Remifentanil ameliorates intestinal ischemia-reperfusion injury

published_or_final_versio

Notch and MAML-1 Complexation Do Not Detectably Alter the DNA Binding Specificity of the Transcription Factor CSL

Canonical Notch signaling is initiated when ligand binding induces proteolytic release of the intracellular part of Notch (ICN) from the cell membrane. ICN then travels into the nucleus where it drives the assembly of a transcriptional activation complex containing the DNA-binding transcription factor CSL, ICN, and a specialized co-activator of the Mastermind family. A consensus DNA binding site motif for the CSL protein was previously defined using selection-based methods, but whether subsequent association of Notch and Mastermind-like proteins affects the DNA binding preferences of CSL has not previously been examined.Here, we utilized protein-binding microarrays (PBMs) to compare the binding site preferences of isolated CSL with the preferred binding sites of CSL when bound to the CSL-binding domains of all four different human Notch receptors. Measurements were taken both in the absence and in the presence of Mastermind-like-1 (MAML1). Our data show no detectable difference in the DNA binding site preferences of CSL before and after loading of Notch and MAML1 proteins.These findings support the conclusion that accrual of Notch and MAML1 promote transcriptional activation without dramatically altering the preferred sites of DNA binding, and illustrate the potential of PBMs to analyze the binding site preferences of multiprotein-DNA complexes

Exercise capacity in patients with repaired Tetralogy of Fallot aged 6 to 63 years

OBJECTIVES: This study aimed to provide a perspective for the interpretation of exercise capacity (peakVO2) in patients with repaired Tetralogy of Fallot (patients with rTOF) by describing the course of peakVO2 from patients aged 6-63 years. METHODS: A retrospective study was performed between September 2001 and December 2016 in the German Heart Centre Munich, Germany, and in the University Medical Centre Groningen, the Netherlands. A total of 1175 cardiopulmonary exercise tests (CPETs) were collected from 586 patients with rTOF, 46% female. Maximal exertion was verified using a respiratory exchange ratio ≥1.00. PeakVO2 was modelled using time-dependent multilevel models for repeated measurements (n=889 in 300 patients), and compared with subject-specific reference values calculated by the models of Bongers et al and Mylius et al. RESULTS: The peakVO2 of patients with rTOF was reduced at all ages. At the age of 6, the peakVO2 was 614 mL/min (70% of predicted (95% CI 67 to 73)). The reduced increase in peakVO2 during adolescence resulted in a significant lower maximum peakVO2 of 1209 mL/min at 25 years (65% predicted, p<0.001). A linear decline after 25 years was observed in patients and references, although patients showed an accelerated decline, with a -0.24% point of predicted (95% CI 0.11 to 0.38) per year without differences between sexes (p=0.263). CONCLUSIONS: This study provides a context for peakVO2 across ages in patients with rTOF under contemporary treatment strategies. It showed that the reduction in peakVO2 originates from childhood and declines over time. Sex differences in patients with rTOF were similar to natural existing sex differences

Time to incorporate time in cost-effectiveness analysis

Cost-effectiveness analysis as a means to evaluate medical innovations has become well accepted in the UK and several other Western countries. An important assumption underlying this method is that costs and effects are constant over time. In reality, however, and especially in the short run, variations in costs and effects are likely to occur. These variations can lead to considerable deviations from the outcome of a conventional economic evaluation, which in turn may lead to serious implementation problems at a local level. Taking time into account explicitly in economic evaluations in health care may enhance their utility for both societal and local decision making, and may ultimately smooth the adoption of new and basically cost-effective health care technologies

GAFF-IC: realistic viscosities for isocyanate molecules with a GAFF-based force field

Aliphatic diisocyanates and their derivatives are key liquid components in the industrial processing of polyurethane materials. In particular, for the synthesis of crosslinked polyurethane materials, the higher functionality molecules obtained by reacting three -or more- diisocyanates are of interest. However, despite their widespread application, the relation between molecular structure and macroscopic physical properties, in particular viscosity, is poorly understood in these systems. In this work, we introduce a new force field parameter set, GAFF-IC, based on the widely-used and versatile GAFF force field, meant for accurate predictions of physical properties of isocyanate-based molecular liquids. The new parameters allow to predict the vaporization enthalpies and densities of several isocyanate-based molecules, which are found in excellent agreement with the available experimental data. The effectiveness and transferability of the improved parameters is verified by calculating the viscosities of several isocyanates, isocyanate dimers (uretdiones) and isocyanate trimers (isocyanurates), resulting in accurate viscosity predictions in excellent agreement with experimental values.This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sk lodowska-Curie Grant Agreement no. 642890 (http://thelink-project.eu/) and it was partially supported by the Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding UID/FIS/04650/2013, and by the project ”Search-ON2: Revitalization of HPC infrastructure of Uminho” (NORTE-07-0162-FEDER-0000869), under the National Strategic Reference Framework, through the European Regional Development Fun

Integrative Genomics Viewer

Author Manuscript 2012 May 07.To the Editor: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.National Institute of General Medical Sciences (U.S.) (R01GM074024)National Cancer Institute (U.S.) (R21CA135827)National Human Genome Research Institute (U.S.) (U54HG003067

Detecting microRNA binding and siRNA off-target effects from expression data.

