Ion channels in control of pancreatic stellate cell migration

Pancreatic stellate cells (PSCs) play a critical role in the progression of pancreatic ductal adenocarcinoma (PDAC). Once activated, PSCs support proliferation and metastasis of carcinoma cells. PSCs even co-metastasise with carcinoma cells. This requires the ability of PSCs to migrate. In recent years, it has been established that almost all “hallmarks of cancer” such as proliferation or migration/invasion also rely on the expression and function of ion channels. So far, there is only very limited information about the function of ion channels in PSCs. Yet, there is growing evidence that ion channels in stromal cells also contribute to tumor progression. Here we investigated the function of K(Ca)3.1 channels in PSCs. K(Ca)3.1 channels are also found in many tumor cells of different origin. We revealed the functional expression of K(Ca)3.1 channels by means of Western blot, immunofluorescence and patch clamp analysis. The impact of K(Ca)3.1 channel activity on PSC function was determined with live-cell imaging and by measuring the intracellular Ca2(+) concentration ([Ca(2+)](i)). K(Ca)3.1 channel blockade or knockout prevents the stimulation of PSC migration and chemotaxis by reducing the [Ca(2+)](i) and calpain activity. K(Ca)3.1 channels functionally cooperate with TRPC3 channels that are upregulated in PDAC stroma. Knockdown of TRPC3 channels largely abolishes the impact of K(Ca)3.1 channels on PSC migration. In summary, our results clearly show that ion channels are crucial players in PSC physiology and pathophysiology

RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.</p

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Keeping people healthy: skill-mix innovations for improved disease prevention and health promotion

This chapter provides an overview of skill-mix strategies that exist in primary and secondary prevention and health promotion, and consider the evidence of their effects while also pointing out the existing gaps in evidence and research. It summarizes common trends and patterns of the major skill-mix developments and reforms that occurred across Europe, and present country examples in different contexts

The role of patient navigators in ambulatory care: overview of systematic reviews

Background: Patient navigators have been introduced across various countries to enable timely access to healthcare services and to ensure completion of diagnosis and follow-up of care. There is an increasing evidence on the the role of patient navigation for patients and healthcare systems. The aim of this study was to analyse the evidence on patient navigation interventions in ambulatory care and to evaluate their effects on individuals and health system outcomes. Methods: An overview of reviews was conducted, following a prespecified protocol. All patients in ambulatory care or transitional care setting were included in this review as long as it was related to the role of patient navigators. The study analysed patient navigators covering a wide range of health professionals such as physicians, nurses, pharmacists, social workers and lay health workers or community-based workers with no or very limited training. Studies including patient-related measures and health system-related outcomes were eligible for inclusion. A rigorous search was performed in multiple data bases. After reaching a high inter-rater agreement of 0.86, title and abstract screening was independently performed. Of an initial 14,248 search results and an additional 62 articles identified through the snowballing approach, a total of 7159 hits were eligible for title/abstract screening. 679 articles were included for full-text screening. Results: Eleven systematic reviews were included covering various patient navigation intervention in cancer care, disease screening, transitional care and for various chronic conditions and multimorbidity. Nine systematic reviews primarily tailored services to ethnic minorities or other disadvantaged groups. Patient navigators performed tasks such as providing education and counselling, translations, home visits, outreach, scheduling of appointments and follow-up. Eight reviews identified positive outcomes in expanding access to care, in particular for vulnerable patient groups. Two reviews on patient navigation in transitional care reported improved patient outcomes, hospital readmission rates and mixed evidence on quality of life and emergency department visits. Two reviews demonstrated improved patient outcomes for persons with various chronic conditions and multimorbidity. Conclusions: Patient navigators were shown to expand access to screenings and health services for vulnerable patients or population groups with chronic conditions who tend to underuse health services