Identification of Pharmacological Modulators of HMGB1-Induced Inflammatory Response by Cell-Based Screening

High mobility group box 1 (HMGB1), a highly conserved, ubiquitous protein, is released into the circulation during sterile inflammation (e.g. arthritis, trauma) and circulatory shock. It participates in the pathogenesis of delayed inflammatory responses and organ dysfunction. While several molecules have been identified that modulate the release of HMGB1, less attention has been paid to identify pharmacological inhibitors of the downstream inflammatory processes elicited by HMGB1 (C23-C45 disulfide C106 thiol form). In the current study, a cell-based medium-throughput screening of a 5000+ compound focused library of clinical drugs and drug-like compounds was performed in murine RAW264.7 macrophages, in order to identify modulators of HMGB1-induced tumor-necrosis factor alpha (TNFα) production. Clinically used drugs that suppressed HMGB1-induced TNFα production included glucocorticoids, beta agonists, and the anti-HIV compound indinavir. A re-screen of the NIH clinical compound library identified beta-agonists and various intracellular cAMP enhancers as compounds that potentiate the inhibitory effect of glucocorticoids on HMGB1-induced TNFα production. The molecular pathways involved in this synergistic anti-inflammatory effect are related, at least in part, to inhibition of TNFα mRNA synthesis via a synergistic suppression of ERK/IκB activation. Inhibition of TNFα production by prednisolone+salbutamol pretreatment was also confirmed in vivo in mice subjected to HMGB1 injection; this effect was more pronounced than the effect of either of the agents administered separately. The current study unveils several drug-like modulators of HMGB1-mediated inflammatory responses and offers pharmacological directions for the therapeutic suppression of inflammatory responses in HMGB1-dependent diseases. © 2013 Gerö et al

Are Metastases from Metastases Clinical Relevant? Computer Modelling of Cancer Spread in a Case of Hepatocellular Carcinoma

Background: Metastasis formation remains an enigmatic process and one of the main questions recently asked is whether metastases are able to generate further metastases. Different models have been proposed to answer this question; however, their clinical significance remains unclear. Therefore a computer model was developed that permits comparison of the different models quantitatively with clinical data and that additionally predicts the outcome of treatment interventions. Methods: The computer model is based on discrete events simulation approach. On the basis of a case from an untreated patient with hepatocellular carcinoma and its multiple metastases in the liver, it was evaluated whether metastases are able to metastasise and in particular if late disseminated tumour cells are still capable to form metastases. Additionally, the resection of the primary tumour was simulated. The simulation results were compared with clinical data. Results: The simulation results reveal that the number of metastases varies significantly between scenarios where metastases metastasise and scenarios where they do not. In contrast, the total tumour mass is nearly unaffected by the two different modes of metastasis formation. Furthermore, the results provide evidence that metastasis formation is an early event and that late disseminated tumour cells are still capable of forming metastases. Simulations also allow estimating how the resection of the primary tumour delays the patient’s death. Conclusion: The simulation results indicate that for this particular case of a hepatocellular carcinoma late metastases, i.e.

Intra-abdominal hypertension due to heparin - induced retroperitoneal hematoma in patients with ventricle assist devices: report of four cases and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Elevated intra-abdominal pressure (IAP) has been identified as a cascade of pathophysiologic changes leading in end-organ failure due to decreasing compliance of the abdomen and the development of abdomen compartment syndrome (ACS). Spontaneous retroperitoneal hematoma (SRH) is a rare clinical entity seen almost exclusively in association with anticoagulation states, coagulopathies and hemodialysis; that may cause ACS among patients in the intensive care unit (ICU) and if treated inappropriately represents a high mortality rate.</p> <p>Case Presentation</p> <p>We report four patients (a 36-year-old Caucasian female, a 59-year-old White-Asian male, a 64-year-old Caucasian female and a 61-year-old Caucasian female) that developed an intra-abdominal hypertension due to heparin-induced retroperitoneal hematomas after implantation of ventricular assist devices because of heart failure. Three of the patients presented with dyspnea at rest, fatigue, pleura effusions in chest XR and increased heart rate although b-blocker therapy. A 36-year old female (the forth patient) presented with sudden, severe shortness of breath at rest, 10 days after an "acute bronchitis". At the time of the event in all cases international normalized ratio (INR) was <3.5 and partial thromboplastin time <65 sec. The patients were treated surgically, the large hematomas were evacuated and the systemic manifestations of the syndrome were reversed.</p> <p>Conclusion</p> <p>Identifying patients in the ICU at risk for developing ACS with constant surveillance can lead to prevention. ACS is the natural progression of pressure-induced end-organ changes and develops if IAP is not recognized and treated in a timely manner. Failure to recognize and appropriately treat ACS is fatal while timely intervention - if indicated - is associated with improvements in organ function and patient survival. Means for surgical decision making are based on clinical indicators of adverse physiology, rather than on a single measured parameter.</p

