BlogForever D5.3: User Questionnaires and Reports

This report presents the feedback gathered from third party users during the BlogForever Case Studies. Therefore, the research framework is defined and the case studies results are presented, followed by a summary of conclusions and remarks

BlogForever D5.2: Implementation of Case Studies

This document presents the internal and external testing results for the BlogForever case studies. The evaluation of the BlogForever implementation process is tabulated under the most relevant themes and aspects obtained within the testing processes. The case studies provide relevant feedback for the sustainability of the platform in terms of potential users’ needs and relevant information on the possible long term impact

Reversal of English trend towards hospital death in dementia:a population-based study of place of death and associated individual and regional factors, 2001-2010

BACKGROUND: England has one of the highest rates of hospital death in dementia in Europe. How this has changed over time is unknown. This study aimed to analyse temporal trends in place of death in dementia over a recent ten year period. METHODS: Population-based study linking Office for National Statistics mortality data with regional variables, in England 2001–2010. Participants were adults aged over 60 with a death certificate mention of dementia. Multivariable Poisson regression was used to determine the proportion ratio (PR) for death in care home (1) and home/hospice (1) compared to hospital (0). Explanatory variables included individual factors (age, gender, marital status, underlying cause of death), and regional variables derived at area level (deprivation, care home bed provision, urbanisation). RESULTS: 388,899 deaths were included. Most people died in care homes (55.3%) or hospitals (39.6%). A pattern of increasing hospital deaths reversed in 2006, with a subsequent decrease in hospital deaths (−0.93% per year, 95% CI −1.08 to −0.79 p < 0.001), and an increase in care home deaths (0.60% per year, 95% CI 0.45 to 0.75 p < 0.001). Care home death was more likely with older age (PR 1.11, 1.10 to 1.13), and in areas with greater care home bed provision (PR 1.82, 1.79 to 1.85) and affluence (PR 1.29, 1.26 to 1.31). Few patients died at home (4.8%) or hospice (0.3%). Home/hospice death was more likely in affluent areas (PR 1.23, 1.18 to 1.29), for women (PR 1.61, 1.56 to 1.65), and for those with cancer as underlying cause of death (PR 1.84, 1.77 to 1.91), and less likely in the unmarried (PRs 0.51 to 0.66). CONCLUSIONS: Two in five people with dementia die in hospital. However, the trend towards increasing hospital deaths has reversed, and care home bed provision is key to sustain this. Home and hospice deaths are rare. Initiatives which aim to support the end of life preferences for people with dementia should be investigated

Increased Circulating Osteopontin Levels Promote Primary Tumour Growth, but Do Not Induce Metastasis in Melanoma

Osteopontin (OPN) is a phosphoprotein with diverse functions in various physiological and pathological processes. OPN expression is increased in multiple cancers, and OPN within tumour tissue has been shown to promote key stages of cancer development. OPN levels are also elevated in the circulation of cancer patients, which in some cases has been correlated with enhanced metastatic propensity and poor prognosis. However, the precise impact of circulating OPN (cOPN) on tumour growth and progression remains insufficiently understood. To examine the role of cOPN, we used a melanoma model, in which we stably increased the levels of cOPN through adeno-associated virus-mediated transduction. We found that increased cOPN promoted the growth of primary tumours, but did not significantly alter the spontaneous metastasis of melanoma cells to the lymph nodes or lungs, despite an increase in the expression of multiple factors linked to tumour progression. To assess whether cOPN has a role at later stages of metastasis formation, we employed an experimental metastasis model, but again could not detect any increase in pulmonary metastasis in animals with elevated levels of cOPN. These results demonstrate that increased levels of OPN in the circulation play distinct roles during different stages of melanoma progression

Ketogenic diet does not promote triple-negative and luminal mammary tumor growth and metastasis in experimental mice

Vol.:(0123456789)1 3Clinical & Experimental Metastasis https://doi.org/10.1007/s10585-023-10249-z RESEARCH PAPER Ketogenic diet does not promote triple-negative and luminal mammary tumor growth and metastasis in experimental mice Meret Grube1 · Arno Dimmler2 · Anja Schmaus1 · Rafael Saup1 · Tabea Wagner 1 · Boyan K. Garvalov 1 · Jonathan P. Sleeman1,3 · Wilko Thiele 1 Received: 17 October 2023 / Accepted: 21 November 2023 © The Author(s) 2023 Abstract Ketogenic diets (KDs) can improve the well-being and quality of life of breast cancer patients. However, data on the effects of KDs on mammary tumors are inconclusive, and the influence of KDs on metastasis in general remains to be investigated. We therefore assessed the impact of a KD on growth and metastasis of triple negative murine 4T1 mammary tumors, and on the progression of luminal breast tumors in an autochthonous MMTV-PyMT mouse model. We found that KD did not influence the metastasis of 4T1 and MMTV-PyMT mammary tumors, but impaired 4T1 tumor cell proliferation in vivo, and also temporarily reduced 4T1 primary tumor growth. Notably, the ketogenic ratio (the mass of dietary fat in relation to the mass of dietary carbohydrates and protein) that is needed to induce robust ketosis was twice as high in mice as compared to humans. Surprisingly, only female but not male mice responded to KD with a sustained increase in blood β-hydroxybutyrate levels. Together, our data show that ketosis does not foster primary tumor growth and metastasis, suggesting that KDs can be safely applied in the context of luminal breast cancer, and may even be advantageous for patients with triple negative tumors. Furthermore, our data indicate that when performing experiments with KDs in mice, the ketogenic ratio needed to induce ketosis must be verified, and the sex of the mice should also be taken into account

