Increased PXR and Suppressed T-Cell Signaling Are Associated With Malignant Degeneration of Barrett's Esophagus

Background and Aims: Barrett's esophagus (BE) is the precursor lesion for esophageal adenocarcinoma (EAC). To detect EAC in early stage, patients with BE undergo endoscopic surveillance. Surveillance cohorts largely consist of nondysplastic BE (NDBE) patients with a low annual progression risk (&lt;0.5%). Predictive biomarkers for malignant progression of NDBE could improve efficacy of surveillance. Biomarker research has mostly focused on aberrant protein expression on BE epithelial cells. Moreover, insight in cell signaling driving malignant transformation is unknown. This study uses a data-driven approach to analyze tumor-stroma interaction in NDBE which progressed to high-grade dysplasia or EAC. Methods: In this case-control study, we performed RNA sequencing analysis on index NDBE biopsies from 6 patients who, during long-term follow-up, progressed and 7 who did not progress to high-grade dysplasia/EAC. For control samples, squamous and duodenum tissues from BE patients were analyzed. For validation, we used quantitative PCR. Results: Significant differences in BE transcriptomic profiles between progressors and nonprogressors were found by principal component and differential expression analyses. Ingenuity pathway analysis indicated that 8 cell signaling pathways were significantly upregulated in the progressors, and 14 pathways were significantly downregulated. The most interesting finding was the upregulation of the xenobiotic metabolism pregnane X receptor signaling pathway in the progressor cohort, while of the downregulated pathways in progressors, several were related to the immune system. Conclusion: These novel transcriptomic insights are fundamental for developing (chemo-)preventive therapies. These could be therapies, which protect against toxins, including biles, responsible for pregnane X receptor activation or which enhance protective immune mechanisms. The identified RNA markers are promising biomarkers for improving risk stratification in surveillance programs.</p

Hybrid optimization method with general switching strategy for parameter estimation

This article is available from: http://www.biomedcentral.com/1752-0509/2/26[Background] Modeling and simulation of cellular signaling and metabolic pathways as networks of biochemical reactions yields sets of non-linear ordinary differential equations. These models usually depend on several parameters and initial conditions. If these parameters are unknown, results from simulation studies can be misleading. Such a scenario can be avoided by fitting the model to experimental data before analyzing the system. This involves parameter estimation which is usually performed by minimizing a cost function which quantifies the difference between model predictions and measurements. Mathematically, this is formulated as a non-linear optimization problem which often results to be multi-modal (non-convex), rendering local optimization methods detrimental.[Results] In this work we propose a new hybrid global method, based on the combination of an evolutionary search strategy with a local multiple-shooting approach, which offers a reliable and efficient alternative for the solution of large scale parameter estimation problems.[Conclusion] The presented new hybrid strategy offers two main advantages over previous approaches: First, it is equipped with a switching strategy which allows the systematic determination of the transition from the local to global search. This avoids computationally expensive tests in advance. Second, using multiple-shooting as the local search procedure reduces the multi-modality of the non-linear optimization problem significantly. Because multiple-shooting avoids possible spurious solutions in the vicinity of the global optimum it often outperforms the frequently used initial value approach (single-shooting). Thereby, the use of multiple-shooting yields an enhanced robustness of the hybrid approach.This work was supported by the European Community as part of the FP6 COSBICS Project (STREP FP6-512060), the German Federal Ministry of Education and Research, BMBF-project FRISYS (grant 0313921) and Xunta de Galicia (PGIDIT05PXIC40201PM).Peer reviewe

Food and Nutrition Security Indicators: A Review

In this paper, we review existing food and nutrition security indicators, discuss some of their advantages and disadvantages, and finally classify them and describe their relationships and overlaps. In order to achieve this, the paper makes reference to the existing definitions of food and nutrition security (FNS), in particular as they have been agreed upon and implemented in the FoodSecure project (www.foodsecure.eu). The main existing conceptual frameworks of FNS predating the present paper are also used as guidelines and briefly discussed. Finally, we make recommendations in terms of the most appropriate FNS indicators to quantify the impacts of various shocks and interventions on food and nutrition security outcomes

Impact of recurrent mitral regurgitation after mitral valve repair for functional mitral regurgitation: Long-term analysis of competing outcomes