Persistent Place-Making in Prehistory: the Creation, Maintenance, and Transformation of an Epipalaeolithic Landscape

Most archaeological projects today integrate, at least to some degree, how past people engaged with their surroundings, including both how they strategized resource use, organized technological production, or scheduled movements within a physical environment, as well as how they constructed cosmologies around or created symbolic connections to places in the landscape. However, there are a multitude of ways in which archaeologists approach the creation, maintenance, and transformation of human-landscape interrelationships. This paper explores some of these approaches for reconstructing the Epipalaeolithic (ca. 23,000–11,500&nbsp;years BP) landscape of Southwest Asia, using macro- and microscale geoarchaeological approaches to examine how everyday practices leave traces of human-landscape interactions in northern and eastern Jordan. The case studies presented here demonstrate that these Epipalaeolithic groups engaged in complex and far-reaching social landscapes. Examination of the Early and Middle Epipalaeolithic (EP) highlights that the notion of “Neolithization” is somewhat misleading as many of the features we use to define this transition were already well-established patterns of behavior by the Neolithic. Instead, these features and practices were enacted within a hunter-gatherer world and worldview

Embedding design descriptions using lattice structures: Technical requirements, user perspectives and implementation

Commercially available engineering design tools typically operate on native data formats and support individual designers creating design descriptions which are shared within product development teams and across supply networks. The use of such tools results in a multiplicity of design descriptions. For example, a CAD system may be used to create a design Bill-of-Materials (BoM), which is a form of design description, but different BoMs are needed for downstream processes such as manufacturing and servicing. Conventional approaches to the integration of design descriptions is through the use of data exchange technologies or a common underlying meta-model to support, ultimately, a single, shared digital design description. These approaches have architectural elegance but their realworld feasibility is limited by the heterogeneous environment in which they must be implemented. The research reported in this paper challenges this thinking and explores the feasibility of embedding design descriptions into each other. We report early results exploring the feasibility of using lattice theory, where lattices are in the form of partially ordered sets, to embed multiple design structures into a given design description

Observationally derived rise in methane surface forcing mediated by water vapour trends

Atmospheric methane (CH4) mixing ratios exhibited a plateau between 1995 and 2006 and have subsequently been increasing. While there are a number of competing explanations for the temporal evolution of this greenhouse gas, these prominent features in the temporal trajectory of atmospheric CH4 are expected to perturb the surface energy balance through radiative forcing, largely due to the infrared radiative absorption features of CH4. However, to date this has been determined strictly through radiative transfer calculations. Here, we present a quantified observation of the time series of clear-sky radiative forcing by CH4 at the surface from 2002 to 2012 at a single site derived from spectroscopic measurements along with line-by-line calculations using ancillary data. There was no significant trend in CH4 forcing between 2002 and 2006, but since then, the trend in forcing was 0.026 ± 0.006 (99.7% CI) W m2 yr-1. The seasonal-cycle amplitude and secular trends in observed forcing are influenced by a corresponding seasonal cycle and trend in atmospheric CH4. However, we find that we must account for the overlapping absorption effects of atmospheric water vapour (H2O) and CH4 to explain the observations fully. Thus, the determination of CH4 radiative forcing requires accurate observations of both the spatiotemporal distribution of CH4 and the vertically resolved trends in H2O