Hyaluronic acid-CD44 interactions promote BMP4/7-dependent Id1/3 expression in melanoma cells

Abstract BMP4/7-dependent expression of inhibitor of differentiation/DNA binding (Id) proteins 1 and 3 has been implicated in tumor progression and poor prognosis of malignant melanoma patients. Hyaluronic acid (HA), a pericellular matrix component, supports BMP7 signalling in murine chondrocytes through its receptor CD44. However, its role in regulating BMP signalling in melanoma is not clear. In this study we found that depletion of endogenously-produced HA by hyaluronidase treatment or by inhibition of HA synthesis by 4-methylumbelliferone (4-MU) resulted in reduced BMP4/7-dependent Id1/3 protein expression in mouse melanoma B16-F10 and Ret cells. Conversely, exogenous HA treatment increased BMP4/7-dependent Id1/3 protein expression. Knockdown of CD44 reduced BMP4/7-dependent Id1/3 protein expression, and attenuated the ability of exogenous HA to stimulate Id1 and Id3 expression in response to BMP. Co-IP experiments demonstrated that CD44 can physically associate with the BMP type II receptor (BMPR) ACVR2B. Importantly, we found that coordinate expression of Id1 or Id3 with HA synthases HAS2, HAS3, and CD44 is associated with reduced overall survival of cutaneous melanoma patients. Our results suggest that HA-CD44 interactions with BMPR promote BMP4/7-dependent Id1/3 protein expression in melanoma, contributing to reduced survival in melanoma patients

Quantitative detection of disseminated melanoma cells by trp-1 transcript analysis reveals stochastic distribution of pulmonary metastases

A better understanding of the process of melanoma metastasis is required to underpin the development of novel therapies that will improve patient outcomes. The use of appropriate animal models is indispensable for investigating the mechanisms of melanoma metastasis. However, reliable and practicable quantification of metastases in experimental mice remains a challenge, particularly if the metastatic burden is low. Here, we describe a qRT-PCR-based protocol that employs the melanocytic marker Trp-1 for the sensitive quantification of melanoma metastases in the murine lung. Using this protocol, we were able to detect the presence of as few as 100 disseminated melanoma cells in lung tissue. This allowed us to quantify metastatic burden in a spontaneous syngeneic B16-F10 metastasis model, even in the absence of visible metastases, as well as in the autochthonous Tg(Grm1)/Cyld$^{-/-}$ melanoma model. Importantly, we also observed an uneven distribution of disseminated melanoma cells amongst the five lobes of the murine lung, which varied considerably from animal to animal. Together, our findings demonstrate that the qRT-PCR-based detection of Trp-1 allows the quantification of low pulmonary metastatic burden in both transplantable and autochthonous murine melanoma models, and show that the analysis of lung metastasis in such models needs to take into account the stochastic distribution of metastatic lesions amongst the lung lobes

Acquisition and maintenance of constraints in engineering design

The Designers' Workbench is a system, developed by the Advanced Knowledge Technologies (AKT) consortium to support designers in large organizations, such as Rolls- Royce, by making sure that a design is consistent with the specification for the particular design as well as with the company's design rule book(s). Currently, to capture the constraint information, a domain expert (design engineer) has to work with a knowledge engineer to identify the constraints, and it is then the task of the knowledge engineer to encode these into the Workbench's knowledge base (KB). This is an error prone and time consuming task. It is highly desirable to relieve the knowledge engineer of this task, and so we have developed a tool, ConEditor, that enables domain experts themselves to capture and maintain these constraints. The tool allows the user to combine selected entities from the domain ontology with keywords and operators of a constraint language to form a constraint expression. We hypothesize that to apply constraints appropriately, it is necessary to understand the context in which each constraint is applicable. We refer to this as "application conditions". We plan to make these application conditions machine interpretable and investigate how they, together with a domain ontology, can be used to support the verification and maintenance of constraints