Aims Recurrent mitral regurgitation (MR) has been reported after mitral valve repair for functional MR. However, the impact of recurrent MR on long-term survival remains poorly defined. In the present study, mortality-adjusted recurrent MR rates, the clinical impact of recurrent MR and its determinants were studied in patients after mitral valve repair with revascularization for functional MR in the setting of ischaemic heart disease. Methods and results Long-term clinical and echocardiographic outcome was evaluated in 261 consecutive patients after restrictive mitral annuloplasty and revascularization for moderate to severe functional MR, between 2000 and 2014. The cumulative incidence of recurrent MR ≥ Grade 2, assessed by competing risk analysis, was 9.6 ± 1.8% at 1-year, 20.3 ± 2.5% at 5-year, and 27.6 ± 2.9% at 10-year follow-up. Cumulative survival was 85.8% [95% confidence interval (CI) 81.0–90.0] at 1-year, 67.3% (95% CI 61.1–72.6%) at 5-year, and 46.1% (95% CI 39.4–52.6%) at 10-year follow-up. Age, preoperative New York Heart Association Class III or IV, a history of renal failure, and recurrence of MR expressed as a time-dependent variable [HR 3.28 (1.87–5.75), P < 0.001], were independently associated with an increased mortality risk. Female gender, a history of ST-elevation myocardial infarction, a preoperative QRS duration ≥120 ms, a higher preoperative MR grade, and a higher indexed left ventricular end-systolic volume were independently associated with an increased likelihood of recurrent MR. Conclusion Mitral valve repair for functional ischaemic MR resulted in a low incidence of recurrent MR with favourable clinical outcome up to 10 years after surgery. Presence of recurrent MR at any moment after surgery proved to be independently associated with an increased risk for mortality

Single-cell transcriptomics following ischemic injury identifies a role for B2M in cardiac repair

The efficiency of the repair process following ischemic cardiac injury is a crucial determinant for the progression into heart failure and is controlled by both intra- and intercellular signaling within the heart. An enhanced understanding of this complex interplay will enable better exploitation of these mechanisms for therapeutic use. We used single-cell transcriptomics to collect gene expression data of all main cardiac cell types at different time-points after ischemic injury. These data unveiled cellular and transcriptional heterogeneity and changes in cellular function during cardiac remodeling. Furthermore, we established potential intercellular communication networks after ischemic injury. Follow up experiments confirmed that cardiomyocytes express and secrete elevated levels of beta-2 microglobulin in response to ischemic damage, which can activate fibroblasts in a paracrine manner. Collectively, our data indicate phase-specific changes in cellular heterogeneity during different stages of cardiac remodeling and allow for the identification of therapeutic targets relevant for cardiac repair

Donor InSight: characteristics and representativeness of a Dutch cohort study on blood and plasma donors

BACKGROUND AND OBJECTIVES: More insight into donor health and behaviour may contribute to more efficient and focused strategies regarding donor care and management. Donor InSight (DIS) is a Dutch cohort study of blood and plasma donors. We aimed to outline the objectives and methods of DIS, describe the cohort, and compare it to the active Dutch donor population. MATERIALS AND METHODS: In 2007-2009 (DIS-I, n = 31 338) and 2012-2013 (DIS-II, 34 826, of whom 22 132 also participated in DIS-I) questionnaire data on demographics, donation, lifestyle, family composition, health and disease were collected. A second follow-up (DIS-III, n = 3046), including donors with differing haemoglobin trajectories, was completed in 2015-2016. DIS-III includes data on genetic determinants, iron and red cell indices. Representativeness of the DIS-I sample for the entire Dutch donor population was assessed by comparing characteristics of both. RESULTS: Donor InSight was initially set up because of a need for more detailed information and evidence as a basis for decision-making in blood banks. DIS-I sample is comparable to the total Dutch donor population in terms of age, body mass index, haemoglobin level, blood pressure, blood type and donation behaviour. CONCLUSION: Donor InSight is a cohort study representative of the Dutch donor population. It provides evidence to support evidence-based decision making

Topology Optimization and Additive Manufacturing – A Perfect Symbiosis?

Additive Manufacturing (AM) increasingly enables the realization of structures, which have a much greater freedom of design und can therefore better use nature as a design ideal. Bionic design principles have already been introduced into general design approaches, and several topology optimization systems (TO) are available today to increase structural stiffness and to enable lightweight design. AM and TO, used in synergy, promise completely new application areas. However, staircase effects resulting from a layer-by-layer build process and unavoidable support structures which must be mechanically removed afterwards are disadvantageous with respect to surface texture and strength properties. The present article addresses the question of how far the notches resulting from the staircase effect of Additive Manufacturing and the support structures removed decrease the strength of components. Most engineers try to follow the inner flow of forces in a part’s design by smoothening surfaces in notched areas. Considering this, a elected component is investigated with finite element analysis (FEA) with special regard for the concentration of tress arising from surface notch effects. An outlook is given as regards how a reduction of the notch effect from the taircase effect can be achieved effectively

Reversible cause of cardiac arrest and secondary prevention implantable cardioverter defibrillators in patients with coronary artery disease: Value of complete revascularization and lge-cmr

