Breast cancer cells stimulate osteoprotegerin (OPG) production by endothelial cells through direct cell contact

<p>Abstract</p> <p>Background</p> <p>Angiogenesis, the sprouting of capillaries from existing blood vessels, is central to tumour growth and progression, however the molecular regulation of this process remains to be fully elucidated. The secreted glycoprotein osteoprotegerin (OPG) is one potential pro-angiogenic factor, and clinical studies have demonstrated endothelial cells within a number of tumour types to express high levels of OPG compared to those in normal tissue. Additionally, OPG can increase endothelial cell survival, proliferation and migration, as well as induce endothelial cell tube formation <it>in vitro</it>. This study aims to elucidate the processes involved in the pro-angiogenic effects of OPG <it>in vitro</it>, and also how OPG levels may be regulated within the tumour microenvironment.</p> <p>Results</p> <p>It has previously been demonstrated that OPG can induce tube formation on growth factor reduced matrigel. In this study, we demonstrate that OPG enhances the pro-angiogenic effects of VEGF and that OPG does not stimulate endothelial cell tube formation through activation of the VEGFR2 receptor. We also show that cell contact between HuDMECs and the T47D breast cancer cell line increases endothelial cell OPG mRNA and protein secretion levels in <it>in vitro </it>co-cultures. These increases in endothelial cell OPG secretion were dependent on α_νβ₃ligation and NFκB activation. In contrast, the pro-angiogenic factors VEGF, bFGF and TGFβ had no effect on HuDMEC OPG levels.</p> <p>Conclusion</p> <p>These findings suggest that the VEGF signalling pathway is not involved in mediating the pro-angiogenic effects of OPG on endothelial cells <it>in vitro</it>. Additionally, we show that breast cancer cells cause increased levels of OPG expression by endothelial cells, and that direct contact between endothelial cells and tumour cells is required in order to increase endothelial OPG expression and secretion. Stimulation of OPG secretion was shown to involve α_νβ₃ligation and NFκB activation.</p

Arbeidsulykker i havbruk - Analyser av registrerte personulykker på havbruksanlegg og -fartøy

Denne rapporten presenterer analyser av registrerte arbeidsulykker i havbruksnæringa i Norge basert på tre ulike kilder: Sjøfartsdirektoratet (2012-2022), Arbeidstilsynet (2011- 2022) og SINTEF Ocean (yrkesdød 1982-2022). I tillegg er det presentert sykefraværsdata fra SSB (2018-2022). Arbeidstilsynets registreringer viser at det har vært 3-4 personskader per 1000 sysselsatte i akvakulturnæringa siden 2015. De vanligste personskadetypene i Arbeidstilsynets register er «fall», «klemt/fanget» og «støt/treff av gjenstand» og «elektrisk spenning». Registrerte ulykker per år i Sjøfartsdirektoratets register har økt fra 8 i 2012 til 43 i 2022, mer enn halvparten på brønnfartøy. De fleste ulykkeshendelsene skjedde på dekk med dekkskraner og annet løfteutstyr. De fire ulykkeshendelsene som skjedde oftest, var «støt/klem», «fall om bord», «stikk/kutt» og «kontakt med kjemikalier». SINTEF Ocean har registrert 38 dødsfall knyttet til havbruksvirksomhet fra 1982-2022, 10 av disse i perioden 2012-2022.Arbeidsulykker i havbruk - Analyser av registrerte personulykker på havbruksanlegg og -fartøypublishedVersio

The endocrine influence on the bone microenvironment in early breast cancer

Multiple factors influence the survival of disseminated breast tumour cells (DTCs) in bone. Whilst gene signature studies have identified genes that predict a propensity of tumours to metastasise to bone, the bone environment is key in determining the fate of these tumour cells. Breast cancer cells locate to specific niches within the bone that support their survival, regulated by host factors within the bone microenvironment including bone cells, cells of the bone micro vasculature, immune cells and the extracellular matrix. Reproductive endocrine hormones affect bone and clinical studies across the menopausal transition have provided comprehensive understanding of the changes in the bone microenvironment during this time. Menopause is characterised by a decrease in ovarian oestradiol and inhibins, with an increase in pituitary follicle stimulating hormone and this review will focus on the role of these 3 hormones in determining the fate of DTCs in bone. Both in vivo and clinical data suggest premenopausal bone is a conducive environment for growth of breast cancer cells in bone. Adjuvant cancer treatment aims to reduce the risk of tumour recurrence by targeting DTCs and drugs targeting the bone resorbing osteoclasts, such as bisphosphonates, have been evaluated in this setting. Both preclinical and adjuvant clinical studies and have shown that bisphosphonates ability to decrease tumour growth in bone is influenced by levels of endocrine hormones, with enhanced effects in a postmenopausal bone microenvironment. The challenge is to understand the molecular mechanisms behind this phenomenon and to evaluate if alternative adjuvant bone targeted therapies may be effective in premenopausal women

In vivo models in breast cancer research: progress, challenges and future directions

