Development of human pancreatic cancer avatars as a model for dynamic immune landscape profiling and personalized therapy.

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, a disease with dismal overall survival. Advances in treatment are hindered by a lack of preclinical models. Here, we show how a personalized organotypic "avatar" created from resected tissue allows spatial and temporal reporting on a complete in situ tumor microenvironment and mirrors clinical responses. Our perfusion culture method extends tumor slice viability, maintaining stable tumor content, metabolism, stromal composition, and immune cell populations for 12 days. Using multiplexed immunofluorescence and spatial transcriptomics, we identify immune neighborhoods and potential for immunotherapy. We used avatars to assess the impact of a preclinically validated metabolic therapy and show recovery of stromal and immune phenotypes and tumor redifferentiation. To determine clinical relevance, we monitored avatar response to gemcitabine treatment and identify a patient avatar-predictable response from clinical follow-up. Thus, avatars provide valuable information for syngeneic testing of therapeutics and a truly personalized therapeutic assessment platform for patients.

Heparin and heparin proteoglycan-mimetics activate platelets via PEAR1 and PI3Kß.

BACKGROUND: Platelet endothelial aggregation receptor 1 (PEAR1) is a single-transmembrane orphan receptor primarily expressed on platelets and endothelial cells. Genetic variants of PEAR1 have repeatedly and independently been identified to be associated with cardiovascular diseases, including coronary artery disease. OBJECTIVES: We have identified sulfated fucoidans and their mimetics as ligands for PEAR1 and proposed that its endogenous ligand is a sulfated proteoglycan. The aim of this study was to test this hypothesis. METHODS: A heparin proteoglycan-mimetic (HPGM) was created by linking unfractionated heparin (UFH) to albumin. The ability of the HPGM, UFH and selectively desulfated heparins to stimulate platelet aggregation and protein phosphorylation was investigated. Nanobodies against the 12th to 13th epidermal growth factor-like repeat of PEAR1 and phosphoinositide 3-kinase (PI3K) isoform-selective inhibitors were tested for the inhibition of platelet activation. RESULTS: We show that HPGM, heparin conjugated to an albumin protein core, stimulates aggregation and phosphorylation of PEAR1 in washed platelets. Platelet aggregation was abolished by an anti-PEAR1 nanobody, Nb138. UFH stimulated platelet aggregation in washed platelets, but desulfated UFH did not. Furthermore, HPGM, but not UFH, stimulated maximal aggregation in platelet-rich plasma. However, both HPGM and UFH increased integrin αIIbß3 activation in whole blood. By using PI3K isoform-selective inhibitors, we show that PEAR1 activates PI3Kß, leading to Akt phosphorylation. CONCLUSION: Our findings reveal that PEAR1 is a receptor for heparin and HPGM and that PI3Kß is a key signaling molecule downstream of PEAR1 in platelets. These findings may have important implications for our understanding of the role of PEAR1 in cardiovascular disease.

Improving the visibility and communication of treatment escalation plans in Somerset NHS foundation trust.

BACKGROUND: Advance care treatment escalation plans (TEPs) are often lost between healthcare settings, leading to duplication of work and loss of patient autonomy. OBJECTIVE: This quality improvement project reviewed the usage of TEP forms and aimed to improve completeness of documentation and visibility between admissions. METHODS: Over four months we monitored TEP form documentation using a standardised data extraction form. This examined section completion, seniority of documenting clinician and transfer of forms to our hospital electronic patient record (EPRO). We added reminders to computer monitors on wards to improve EPRO upload. RESULTS: Initial data demonstrated that 95% of patients (n = 230) had a TEP, with 99% of TEPs recording resuscitation status. However, other sections were not well documented (patient capacity 57% completion and personal priorities 45% completion, respectively). Only 11.9% of TEPs documented consultant involvement. Furthermore, only 44% of TEPs with a do not attempt resuscitation (DNACPR) decision were uploaded. Following this, we added reminders to computer monitors explaining how to upload TEP decisions to EPRO, which increased EPRO uploads to 74%. CONCLUSION: Communication of TEPs needs improving across healthcare settings. This project showed that the use of a physical reminder can greatly improve communication of treatment escalation decisions. Furthermore, this intervention has inspired future projects aiming at making communication more sustainable through the use of discharge summaries.

Clinical perspective and practices on pleural effusions in chronic systemic inflammatory diseases.

Systemic inflammatory diseases are a heterogeneous family of autoimmune chronic inflammatory disorders that affect multiple systems within the human body. Connective tissue disease (CTD) is a large group within this family characterised by immune-mediated inflammation of the connective tissue. This group of disorders are often associated with pleural manifestations. CTD-induced pleuritis exhibits a wide variety of symptoms and signs including exudative pleural effusions and chest pain. Accurate estimation of prevalence for CTD-related pleuritis is challenging as small effusions are asymptomatic and remain undetected. Rheumatoid arthritis and systemic lupus erythematosus are frequent CTDs and present with pleural pathology in approximately 5-20% and 17-60% of cases, respectively. By contrast, pleural involvement in systemic sclerosis, eosinophilia-myalgia syndrome, mixed connective tissue disease, ankylosing spondylitis, polymyositis and dermatomyositis syndrome is rare. Clinical management depends on the severity of symptoms; however, most effusions resolve spontaneously. In this review we discuss the pathophysiological mechanisms and the clinical considerations of CTD-induced pleuritis.