BACKGROUND: In survivors of sudden cardiac arrest with obstructive coronary artery disease, it remains challenging to distinguish ischemia as a reversible cause from irreversible scar-related ventricular arrhythmias. We aimed to evaluate the value of implantable cardioverter-defibrillator (ICD) implantation in sudden cardiac arrest survivors with presumably reversible ischemia and complete revascularization. METHODS AND RESULTS: This multicenter retrospective cohort study included 276 patients (80% men, age 67±10 years) receiving ICD implantation for secondary prevention. Angiography was performed before ICD implantation. A subgroup of 166 (60%) patients underwent cardiac magnetic resonance imaging with late gadolinium enhancement before implantation. Patients were divided in 2 groups, (1) ICD-per-guideline, including 228 patients with incomplete revascularization or left ventricular ejection fraction ≤35%, and (2) ICD-off-label, including 48 patients with complete revascularization and left ventricular ejection fraction >35%. The primary outcome was time to appropriate device therapy (ADT). During 4.0 years (interquartile range, 3.5–4.6) of follow-up, ADT developed in 15% of the ICD-off-label group versus 43% of the ICD-per-guideline group. Time to ADT was comparable in the ICD-off-label and ICD-per-guideline groups (hazard ratio (HR), 0.46; P=0.08). No difference in mortality was observed (HR, 0.95; P=0.93). Independent predictors of ADT included age (HR, 1.03; P=0.01), left ventricular end-diastolic volume HR, (1.05 per 10 mL increase; P>0.01) and extent of transmural late gadolinium enhancement (HR, 1.12; P=0.04). CONCLUSIONS: This study demonstrates that sudden cardiac arrest survivors with coronary artery disease remain at high risk of recurrent ventricular arrhythmia, even after complete revascularization and with preserved left ventricular function. Late gadolinium enhancement–cardiac magnetic resonance imaging derived left ventricular volumes and extent of myocardial scar were independently associated with

TRIM46 Organizes Microtubule Fasciculation in the Axon Initial Segment

Selective cargo transport into axons and dendrites over the microtubule network is essential for neuron polarization. The axon initial segment (AIS) separates the axon from the somatodendritic compartment and controls the microtubule-dependent transport into the axon. Interestingly, the AIS has a characteristic microtubule organization; it contains bundles of closely spaced microtubules with electron dense cross-bridges, referred to as microtubule fascicles. The microtubule binding protein TRIM46 localizes to the AIS and when overexpressed in non-neuronal cells forms microtubule arrays that closely resemble AIS fascicles in neurons. However, the precise role of TRIM46 in microtubule fasciculation in neurons has not been studied. Here we developed a novel correlative light and electron microscopy approach to study AIS microtubule organization. We show that in cultured rat hippocampal neurons of both sexes, TRIM46 levels steadily increase at the AIS during early neuronal differentiation and at the same time closely spaced microtubules form, whereas the fasciculated microtubules appear at later developmental stages. Moreover, we localized TRIM46 to the electron dense cross-bridges and show that depletion of TRIM46 causes loss of cross-bridges and increased microtubule spacing. These data indicate that TRIM46 has an essential role in organizing microtubule fascicles in the AIS.SIGNIFICANCE STATEMENT The axon initial segment (AIS) is a specialized region at the proximal axon where the action potential is initiated. In addition the AIS separates the axon from the somatodendritic compartment, where it controls protein transport to establish and maintain neuron polarity. Cargo vesicles destined for the axon recognize specialized microtubule tracks that enter the AIS. Interestingly the microtubules entering the AIS form crosslinked bundles, called microtubule fascicules. Recently we found that the microtubule-binding protein TRIM46 localizes to the AIS, where it may organize the AIS microtubules. In the present study we developed a novel correlative light and electron microscopy approach to study the AIS microtubules during neuron development and identified an essential role for TRIM46 in microtubule fasciculation

TRIM46 Organizes Microtubule Fasciculation in the Axon Initial Segment

Selective cargo transport into axons and dendrites over the microtubule network is essential for neuron polarization. The axon initial segment (AIS) separates the axon from the somatodendritic compartment and controls the microtubule-dependent transport into the axon. Interestingly, the AIS has a characteristic microtubule organization; it contains bundles of closely spaced microtubules with electron dense cross-bridges, referred to as microtubule fascicles. The microtubule binding protein TRIM46 localizes to the AIS and when overexpressed in non-neuronal cells forms microtubule arrays that closely resemble AIS fascicles in neurons. However, the precise role of TRIM46 in microtubule fasciculation in neurons has not been studied. Here we developed a novel correlative light and electron microscopy approach to study AIS microtubule organization. We show that in cultured rat hippocampal neurons of both sexes, TRIM46 levels steadily increase at the AIS during early neuronal differentiation and at the same time closely spaced microtubules form, whereas the fasciculated microtubules appear at later developmental stages. Moreover, we localized TRIM46 to the electron dense cross-bridges and show that depletion of TRIM46 causes loss of cross-bridges and increased microtubule spacing. These data indicate that TRIM46 has an essential role in organizing microtubule fascicles in the AIS.SIGNIFICANCE STATEMENT The axon initial segment (AIS) is a specialized region at the proximal axon where the action potential is initiated. In addition the AIS separates the axon from the somatodendritic compartment, where it controls protein transport to establish and maintain neuron polarity. Cargo vesicles destined for the axon recognize specialized microtubule tracks that enter the AIS. Interestingly the microtubules entering the AIS form crosslinked bundles, called microtubule fascicules. Recently we found that the microtubule-binding protein TRIM46 localizes to the AIS, where it may organize the AIS microtubules. In the present study we developed a novel correlative light and electron microscopy approach to study the AIS microtubules during neuron development and identified an essential role for TRIM46 in microtubule fasciculation