Anti-emetic effects of thalidomide: evidence, mechanism of action, and future directions

The rationale for using thalidomide (THD) as a treatment for nausea and vomiting during pregnancy in the late 1950s appears to have been based on its sedative or hypnotic properties. In contrast to contemporaneous studies on the anti-emetic activity of phenothiazines, we were unable to identify publications reporting preclinical or clinical evaluation of THD as an anti-emetic. Our survey of the literature revealed a clinical study in 1965 showing THD reduced vomiting in cancer chemotherapy which was substantiated by similar studies from 2000, particularly showing efficacy in the delayed phase of chemotherapy-induced nausea and vomiting. To identify the mechanism(s) potentially involved in thalidomide's anti-emetic activity we reviewed its pharmacology in the light of nausea and vomiting mechanisms and their pharmacology with a particular emphasis on chemotherapy and pregnancy. The process identified the following potential mechanisms: reduced secretion of Growth Differentiation Factor 15, suppression of inflammation/prostaglandin production, downregulation of cytotoxic drug induced upregulation of iNOS, and modulation of BK (KCa1.1) channels and GABAA/glutamate transmission at critical points in the emetic pathways (nucleus tractus solitarius, area postrema). We propose ways to investigate these hypothesized mechanisms and discuss the associated challenges (e.g., objective quantification of nausea) in addition to some of the more general aspects of developing novel drugs to treat nausea and vomiting

Macrophage transactivation for chemokine production identified as a negative regulator of granulomatous inflammation using agent-based modeling

Cellular activation in trans by interferons, cytokines and chemokines is a commonly recognized mechanism to amplify immune effector function and limit pathogen spread. However, an optimal host response also requires that collateral damage associated with inflammation is limited. This may be particularly so in the case of granulomatous inflammation, where an excessive number and / or excessively florid granulomas can have significant pathological consequences. Here, we have combined transcriptomics, agent-based modeling and in vivo experimental approaches to study constraints on hepatic granuloma formation in a murine model of experimental leishmaniasis. We demonstrate that chemokine production by non-infected Kupffer cells in the Leishmania donovani-infected liver promotes competition with infected KCs for available iNKT cells, ultimately inhibiting the extent of granulomatous inflammation. We propose trans-activation for chemokine production as a novel broadly applicable mechanism that may operate early in infection to limit excessive focal inflammation

Engineering simulations for cancer systems biology

Computer simulation can be used to inform in vivo and in vitro experimentation, enabling rapid, low-cost hypothesis generation and directing experimental design in order to test those hypotheses. In this way, in silico models become a scientific instrument for investigation, and so should be developed to high standards, be carefully calibrated and their findings presented in such that they may be reproduced. Here, we outline a framework that supports developing simulations as scientific instruments, and we select cancer systems biology as an exemplar domain, with a particular focus on cellular signalling models. We consider the challenges of lack of data, incomplete knowledge and modelling in the context of a rapidly changing knowledge base. Our framework comprises a process to clearly separate scientific and engineering concerns in model and simulation development, and an argumentation approach to documenting models for rigorous way of recording assumptions and knowledge gaps. We propose interactive, dynamic visualisation tools to enable the biological community to interact with cellular signalling models directly for experimental design. There is a mismatch in scale between these cellular models and tissue structures that are affected by tumours, and bridging this gap requires substantial computational resource. We present concurrent programming as a technology to link scales without losing important details through model simplification. We discuss the value of combining this technology, interactive visualisation, argumentation and model separation to support development of multi-scale models that represent biologically plausible cells arranged in biologically plausible structures that model cell behaviour, interactions and response to therapeutic interventions

Utilising a simulation platform to understand the effect of domain model assumptions