Reputations count: why benchmarking performance is improving health care across the world.

This paper explores what motivates improved health care performance. Previously, many have thought that performance would either improve via choice and competition or by relying on trust and altruism. But neither assumption is supported by available evidence. So instead we explore a third approach of reciprocal altruism with sanctions for unacceptably poor performance and rewards for high performance. These rewards and sanctions, however, are not monetary, but in the form of reputational effects through public reporting of benchmarking of performance. Drawing on natural experiments in Italy and the United Kingdom, we illustrate how public benchmarking can improve poor performance at the national level through 'naming and shaming' and enhance good performance at the sub-national level through 'competitive benchmarking' and peer learning. Ethnographic research in Zambia also showed how reputations count. Policy-makers could use these effects in different ways to improve public services.

Imbalance in the response of pre- and post-synaptic components to amyloidopathy.

Alzheimer's disease (AD)-associated synaptic dysfunction drives the progression of pathology from its earliest stages. Amyloid ß (Aß) species, both soluble and in plaque deposits, have been causally related to the progressive, structural and functional impairments observed in AD. It is, however, still unclear how Aß plaques develop over time and how they progressively affect local synapse density and turnover. Here we observed, in a mouse model of AD, that Aß plaques grow faster in the earlier stages of the disease and if their initial area is >500 µm2; this may be due to deposition occurring in the outer regions of the plaque, the plaque cloud. In addition, synaptic turnover is higher in the presence of amyloid pathology and this is paralleled by a reduction in pre- but not post-synaptic densities. Plaque proximity does not appear to have an impact on synaptic dynamics. These observations indicate an imbalance in the response of the pre- and post-synaptic terminals and that therapeutics, alongside targeting the underlying pathology, need to address changes in synapse dynamics.

Turn It Off: An Action Research Study of Top Management Influence on Energy Conservation in the Workplace.

This paper reports the results of an intervention study that aimed to encourage workplace energy conservation behavior by office-based employees. Taking a co-production approach we worked with the participating organization to design and implement an intervention that used the influence of top management commitment and prompts to encourage workplace energy reduction. Whilst past research has shown top management is related to workplace pro-environmental behavior, this study extends this work by examining a field-based intervention over a longitudinal period. The efficacy of the intervention was measured using observational and self-reported data over a period of 6 months. Results showed that there were significant changes in objective and self-reported energy conservation behavior, perceived top management commitment, organizational culture, norms, and knowledge regarding energy conservation behavior over the course of the study. The findings also demonstrated that the intervention was most successful for those behaviors where employees have individual responsibility. Implications for future research and practice are discussed.

Environmental DNA for wildlife biology and biodiversity monitoring.

Extraction and identification of DNA from an environmental sample has proven noteworthy recently in detecting and monitoring not only common species, but also those that are endangered, invasive, or elusive. Particular attributes of so-called environmental DNA (eDNA) analysis render it a potent tool for elucidating mechanistic insights in ecological and evolutionary processes. Foremost among these is an improved ability to explore ecosystem-level processes, the generation of quantitative indices for analyses of species, community diversity, and dynamics, and novel opportunities through the use of time-serial samples and unprecedented sensitivity for detecting rare or difficult-to-sample taxa. Although technical challenges remain, here we examine the current frontiers of eDNA, outline key aspects requiring improvement, and suggest future developments and innovations for research.

Correlations between the role, sequence conservation, genomic location and severity of phenotype in myxobacterial developmental genes.

Myxobacterial development requires the coordinated action of both intracellular and intercellular signalling pathways. A dataset of myxobacterial developmental gene properties suggests that genes encoding components of intracellular pathways tend to be less conserved, yield less severe phenotypes upon deletion and lie closer to the chromosomal origin than intercellular signalling genes. It would seem that there is a stronger negative selection affecting the mutation of intercellular signalling pathway genes than intracellular genes. Presumably, this is because the loss of social behaviour (and consequently sporulation) upon mutation of an intercellular gene is profoundly detrimental to the perpetuation of the organism. Conversely, mutation of an intracellular gene would typically result in a socially capable mutant. The correlations presented here between the severity of phenotype, genomic location and the degree of sequence conservation should aid rational exploration of the genomics of social development in the myxobacteria.

High-mobility group protein 1(Y): metastasis-associated or metastasis-inducing?

Metastasis is the major cause of mortality and morbidity for patients with cancer. The high-mobility group protein 1(Y) [HMG-1(Y)] has a role in the transcription of many genes involved at different steps in the metastatic cascade and has been linked with cancer in human and animal models. This may represent a potential therapeutic target for patients. The following review summarizes and critically appraises the evidence for the role of HMG-1(Y) in metastasis.