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The tumor microenvironment (TME) is highly heterogeneous and can dictate the success of therapeutic interventions. Identifying TMEs that are susceptible to specific therapeutic interventions paves the way for more personalized and effective treatments. In this study, using a spontaneous murine model of breast cancer, we characterize a TME that is responsive to inhibitors of the heme degradation pathway mediated by heme oxygenase (HO), resulting in CD8+ T cell- and NK cell-dependent tumor control. A hallmark of this TME is a chronic type I interferon (IFN) signal that is directly involved in orchestrating the antitumor immune response. Importantly, we identify that similar TMEs exist in human breast cancer that are associated with patient prognosis. Leveraging these observations, we demonstrate that combining a STING agonist, which induces type I IFN responses, with an HO inhibitor produces a synergistic effect leading to superior tumor control. This study highlights HO activity as a potential resistance mechanism for type I IFN responses in cancer, supporting a therapeutic rationale for targeting the heme degradation pathway to enhance the efficacy of STING agonists.

Older adults may become especially sensitive to potential memory and cognitive decline before any measurable decline is present. The current study sought to develop a version of the Visual Approach/Avoidance by the Self Task (VAAST) to measure older adult stereotype threat. A comparative sample of older and younger adults were recruited with each completing the VAAST coded with words commonly associated with positive or negative aging. Results showed expected differences for older and young adults across valance and movement domains. Additionally, a greater response difference was observed between young and old adults for negative word movement. These results support that older adults have an implicit motivation to avoid threatening stimuli related to age related stereotype threat and avoid negative words, unlike the younger population. Findings indicate that older adults develop negative stereotyped words into their self-concept and support the use of The VAAST as a research tool in this domain.

The Virtual Brain (TVB) is now available as open-source services on the cloud research platform EBRAINS (ebrains.eu). It offers software for constructing, simulating and analysing brain network models including the TVB simulator; magnetic resonance imaging (MRI) processing pipelines to extract structural and functional brain networks; combined simulation of large-scale brain networks with small-scale spiking networks; automatic conversion of user-specified model equations into fast simulation code; simulation-ready brain models of patients and healthy volunteers; Bayesian parameter optimization in epilepsy patient models; data and software for mouse brain simulation; and extensive educational material. TVB cloud services facilitate reproducible online collaboration and discovery of data assets, models, and software embedded in scalable and secure workflows, a precondition for research on large cohort data sets, better generalizability, and clinical translation.

High grade serous ovarian cancer (HGSOC) is a lethal gynecologic malignancy in which chemoresistant recurrence rates remain high. Furthermore, HGSOC patients have demonstrated overall low response rates to clinically available immunotherapies. Amphiregulin (AREG), a low affinity epidermal growth factor receptor ligand is known to be significantly upregulated in HGSOC patient tumors following neoadjuvant chemotherapy exposure. While much is known about AREG’s role in oncogenesis and classical immunity, it is function in tumor immunology has been comparatively understudied. Therefore, the objective of this present study was to elucidate how increased AREG exposure impacts the ovarian tumor immune microenvironment (OTIME). Using NanoString IO 360 and protein analysis, it was revealed that treatment with recombinant AREG led to prominent upregulation of genes associated with ovarian pathogenesis and immune evasion ( CXCL8 , CXCL1 , CXCL2 ) along with increased STAT3 activation in HGSOC cells. In vitro co-culture assays consisting of HGSOC cells and peripheral blood mononuclear cells (PBMCs) stimulated with recombinant AREG (rAREG) led to significantly enhanced tumor cell viability. Moreover, PBMCs stimulated with rAREG exhibited significantly lower levels of IFNy and IL-2 . In vivo rAREG treatment promoted significant reductions in circulating levels of IL-2 and IL-5. Intratumoral analysis of rAREG treated mice revealed a significant reduction in CD8 + T cells coupled with an upregulation of PD-L1. Finally, combinatorial treatment with an AREG neutralizing antibody and carboplatin led to a synergistic reduction of cell viability in HGSOC cell lines OVCAR8 and PEA2. Overall, this study demonstrates AREG’s ability to modulate cytotoxic responses within the OTIME and highlights its role as a novel HGSOC immune target.

