up to 24 months post-MI, emergency department presentations, health-related quality of life, mortality, cardiac rehabilitation attendance and healthcare costs. Health literacy will be observed as a predictor variable and will be determined using the 12-item version of the European Health Literacy Survey (HLS-Q12). Ethics and dissemination: Ethics approval for this study has been received from the relevant human research ethics committee (HREC) at each of the participating health services (lead site Monash Health HREC; approval number: RES-21- 0000- 242A) and Services Australia HREC (reference number: RMS1672). Informed written consent will be sought from all participants. Study results will be published in peer-reviewed journals and collated in reports for participating health services and participants. Trial registration number: ACTRN12621001224819.Alison Beauchamp, Jason Talevski, Stephen J Nicholls, Anna Wong Shee, Catherine Martin, William Van Gaal, Ernesto Oqueli, Jaithri Ananthapavan, Laveena Sharma, Adrienne O, Neil, Sharon Lee Brennan-Olsen, Rebecca Leigh Jessu

Genetically Determined Height and Risk of Non-hodgkin Lymphoma

Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00\u20131.17, p = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01\u20131.31, p = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes