Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-β-induced collagen expression in hepatic stellate cells

During chronic liver injury hepatic stellate cells (HSCs), the principal source of extracellular matrix in the fibrotic liver, transdifferentiate into pro-fibrotic myofibroblast-like cells - a process potentially regulated by microRNAs (miRNAs). Recently, we found serum miRNA-25-3p (miR-25) levels were upregulated in children with Cystic Fibrosis (CF) without liver disease, compared to children with CF-associated liver disease and healthy individuals. Here we examine the role of miR-25 in HSC biology. MiR-25 was detected in the human HSC cell line LX-2 and in primary murine HSCs, and increased with culture-induced activation. Transient overexpression of miR-25 inhibited TGF-β and its type 1 receptor (TGFBR1) mRNA expression, TGF-β-induced Smad2 phosphorylation and subsequent collagen1α1 induction in LX-2 cells. Pull-down experiments with biotinylated miR-25 revealed Notch signaling (co-)activators ADAM-17 and FKBP14 as miR-25 targets in HSCs. NanoString analysis confirmed miR-25 regulation of Notch- and Wnt-signaling pathways. Expression of Notch signaling pathway components and endogenous Notch1 signaling was downregulated in miR-25 overexpressing LX-2 cells, as were components of Wnt signaling such as Wnt5a. We propose that miR-25 acts as a negative feedback anti-fibrotic control during HSC activation by reducing the reactivity of HSCs to TGF-β-induced collagen expression and modulating the cross-talk between Notch, Wnt and TGF-β signaling

Kinome profiling reveals breast cancer heterogeneity and identifies targeted therapeutic opportunities for triple negative breast cancer

Our understanding of breast cancer heterogeneity at the protein level is limited despite proteins being the ultimate effectors of cellular functions. We investigated the heterogeneity of breast cancer (41 primary tumors and 15 breast cancer cell lines) at the protein and phosphoprotein levels to identify activated oncogenic pathways and developing targeted therapeutic strategies. Heterogeneity was observed not only across histological subtypes, but also within subtypes. Tumors of the Triple negative breast cancer (TNBC) subtype distributed across four different clusters where one cluster (cluster ii) showed high deregulation of many proteins and phosphoproteins. The majority of TNBC cell lines, particularly mesenchymal lines, resembled the cluster ii TNBC tumors. Indeed, TNBC cell lines were more sensitive than non-TNBC cell lines when treated with targeted inhibitors selected based on upregulated pathways in cluster ii. In line with the enrichment of the upregulated pathways with onco-clients of Hsp90, we found synergy in combining Hsp90 inhibitors with several kinase inhibitors, particularly Erk5 inhibitors. The combination of Erk5 and Hsp90 inhibitors was effective in vitro and in vivo against TNBC leading to upregulation of pro-apoptotic effectors. Our studies contribute to proteomic profiling and improve our understanding of TNBC heterogeneity to provide therapeutic opportunities for this disease

Improving hand hygiene compliance in nursing homes: Protocol for a cluster randomized controlled trial (HANDSOME Study)

Background: Hand hygiene compliance is considered the most (cost-)effective measure for preventing health care-associated infections. While hand hygiene interventions have frequently been implemented and assessed in hospitals, there is limited knowledge about hand hygiene compliance in other health care settings and which interventions and implementation methods are effective. Objective: This study aims to evaluate the effect of a multimodal intervention to increase hand hygiene compliance of nurses in nursing homes through a cluster randomized controlled trial (HANDSOME study). Methods: Nursing homes were randomly allocated to 1 of 3 trial arms: Receiving the intervention at a predetermined date, receiving the identical intervention after an infectious disease outbreak, or serving as a control arm. Hand hygiene was evaluated in nursing homes by direct observation at 4 timepoints. We documented compliance with the World Health Organization's 5 moments of hand hygiene, specifically before touching a patient, before a clean/aseptic procedure, after body fluid exposure risk, after touching a patient, and after touching patient surroundings. The primary outcome is hand hygiene compliance of the nurses to the standards of the World Health Organization. The secondary outcome is infectious disease incidence among residents. Infectious disease incidence was documented by a staff member at each nursing home unit. Outcomes will be compared with the presence of norovirus, rhinovirus, and Escherichia coli on surfaces in the nursing homes, as measured using quantitative polymerase chain reaction. Results: The study was funded in September 2015. Data collection started in October 2016 and was completed in October 2017. Data analysis will be completed in 2020. Conclusions: HANDSOME studies the effectiveness of a hand hygiene intervention specifically for the nursing hom

Accuracy of routine laboratory tests to predict mortality and deterioration to severe or critical COVID-19 in people with SARS-CoV-2

Objectives This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows:  To assess the accuracy of routine blood-based laboratory tests to predict mortality and deterioration to severe or critical (from mild or moderate) COVID-19 in people with SARS-CoV-2 infection. Secondary objectives Where data are available, we will investigate whether prognostic accuracy varies according to a specific measurement or test, reference standard, timing of outcome verification, sample type, study design, and setting, including prevalence of the target condition (either by stratified analysis or meta-regression)

Hormonal control during infancy and testicular adrenal rest tumor development in males with congenital adrenal hyperplasia: a retrospective multicenter cohort study

IMPORTANCE Testicular adrenal rest tumors (TARTs), often found in male patients with congenital adrenal hyperplasia (CAH), are benign lesions causing testicular damage and infertility. We hypothesize that chronically elevated adrenocorticotropic hormone exposure during early life may promote TART development. OBJECTIVE This study aimed to examine the association between commencing adequate glucocorticoid treatment early after birth and TART development. DESIGN AND PARTICIPANTS This retrospective multicenter (n = 22) open cohort study collected longitudinal clinical and biochemical data of the first 4 years of life using the I-CAH registry and included 188 male patients (median age 13 years; interquartile range: 10-17) with 21-hydroxylase deficiency (n = 181) or 11-hydroxylase deficiency (n = 7). All patients underwent at least 1 testicular ultrasound. RESULTS TART was detected in 72 (38%) of the patients. Prevalence varied between centers. When adjusted for CAH phenotype, a delayed CAH diagnosis of >1 year, compared with a diagnosis within 1 month of life, was associated with a 2.6 times higher risk of TART diagnosis. TART onset was not predicted by biochemical disease control or bone age advancement in the first 4 years of life, but increased height standard deviation scores at the end of the 4-year study period were associated with a 27% higher risk of TART diagnosis. CONCLUSIONS AND RELEVANCE A delayed CAH diagnosis of >1 year vs CAH diagnosis within 1 month after birth was associated with a higher risk of TART development, which may be attributed to poor disease control in early life

Palliative care implementation in long-term care facilities : European Association for Palliative Care white paper

Objectives: The number of older people dying in long-term care facilities (LTCFs) is increasing globally, but care quality may be variable. A framework was developed drawing on empirical research findings from the Palliative Care for Older People (PACE) study and a scoping review of literature on the implementation of palliative care interventions in LTCFs. The PACE study mapped palliative care in LTCFs in Europe, evaluated quality of end-of-life care and quality of dying in a cross-sectional study of deceased residents of LTCFs in 6 countries, and undertook a cluster-randomized control trial that evaluated the impact of the PACE Steps to Success intervention in 7 countries. Working with the European Association for Palliative Care, a white paper was written that outlined recommendations for the implementation of interventions to improve palliative and end-of-life care for all older adults with serious illness, regardless of diagnosis, living in LTCFs. The goal of the article is to present these key domains and recommendations. Design: Transparent expert consultation. Setting: International experts in LTCFs. Participants: Eighteen (of 20 invited) international experts from 15 countries participated in a 1-day face-to-face Transparent Expert Consultation (TEC) workshop in Bern, Switzerland, and 21 (of 28 invited) completed a follow-up online survey. Methods: The TEC study used (1) a face-to-face workshop to discuss a scoping review and initial recommendations and (2) an online survey. Results: Thirty recommendations about implementing palliative care for older people in LTCFs were refined during the TEC workshop and, of these, 20 were selected following the survey. These 20 recommendations cover domains at micro (within organizations), meso (across organizations), and macro (at national or regional) levels addressed in 3 phases: establishing conditions for action, embedding in everyday practice, and sustaining ongoing change. Conclusions and implications: We developed a framework of 20 recommendations to guide implementation of improvements in palliative care in LTCFs. (C) 2020 AMDA - The Society for Post-Acute and Long-Term Care Medicine

Metabolomics Profile in Depression:A Pooled Analysis of 230 Metabolic Markers in 5283 Cases With Depression and 10,145 Controls

Background: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and nondepressed persons. Methods: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids, and low-molecular-weight metabolites; 98 lipid composition and particle concentration measures of lipoprotein subclasses; and 81 lipid and fatty acids ratios. For each metabolite measure, logistic regression analyses adjusted for gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses. Results: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q <.05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus symptoms. Conclusions: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity

Epigenome erosion and SOX10 drive neural crest phenotypic mimicry in triple-negative breast cancer

Intratumoral heterogeneity is caused by genomic instability and phenotypic plasticity, but how these features co-evolve remains unclear. SOX10 is a neural crest stem cell (NCSC) specifier and candidate mediator of phenotypic plasticity in cancer. We investigated its relevance in breast cancer by immunophenotyping 21 normal breast and 1860 tumour samples. Nuclear SOX10 was detected in normal mammary luminal progenitor cells, the histogenic origin of most TNBCs. In tumours, nuclear SOX10 was almost exclusive to TNBC, and predicted poorer outcome amongst cross-sectional (p = 0.0015, hazard ratio 2.02, n = 224) and metaplastic (p = 0.04, n = 66) cases. To understand SOX10’s influence over the transcriptome during the transition from normal to malignant states, we performed a systems-level analysis of co-expression data, de-noising the networks with an eigen-decomposition method. This identified a core module in SOX10’s normal mammary epithelial network that becomes rewired to NCSC genes in TNBC. Crucially, this reprogramming was proportional to genome-wide promoter methylation loss, particularly at lineage-specifying CpG-island shores. We propose that the progressive, genome-wide methylation loss in TNBC simulates more primitive epigenome architecture, making cells vulnerable to SOX10-driven reprogramming. This study demonstrates potential utility for SOX10 as a prognostic biomarker in TNBC and provides new insights about developmental phenotypic mimicry—a major contributor to intratumoral heterogeneity

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]