Sylamer is a method for detecting microRNA target and small interfering RNA off-target signals in 3' untranslated regions from a ranked gene list, sorted from upregulated to downregulated, after a microRNA perturbation or RNA interference experiment. The output is a landscape plot that tracks occurrence biases using hypergeometric P-values for all words across the gene ranking. We demonstrated the utility, speed and accuracy of this approach on several datasets

Immunohistochemical evaluation of human epidermal growth factor receptor 2 and estrogen and progesterone receptors in breast carcinoma in Jordan

INTRODUCTION: Although breast carcinoma (BC) is the most common malignancy affecting Jordanian females and the affected population in Jordan is younger than that in the West, no information is available on its biological characteristics. Our aims in this study are to evaluate the expression of estrogen receptor (ER) and progesterone receptor (PR) and Her-2/neu overexpression in BC in Jordan, and to compare the expression of these with other prognostic parameters for BC such as histological type, histological grade, tumor size, patients' age, and number of lymph node metastases. METHOD: This is a retrospective study conducted in the Department of Pathology at Jordan University of Science and Technology. A confirmed 91 cases of BC diagnosed in the period 1995 to 1998 were reviewed and graded. We used immunohistochemistry to evaluate the expression of ER, PR, and Her-2. Immunohistochemical findings were correlated with age, tumor size, grade and axillary lymph node status. RESULTS: Her-2 was overexpressed in 24% of the cases. The mean age of Her-2 positive cases was 42 years as opposed to 53 years among Her-2 negative cases (p = 0.0001). Her-2 expression was inversely related to ER and PR expression. Her-2 positive tumors tended to be larger than Her-2 negative tumors with 35% overexpression among T3 tumors as opposed to 22% among T2 tumors (p = 0.13). Her-2 positive cases tended to have higher rates of axillary metastases, but this did not reach statistical significance. ER and PR positive cases were seen in older patients with smaller tumor sizes. CONCLUSION: Her-2 overexpression was seen in 24% of BC affecting Jordanian females. Her-2 overexpression was associated with young age at presentation, larger tumor size, and was inversely related to ER and PR expression. One-fifth of the carcinomas were Her-2 positive and ER negative. This group appears to represent an aggressive form of BC presenting at a young age with large primary tumors and a high rate of four or more axillary lymph node metastases

Chemotherapy-Response Monitoring of Breast Cancer Patients Using Quantitative Ultrasound-Based Intra-Tumour Heterogeneities

© 2017 The Author(s). Anti-cancer therapies including chemotherapy aim to induce tumour cell death. Cell death introduces alterations in cell morphology and tissue micro-structures that cause measurable changes in tissue echogenicity. This study investigated the effectiveness of quantitative ultrasound (QUS) parametric imaging to characterize intra-tumour heterogeneity and monitor the pathological response of breast cancer to chemotherapy in a large cohort of patients (n = 100). Results demonstrated that QUS imaging can non-invasively monitor pathological response and outcome of breast cancer patients to chemotherapy early following treatment initiation. Specifically, QUS biomarkers quantifying spatial heterogeneities in size, concentration and spacing of acoustic scatterers could predict treatment responses of patients with cross-validated accuracies of 82 ± 0.7%, 86 ± 0.7% and 85 ± 0.9% and areas under the receiver operating characteristic (ROC) curve of 0.75 ± 0.1, 0.80 ± 0.1 and 0.89 ± 0.1 at 1, 4 and 8 weeks after the start of treatment, respectively. The patients classified as responders and non-responders using QUS biomarkers demonstrated significantly different survivals, in good agreement with clinical and pathological endpoints. The results form a basis for using early predictive information on survival-linked patient response to facilitate adapting standard anti-cancer treatments on an individual patient basis

A Linear Model for Transcription Factor Binding Affinity Prediction in Protein Binding Microarrays

Protein binding microarrays (PBM) are a high throughput technology used to characterize protein-DNA binding. The arrays measure a protein's affinity toward thousands of double-stranded DNA sequences at once, producing a comprehensive binding specificity catalog. We present a linear model for predicting the binding affinity of a protein toward DNA sequences based on PBM data. Our model represents the measured intensity of an individual probe as a sum of the binding affinity contributions of the probe's subsequences. These subsequences characterize a DNA binding motif and can be used to predict the intensity of protein binding against arbitrary DNA sequences. Our method was the best performer in the Dialogue for Reverse Engineering Assessments and Methods 5 (DREAM5) transcription factor/DNA motif recognition challenge. For the DREAM5 bonus challenge, we also developed an approach for the identification of transcription factors based on their PBM binding profiles. Our approach for TF identification achieved the best performance in the bonus challenge