Hemodynamic effects of lung recruitment maneuvers in acute respiratory distress syndrome

Background: Clinical trials have, so far, failed to establish clear beneficial outcomes of recruitment maneuvers (RMs) on patient mortality in acute respiratory distress syndrome (ARDS), and the effects of RMs on the cardiovascular system remain poorly understood. Methods: A computational model with highly integrated pulmonary and cardiovascular systems was configured to replicate static and dynamic cardio-pulmonary data from clinical trials. Recruitment maneuvers (RMs) were executed in 23 individual in-silico patients with varying levels of ARDS severity and initial cardiac output. Multiple clinical variables were recorded and analyzed, including arterial oxygenation, cardiac output, peripheral oxygen delivery and alveolar strain. Results: The maximal recruitment strategy (MRS) maneuver, which implements gradual increments of positive end expiratory pressure (PEEP) followed by PEEP titration, produced improvements in PF ratio, carbon dioxide elimination and dynamic strain in all 23 in-silico patients considered. Reduced cardiac output in the moderate and mild in silico ARDS patients produced significant drops in oxygen delivery during the RM (average decrease of 423 ml min-1 and 526 ml min-1, respectively). In the in-silico patients with severe ARDS, however, significantly improved gas-exchange led to an average increase of 89 ml min-1 in oxygen delivery during the RM, despite a simultaneous fall in cardiac output of more than 3 l min-1 on average. Post RM increases in oxygen delivery were observed only for the in silico patients with severe ARDS. In patients with high baseline cardiac outputs (>6.5 l min-1), oxygen delivery never fell below 700 ml min-1. Conclusions: Our results support the hypothesis that patients with severe ARDS and significant numbers of alveolar units available for recruitment may benefit more from RMs. Our results also indicate that a higher than normal initial cardiac output may provide protection against the potentially negative effects of high intrathoracic pressures associated with RMs on cardiac function. Results from in silico patients with mild or moderate ARDS suggest that the detrimental effects of RMs on cardiac output can potentially outweigh the positive effects of alveolar recruitment on oxygenation, resulting in overall reductions in tissue oxygen delivery

The behaviour of repeat visitors to museums: Review and empirical findings

This study presents a theoretical and operational framework for analysing repeat visit to museums. Starting from the literature on repeat visit in tourism, the specificities of these cultural attractions are made explicit through a review of theoretical and applied works. Consistently with previous contributors, the paper suggests that the analysis of actual past behaviours has to be preferred to the one of attitudes. The application of proper econometric models is also remarked in order to put into account individual profiles. Information coming from three techniques is then used in an integrated way in order to provide a more comprehensive view of the phenomenon. Evidence from an ad hoc survey suggests the necessity to give a greater attention to perceived cultural value during the visit, promoting cultural events during the week and addressed to children, and taking care of those visitors that come from far places also through an integrated tourist supply. © 2013 Springer Science+Business Media Dordrecht

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Linking Proteomic and Transcriptional Data through the Interactome and Epigenome Reveals a Map of Oncogene-induced Signaling

Cellular signal transduction generally involves cascades of post-translational protein modifications that rapidly catalyze changes in protein-DNA interactions and gene expression. High-throughput measurements are improving our ability to study each of these stages individually, but do not capture the connections between them. Here we present an approach for building a network of physical links among these data that can be used to prioritize targets for pharmacological intervention. Our method recovers the critical missing links between proteomic and transcriptional data by relating changes in chromatin accessibility to changes in expression and then uses these links to connect proteomic and transcriptome data. We applied our approach to integrate epigenomic, phosphoproteomic and transcriptome changes induced by the variant III mutation of the epidermal growth factor receptor (EGFRvIII) in a cell line model of glioblastoma multiforme (GBM). To test the relevance of the network, we used small molecules to target highly connected nodes implicated by the network model that were not detected by the experimental data in isolation and we found that a large fraction of these agents alter cell viability. Among these are two compounds, ICG-001, targeting CREB binding protein (CREBBP), and PKF118–310, targeting β-catenin (CTNNB1), which have not been tested previously for effectiveness against GBM. At the level of transcriptional regulation, we used chromatin immunoprecipitation sequencing (ChIP-Seq) to experimentally determine the genome-wide binding locations of p300, a transcriptional co-regulator highly connected in the network. Analysis of p300 target genes suggested its role in tumorigenesis. We propose that this general method, in which experimental measurements are used as constraints for building regulatory networks from the interactome while taking into account noise and missing data, should be applicable to a wide range of high-throughput datasets.National Science Foundation (U.S.) (DB1-0821391)National Institutes of Health (U.S.) (Grant U54-CA112967)National Institutes of Health (U.S.) (Grant R01-GM089903)National Institutes of Health (U.S.) (P30-ES002109

