A BAYESIAN APPROACH TO DOSE-RESPONSE ASSESSMENT AND DRUG-DRUG INTERACTION ANALYSIS: APPLICATION TO IN VITRO STUDIES

The considerable search for synergistic agents in cancer research is motivated by the therapeutic benefits achieved by combining anti-cancer agents. Synergistic agents make it possible to reduce dosage while maintaining or enhancing a desired effect. Other favorable outcomes of synergistic agents include reduction in toxicity and minimizing or delaying drug resistance. Dose-response assessment and drug-drug interaction analysis play an important part in the drug discovery process, however analysis are often poorly done. This dissertation is an effort to notably improve dose-response assessment and drug-drug interaction analysis. The most commonly used method in published analysis is the Median-Effect Principle/Combination Index method (Chou and Talalay, 1984). The Median-Effect Principle/Combination Index method leads to inefficiency by ignoring important sources of variation inherent in dose-response data and discarding data points that do not fit the Median-Effect Principle. Previous work has shown that the conventional method yields a high rate of false positives (Boik, Boik, Newman, 2008; Hennessey, Rosner, Bast, Chen, 2010) and, in some cases, low power to detect synergy. There is a great need for improving the current methodology. We developed a Bayesian framework for dose-response modeling and drug-drug interaction analysis. First, we developed a hierarchical meta-regression dose-response model that accounts for various sources of variation and uncertainty and allows one to incorporate knowledge from prior studies into the current analysis, thus offering a more efficient and reliable inference. Second, in the case that parametric dose-response models do not fit the data, we developed a practical and flexible nonparametric regression method for meta-analysis of independently repeated dose-response experiments. Third, and lastly, we developed a method, based on Loewe additivity that allows one to quantitatively assess interaction between two agents combined at a fixed dose ratio. The proposed method makes a comprehensive and honest account of uncertainty within drug interaction assessment. Extensive simulation studies show that the novel methodology improves the screening process of effective/synergistic agents and reduces the incidence of type I error. We consider an ovarian cancer cell line study that investigates the combined effect of DNA methylation inhibitors and histone deacetylation inhibitors in human ovarian cancer cell lines. The hypothesis is that the combination of DNA methylation inhibitors and histone deacetylation inhibitors will enhance antiproliferative activity in human ovarian cancer cell lines compared to treatment with each inhibitor alone. By applying the proposed Bayesian methodology, in vitro synergy was declared for DNA methylation inhibitor, 5-AZA-2'-deoxycytidine combined with one histone deacetylation inhibitor, suberoylanilide hydroxamic acid or trichostatin A in the cell lines HEY and SKOV3. This suggests potential new epigenetic therapies in cell growth inhibition of ovarian cancer cells.

My patient is thrombocytopenic! Is (s)he? Why? And what shall I do? A practical approach to thrombocytopenia

Solving the riddle of a thrombocytopenic patient is a difficult and fascinating task. The spectrum of possible aetiologies is wide, ranging from an in vitro artefact to severe treatment-resistant thrombocytopenic bleeding conditions, or even life-threatening prothrombotic states. Moreover, thrombocytopenia by itself does not protect from thrombosis and sometimes a patient with a low platelet count requires concomitant antithrombotic treatment as well. In order to identify and treat the cause and the effects of the thrombocytopenia, you have to put together several pieces of information, solving a unique jig-jaw puzzle. The present work is not a textbook article about thrombocytopenia, rather a collection of differential diagnostic thoughts, treatment concepts, and some basic knowledge, that you can retrieve when facing your next thrombocytopenic patient. Enjoy reading it, but most importantly enjoy taking care of patients with a low platelet count. I bet the present work will assist you in this challenging and rewarding clinical task.

Project Alpha: A culturally appropriate approach to adolescent male sex education

In the United States today, adolescents face unacceptably high rates of mortality and morbidity due to the contraction of HIV/AIDS, sexually transmitted diseases and teenage pregnancy. In view of these rates, there is a need for applied preventive interventions to delay adolescent sexual behavior until adulthood. Project Alpha was a school-adopted, quasi-experimental program for adolescent male students attending Sharpstown High School in Houston, Texas. This intervention used student newsletters to provide specific role-model stories on community and student role models who have changed attitudes or improved efficacy to abstain from sexual behavior until adulthood. It was hypothesized that teenagers exposed to the intervention would show improvements in knowledge, beliefs, avoidance skills, perceived norms, intentions and self-efficacy to delay sexual behavior compared to no-treatment reference teenagers in the same school.^ In total, the Project Alpha program had a significant effect on student knowledge, beliefs (towards abstinence and having sex with multiple partners), perceived risk (HIV/STD testing), self-efficacy (could avoid sex with attractive girl who wants to have sex), perceived social norms (friends believing in sexual abstinence) and sexual intentions. However, no significant intervention effects were found in student's beliefs (that it was OK to have sex with girlfriend), perceived risk of HIV/STD, self-efficacy (to avoid sex with girlfriend) and social norms (friends believe it is OK to have sex with a girlfriend and multiple partners in the same month). ^