© The Author(s) 2014. This article is published with open access at Springerlink.com. Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.Computational and mathematical modelling approaches are increasingly being adopted in attempts to further our understanding of complex biological systems. This approach can be subjected to strong criticism as substantial aspects of the biological system being captured are not currently known, meaning assumptions need to be made that could have a critical impact on simulation response. We have utilised the CoSMoS process in the development of an agent-based simulation of the formation of Peyer's patches (PP), gut-associated lymphoid organs that have a key role in the initiation of adaptive immune responses to infection. Although the use of genetic tools, imaging technologies and ex vivo culture systems has provided significant insight into the cellular components and associated pathways involved in PP development, interesting questions remain that cannot be addressed using these approaches, and as such well justified assumptions have been introduced into our model to counter this. Here we focus not on the development of the model itself, but instead demonstrate how the resultant simulation can be used to assess how these assumptions impact the simulation response. For example, we consider the impact of our assumption that the migration rate of lymphoid tissue cells into the gut remains constant throughout PP development. We demonstrate that an analysis of the assumptions made in the construction of the domain model may either increase confidence in the model as a representation of the biological system it captures, or may suggest areas where further biological experimentation is required.This work was funded by the Wellcome Trust [ref:097829] through the Centre for Chronic Diseases and Disorders (C2D2) at the University of York. Paul Andrews is funded by EPSRC grant EP/I005943/1 “Resilient Futures.” Henrique Veiga-Fernandes is funded by Fundação para a Ciência e Tecnologia (PTDC/SAU-MII/100016/2008), Portugal, European Molecular Biology Organisation (Project 1648) and European Research Council (Project 207057). Jon Timmis is part funded by the Royal Society and the Royal Academy of Engineering. Funding for Mark Coles comes from grants from the Human Frontiers Science Program (RGP0006/2009) and the Medical Research Council (G0601156).info:eu-repo/semantics/publishedVersio

The Appalachian Model Teaching Consortium: Preparing Teachers for Rural Appalachia

The Appalachian Model Teacher Consortium is a partnership involving Radford University, Wytheville Community College, and the Grayson County (Virginia) School System. Its purpose is to prepare highly qualified teachers for rural southwest Virginia. The model was developed in response to the growing teacher shortage facing school districts in rural southwest Virginia. Poorer, more rural districts often have weaker tax bases that provide limited, and at times inadequate, financial support for their school districts. This lack of local resources often results in lower salaries and benefits when compared to many districts that compete for the shrinking pool of potential teachers. Additionally, rural communities are often geographically isolated areas and have fewer amenities that attract young teachers from outside the district. The Appalachian Model Teacher Consortium attempts to naturalize shortages by recruiting potential teachers from the local area, and providing incentives for them to stay and teach in their home community

Factors to Consider in Improving Prescription Drug Pharmacy Leaflets

Today, when consumers receive prescription drug pharmacy leaflets (also known as ‘consumer medication information’ or CMI), they often appear in small font size, with cluttered layouts, and distracting information. This problem has attracted the attention of the U.S. Food and Drug Administration in advocating for more comprehendible, accurate, and easy-to-access CMI formats. Our study of four different CMI prototypes shows that an expanded Over-the-Counter (OTC) Drug Facts prototype is the best for improving comprehension accuracy, and is especially effective for those with lower health literacy and health motivation. A simpler OTC prototype did not aid accuracy scores due in part to its lack of complexity; whereas the most complex prototype (the revised medication guide – similar to most CMI today) reduced leaflet likability and usage intentions. Finally, continued leaflet availability improved accuracy scores for lower health literacy and health motivation respondents. Implications for marketing and public health policy are offered

The effect of electrical stimulation on corticospinal excitability is dependent on application duration: a same subject pre-post test design

Background: In humans, corticospinal excitability is known to increase following motor electrical stimulation (ES) designed to mimic a voluntary contraction. However, whether the effect is equivalent with different application durations and whether similar effects are apparent for short and long applications is unknown. The aim of this study was to investigate whether the duration of peripheral motor ES influenced its effect on corticospinal excitability