This article describes the rapid, system-wide reconfiguration of local and network services in response to the newly described paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) (also known as multisystem inflammatory syndrome in children). Developing the model of care for this novel disease, whose natural history, characteristics and treatment options were still unclear, presented distinct challenges.We analyse this redesign through the lens of healthcare management science, and outline transferable principles which may be of specific and urgent relevance for paediatricians yet to experience the full impact of the COVID-19 pandemic; and more generally, for those developing a new clinical service or healthcare operating model to manage the sudden emergence of any unanticipated clinical entity. Health service leaders in areas where COVID-19 is, or will soon be, in the ascendancy, and who are anticipating the imminent influx of PIMS-TS, should use these principles and recommendations to plan an agile, responsive and system-wide model of care for these children.

Objective Legislation to safeguard children from maltreatment by carers or violence by others was advanced in England and Scotland around 2004–2005 and resulted in different policies and services. We examined whether subsequent trends in injury admissions to hospital related to maltreatment or violence varied between the two countries. Setting and participants We analysed rates of all unplanned injury admission to National Health Service (NHS) hospitals in England and Scotland between 2005 and 2011 for children and adolescents aged less than 19 years. Outcomes We compared incidence trends for maltreatment or violence-related (MVR) injury and adjusted rate differences between 2005 and 2011 using Poisson or negative binomial regression models to adjust for seasonal effects and secular trends in non-MVR injury. Infants, children 1–10 years and adolescents 11–18 years were analysed separately. Results In 2005, MVR rates were similar in England and Scotland for infants and 1–10-year-olds, but almost twice as high in Scotland for 11–18-year-olds. MVR rates for infants increased by similar amounts in both countries, in line with rising non-MVR rates in England but contrary to declines in Scotland. Among 1–10-year-olds, MVR rates increased in England and declined in Scotland, in line with increasing non-MVR rates in England and declining rates in Scotland. Among 11–18-year-olds, MVR rates declined more steeply in Scotland than in England along with declines in non-MVR trends. Conclusions Diverging trends in England and Scotland may reflect true changes in the occurrence of MVR injury or differences in the way services recognise and respond to these children, record such injuries or a combination of these factors. Further linkage of data from surveys and services for child maltreatment and violence could help distinguish the impact of policies.

Ovarian high grade serous carcinoma (HGSC) remains a disease of poor prognosis that is unresponsive to current immune checkpoint inhibitors. Although PI3K pathway alterations are common in HGSC, attempts to target this pathway have been unsuccessful. We hypothesised aberrant PI3K pathway activation may alter the HGSC immune microenvironment and present a novel targeting strategy. We used both murine models and HGSC patient samples to study the impact of loss of Pten, a negative regulator of PI3K pathway signalling. We identified populations of resident macrophages specifically in Pten null omental tumours. These macrophages derive from peritoneal fluid macrophages and have a unique gene expression programme, marked by high levels of HMOX1 expression, the gene for the enzyme heme oxygenase-1. Targeting resident peritoneal macrophages prevents appearance of HMOX1hi macrophages and in doing so reduces tumour growth. Furthermore, direct inhibition of HMOX1 extends survival in vivo. HMOX1hi macrophages with corresponding gene expression programmes are also identified in human HGSC tumours and their presence correlates with activated tumoural PI3K pathway/mTOR signalling and poor overall survival in HGSC patients. In contrast, tumours with low number of HMOX1hi macrophages are marked by increased adaptive immune response gene expression. Our data suggest that HMOX1hi macrophages represent a potential therapeutic target and biomarker for poor prognosis HGSC.

The Virtual Brain (TVB) is now available as open-source cloud ecosystem on EBRAINS, a shared digital research platform for brain science. It offers services for constructing, simulating and analysing brain network models (BNMs) including the TVB network simulator; magnetic resonance imaging (MRI) processing pipelines to extract structural and functional connectomes; multiscale co-simulation of spiking and large-scale networks; a domain specific language for automatic high-performance code generation from user-specified models; simulation-ready BNMs of patients and healthy volunteers; Bayesian inference of epilepsy spread; data and code for mouse brain simulation; and extensive educational material. TVB cloud services facilitate reproducible online collaboration and discovery of data assets, models, and software embedded in scalable and secure workflows, a precondition for research on large cohort data sets, better generalizability and clinical translation.