A social network-based approach to assess de facto independence of regulatory agencies

This article uses a policy network perspective to assess the independence of regulatory agencies (RAs) in liberalized public utility sectors. We focus on the de facto independence of RAs from elected politicians, regulatees and other co-regulators. We go further than previous studies, which only undertook a general analysis of the de jure independence of RAs from political authorities. Specifically, we apply a social network analysis (SNA), which concentrates on the attributes and relational profiles of all actors involved in new regulatory arrangements. The concept of de facto independence is applied to the Swiss telecommunications sector in order to provide initial empirical insights. Results clearly show that SNA indicators are an appropriate tool to identify the de facto independence of RAs and can improve knowledge about the issues arising from the emergence of the ‘regulatory State’.

Itineraries of pottery: a mixed methods approach to mobility

Neolithic wetland sites in the Swiss Plateau provide an extraordinary database for the study of mobilities, entanglements and transformations in material culture. Based on dendrochronologically dated settlements between 3900 and 3500 BC, two regional pottery styles and their local variations are well known, Pfyn and Cortaillod. The vessels share the same habitus and were made of local raw materials. However, some vessels specific to other pottery styles are also present in the sites. By focusing on itineraries of vessels and shifts in pottery knowledge, their appropriation in different contexts and the resulting material entanglements, we want to approach the multiple regimes of mobility: At Lake Constance - known for Pfyn pottery - specific Michelsberg vessels like tulip beakers and lugged jars occur in small numbers. These travelling objects were produced with exogenous raw materials and transported to the sites from Southern Germany. At Concise (Lake Neuchâtel) besides the local Cortaillod pottery the whole repertoire of NMB pottery, characteristic for Eastern France, was also produced. Further cases from the same space-time frame point to other regimes of mobility. In our two PhD-projects we compare pottery practices - styles, techniques, raw materials - from over 20 key sites in the region. Based on Bourdieu’s reflexive anthropology, we apply different qualitative and quantitative archaeological and archaeometrical methods, thus striving for a deeper understanding of habitus and the transformative potential of moving people, objects and ideas on local and regional scales and related social contexts.

A multi-level stakeholder approach to sustainable land management

Soils provide us with over 90% of all human food, livestock feed, fibre and fuel on Earth. Soils, however, have more than just productive functions. The key challenge in coming years will be to address the diverse and potentially conflicting demands now being made by human societies and other forms of life, while ensuring that future generations have the same potential to use soils and land of comparable quality. In a multi-level stakeholder approach, down-to-earth action will have to be supplemented with measures at various levels, from households to communities, and from national policies to international conventions. Knowledge systems, both indigenous and scientific, and related research and learning processes must play a central role. Ongoing action can be enhanced through a critical assessment of the impact of past achievements, and through better cooperation between people and institutions.

A unified approach to architecture conformance checking

Architectural decisions can be interpreted as structural and behavioral constraints that must be enforced in order to guarantee overarching qualities in a system. Enforcing those constraints in a fully automated way is often challenging and not well supported by current tools. Current approaches for checking architecture conformance either lack in usability or offer poor options for adaptation. To overcome this problem we analyze the current state of practice and propose an approach based on an extensible, declarative and empirically-grounded specification language. This solution aims at reducing the overall cost of setting up and maintaining an architectural conformance monitoring environment by decoupling the conceptual representation of a user-defined rule from its technical specification prescribed by the underlying analysis tools. By using a declarative language, we are able to write tool-agnostic rules that are simple enough to be understood by untrained stakeholders and, at the same time, can be can be automatically processed by a conformance checking validator. Besides addressing the issue of cost, we also investigate opportunities for increasing the value of conformance checking results by assisting the user towards the full alignment of the implementation with respect to its architecture. In particular, we show the benefits of providing actionable results by introducing a technique which automatically selects the optimal repairing solutions by means of simulation and profit-based quantification. We perform various case studies to show how our approach can be successfully adopted to support truly diverse industrial projects. We also investigate the dynamics involved in choosing and adopting a new automated conformance checking solution within an industrial context. Our approach reduces the cost of conformance checking by avoiding the need for an explicit management of the involved validation tools. The user can define rules using a convenient high-level DSL which automatically adapts to emerging analysis requirements. Increased usability and modular customization ensure lower costs and a shorter feedback loop.