The PathOlogist: an automated tool for pathway-centric analysis

<p>Abstract</p> <p>Background</p> <p>The PathOlogist is a new tool designed to transform large sets of gene expression data into quantitative descriptors of pathway-level behavior. The tool aims to provide a robust alternative to the search for single-gene-to-phenotype associations by accounting for the complexity of molecular interactions.</p> <p>Results</p> <p>Molecular abundance data is used to calculate two metrics - 'activity' and 'consistency' - for each pathway in a set of more than 500 canonical molecular pathways (source: Pathway Interaction Database, <url>http://pid.nci.nih.gov</url>). The tool then allows a detailed exploration of these metrics through integrated visualization of pathway components and structure, hierarchical clustering of pathways and samples, and statistical analyses designed to detect associations between pathway behavior and clinical features.</p> <p>Conclusions</p> <p>The PathOlogist provides a straightforward means to identify the functional processes, rather than individual molecules, that are altered in disease. The statistical power and biologic significance of this approach are made easily accessible to laboratory researchers and informatics analysts alike. Here we show as an example, how the PathOlogist can be used to establish pathway signatures that robustly differentiate breast cancer cell lines based on response to treatment.</p

Selective Targeting of Tumorigenic Cancer Cell Lines by Microtubule Inhibitors

For anticancer drug therapy, it is critical to kill those cells with highest tumorigenic potential, even when they comprise a relatively small fraction of the overall tumor cell population. We have used the established NCI/DTP 60 cell line growth inhibition assay as a platform for exploring the relationship between chemical structure and growth inhibition in both tumorigenic and non-tumorigenic cancer cell lines. Using experimental measurements of “take rate” in ectopic implants as a proxy for tumorigenic potential, we identified eight chemical agents that appear to strongly and selectively inhibit the growth of the most tumorigenic cell lines. Biochemical assay data and structure-activity relationships indicate that these compounds act by inhibiting tubulin polymerization. Yet, their activity against tumorigenic cell lines is more selective than that of the other microtubule inhibitors in clinical use. Biochemical differences in the tubulin subunits that make up microtubules, or differences in the function of microtubules in mitotic spindle assembly or cell division may be associated with the selectivity of these compounds

The Combination of BH3-Mimetic ABT-737 with the Alkylating Agent Temozolomide Induces Strong Synergistic Killing of Melanoma Cells Independent of p53

Metastatic melanoma has poor prognosis and is refractory to most conventional chemotherapies. The alkylating agent temozolomide (TMZ) is commonly used in treating melanoma but has a disappointing response rate. Agents that can act cooperatively with TMZ and improve its efficacy are thus highly sought after. The BH3 mimetic ABT-737, which can induce apoptosis by targeting pro-survival Bcl-2 family members, has been found to enhance the efficacy of many conventional chemotherapeutic agents in multiple cancers. We found that combining TMZ and ABT-737 induced strong synergistic apoptosis in multiple human melanoma cell lines. When the drugs were used in combination in a mouse xenograft model, they drastically reduced tumor growth at concentrations where each individual drug had no significant effect. We found that TMZ treatment elevated p53 levels, and that the pro-apoptotic protein Noxa was elevated in TMZ/ABT-737 treated cells. Experiments with shRNA demonstrated that the synergistic effect of TMZ and ABT-737 was largely dependent on Noxa. Experiments with nutlin-3, a p53 inducer, demonstrated that p53 induction was sufficient for synergistic cell death with ABT-737 in a Noxa-dependent fashion. However, p53 was not necessary for TMZ/ABT-737 synergy as demonstrated by a p53-null line, indicating that TMZ and ABT-737 together induce Noxa in a p53-independent fashion. These results demonstrate that targeting anti-apoptotic Bcl-2 members is a promising method for treating metastatic melanoma, and that clinical trials with TMZ and Bcl-2 inhibitors are warranted

Quantitative global studies of reactomes and metabolomes using a vectorial representation of reactions and chemical compounds

<p>Abstract</p> <p>Background</p> <p>Global studies of the protein repertories of organisms are providing important information on the characteristics of the protein space. Many of these studies entail classification of the protein repertory on the basis of structure and/or sequence similarities. The situation is different for metabolism. Because there is no good way of measuring similarities between chemical reactions, there is a barrier to the development of global classifications of "metabolic space" and subsequent studies comparable to those done for protein sequences and structures.</p> <p>Results</p> <p>In this work, we propose a vectorial representation of chemical reactions, which allows them to be compared and classified. In this representation, chemical compounds, reactions and pathways may be represented in the same vectorial space. We show that the representation of chemical compounds reflects their physicochemical properties and can be used for predictive purposes. We use the vectorial representations of reactions to perform a global classification of the reactome of the model organism <it>E. coli</it>.</p> <p>Conclusions</p> <p>We show that this unsupervised clustering results in groups of enzymes more coherent in biological terms than equivalent groupings obtained from the EC hierarchy. This hierarchical clustering produces an optimal set of 21 groups which we analyzed for their biological meaning.</p