Research using animal model systems has been instrumental in delivering improved therapies for breast cancer, as well as in generating new insights into the mechanisms that underpin development of the disease. A large number of different models are now available, reflecting different types and stages of the disease; choosing which one to use depends on the specific research question(s) to be investigated. Based on presentations and discussions from leading experts who attended a recent workshop focused on in vivo models of breast cancer, this article provides a perspective on the many varied uses of these models in breast cancer research, their strengths, associated challenges and future directions. Among the questions discussed were: how well do models represent the different stages of human disease; how can we model the involvement of the human immune system and microenvironment in breast cancer; what are the appropriate models of metastatic disease; can we use models to carry out preclinical drug trials and identify pathways responsible for drug resistance; and what are the limitations of patient-derived xenograft models? We briefly outline the areas where the existing breast cancer models require improvement in light of the increased understanding of the disease process, reflecting the drive towards more personalised therapies and identification of mechanisms of drug resistance

The Sharing Experimental Animal Resources, Coordinating Holdings (SEARCH) Framework : Encouraging Reduction, Replacement, and Refinement in Animal Research

National Centre for the Replacement, Refinement and Reduction of Animals in Research https://www.nc3rs.org.uk/ (grant number NC/L001004/1) received by VS. The Pathological Society of Great Britain and Ireland http://www.pathsoc.org/ (grant number OS2015 060 2) received by VS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Students as co-developers of courses in higher education

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Flipping the Classroom for Health Managers

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Strategies and lessons learnt from user involvement in researching quality and safety in nursing homes and homecare

Purpose The purpose is to share strategies, rationales and lessons learnt from user involvement in a quality and safety improvement research project from the practice field in nursing homes and homecare services. Design/methodology/approach This is a viewpoint paper summarizing how researchers and co-researchers from the practice field of nursing homes and homecare services (nurse counsellors from different municipalities, patient ombudsman and next-of-kin representatives/and elderly care organization representant) experienced user involvement through all phases of the research project. The project included implementation of a leadership intervention. Findings Multiple strategies of user involvement were applied during the project including partnership in the consortium, employment of user representatives (co-researchers) and user-led research activities. The rationale was to ensure sound context adaptation of the intervention and development of tailor-made activities and tools based on equality and mutual trust in the collaboration. Both university-based researchers and Co-researchers experienced it as useful and necessary to involve or being involved in all phases of the research project, including the designing, planning, intervention implementation, evaluation and dissemination of results. Originality/value User involvement in research is a growing field. There is limited focus on this aspect in quality and safety interventions in nursing homes and homecare settings and in projects focussing on the leadership' role in improving quality and safety.publishedVersio

HMS-undersøkelsen i havbruk 2023

Denne rapporten presenterer resultatene fra en digital spørreundersøkelse blant 1283 ansatte i havbruksnæringen. Et stort flertall vurderte egen helse som god og trives på jobb. Samtidig var flere eksponert for negative arbeidsmiljøfaktorer som stress, ensidig arbeid og støy. Andre utfordringer kan knyttes til bemanning, målkonflikter mellom sikkerhet og produksjon og involvering i prosedyre-utforming og -innføring. 62 % oppga å ha opplevd nestenulykker i løpet av de siste to årene og 17 % hadde hatt fravær som var arbeidsrelatert i løpet av de siste 12 månedene. Generelt rapporterer de som hovedsakelig jobber på sjø å være mer eksponert for utfordringer knyttet til sikkerhet og arbeidsmiljø sammenlignet med de som jobber på land. Samarbeid, høye effektivitetskrav og verdsetting av arbeidet er områder som kan forbedres i grensesnittet mellom leverandører og oppdrettsselskapene. Se kapittel 8 for utfyllende oppsummering.Fiskeri - og havbruksnæringens forskningsfinansieringpublishedVersio

Endogenous production of IL-1B by breast cancer cells drives metastasis and colonisation of the bone microenvironment

Background: Breast cancer bone metastases are incurable highlighting the need for new therapeutic targets. After colonizing bone, breast cancer cells remain dormant, until signals from the microenvironment stimulate outgrowth into overt metastases. Here we show that endogenous production of IL-1B by tumor cells drives metastasis and growth in bone. Methods: Tumor/stromal IL-B and IL-1R1 expression was assessed in patient samples and effects of the IL-1R antagonist, Anakinra or the IL-1B antibody Canakinumab on tumor growth and spontaneous metastasis were measured in a humanized mouse model of breast cancer bone metastasis. Effects of tumor cell-derived IL-1B on bone colonisation and parameters associated with metastasis were measured in MDA-MB-231, MCF7 and T47D cells transfected with IL-1B/control. Results: In tissue samples from >1300 patients with stage II/III breast cancer, IL-1B in tumor cells correlated with relapse in bone (hazard ratio 1.85; 95% CI 1.05-3.26; P=0.02) and other sites (hazard ratio 2.09; 95% CI 1.26-3.48; P=0.0016). In a humanized model of spontaneous breast cancer metastasis to bone, Anakinra or Canakinumab reduced metastasis and reduced the number of tumor cells shed into the circulation. Production of IL-1B by tumor cells promoted EMT (altered E-Cadherin, N-Cadherin and G-Catenin), invasion, migration and bone colonisation. Contact between tumor and osteoblasts or bone marrow cells increased IL-1B secretion from all three cell types. IL-1B alone did not stimulate tumor cell proliferation. Instead, IL-1B caused expansion of the bone metastatic niche leading to tumor proliferation. Conclusion: Pharmacological inhibition of IL-1B has potential as a novel treatment for breast cancer metastasis