An innovative approach to impacting student academic achievement and attitudes: Pilot study of the HEADS UP Virtual Molecular Biology Lab

Objective. To evaluate the HEADS UP Virtual Molecular Biology Lab, a computer-based simulated laboratory designed to teach advanced high school biology students how to create a mouse model. ^ Design. A randomized clinical control design of forty-four students from two science magnet high schools in Mercedes, Texas was utilized to assess knowledge and skills of molecular laboratory procedures, attitudes towards science and computers as a learning tool, and usability of the program. ^ Measurements. Data was collected using five paper-and-pencil formatted questionnaires and an internal "lab notebook." ^ Results. The Virtual Lab was found to significantly increase student knowledge over time (p<0.005) and with each use (p<0.001) as well as positively increase attitudes towards computers (p<0.001) and skills (p<0.005). No significant differences were seen in science attitude scores.^ Conclusion. These results provide evidence that the HEADS UP Virtual Molecular Biology Lab is a potentially effective educational tool for high school molecular biology education.^

A collaborative filtering approach to mitigate the new user cold start problem.

The new user cold start issue represents a serious problem in recommender systems as it can lead to the loss of new users who decide to stop using the system due to the lack of accuracy in the recommenda- tions received in that first stage in which they have not yet cast a significant number of votes with which to feed the recommender system?s collaborative filtering core. For this reason it is particularly important to design new similarity metrics which provide greater precision in the results offered to users who have cast few votes. This paper presents a new similarity measure perfected using optimization based on neu- ral learning, which exceeds the best results obtained with current metrics. The metric has been tested on the Netflix and Movielens databases, obtaining important improvements in the measures of accuracy, precision and recall when applied to new user cold start situations. The paper includes the mathematical formalization describing how to obtain the main quality measures of a recommender system using leave- one-out cross validation.

An approach to stakeholders involvement in the preparedness for nuclear and radiological emergency response & recovery in Spain

The elaboration of a generic decision-making strategy to address the evolution of an emergency situation, from the stages of response to recovery, and including a planning stage, can facilitate timely, effective and consistent decision making by the response organisations at every level within the emergency management structure and between countries, helping to ensure optimal protection of health, environment, and society. The degree of involvement of stakeholders in this process is a key strategic element for strengthening the local preparedness and response and can help a successful countermeasures strategy. A significant progress was made with the multi-national European project EURANOS (2004-2009) which brought together best practice, knowledge and technology to enhance the preparedness for Europe's response to any radiation emergency and long term contamination. The subsequent establishment of a European Technology Platform and the recent launch of the research project NERIS-TP ("Towards a self sustaining European Technology Platform (NERIS-TP) on Preparedness for Nuclear and Radiological Emergency Response and Recovery") are aimed to continue with the remaining tasks for gaining appropriate levels of emergency preparedness at local level in most European countries. One of the objectives of the NERIS-TP project is: Strengthen the preparedness at the local/national level by setting up dedicated fora and developing new tools or adapting the tools developed within the EURANOS projects (such as the governance framework for preparedness, the handbooks on countermeasures, the RODOS system, and the MOIRA DSS for long term contamination in catchments) to meet the needs of local communities. CIEMAT and UPM in close interaction with the Nuclear Safety Council will explore, within this project, the use and application in Spain of such technical tools, including other national tools and information and communication strategies to foster cooperation between local, national and international stakeholders. The aim is identify and involve relevant stakeholders in emergency preparedness to improve the development and implementation of appropriate protection strategies as part of the consequence management and the transition to recovery. In this paper, an overview of the "state of the art" on this area in Spain and the methodology and work Plan proposed by the Spanish group within the project NERIS to grow the stakeholder involvement in the preparedness to emergency response and recovery is presented.

A constraint-based approach to quality assurance in service choreographies.

Knowledge about the quality characteristics (QoS) of service com- positions is crucial for determining their usability and economic value. Ser- vice quality is usually regulated using Service Level Agreements (SLA). While end-to-end SLAs are well suited for request-reply interactions, more complex, decentralized, multiparticipant compositions (service choreographies) typ- ically involve multiple message exchanges between stateful parties and the corresponding SLAs thus encompass several cooperating parties with interde- pendent QoS. The usual approaches to determining QoS ranges structurally (which are by construction easily composable) are not applicable in this sce- nario. Additionally, the intervening SLAs may depend on the exchanged data. We present an approach to data-aware QoS assurance in choreographies through the automatic derivation of composable QoS models from partici- pant descriptions. Such models are based on a message typing system with size constraints and are derived using abstract interpretation. The models ob- tained have multiple uses including run-time prediction, adaptive participant selection, or design-time compliance checking. We also present an experimen- tal evaluation and discuss the benefits of the proposed approach.

A guided heuristic approach to the MEG inverse problem.

There is general agreement within the scientific community in considering Biology as the science with more potential to develop in the XXI century. This is due to several reasons, but probably the most important one is the state of development of the rest of experimental and technological sciences. In this context, there are a very rich variety of mathematical tools, physical techniques and computer resources that permit to do biological experiments that were unbelievable only a few years ago. Biology is nowadays taking advantage of all these newly developed technologies, which are been applied to life sciences opening new research fields and helping to give new insights in many biological problems. Consequently, biologists have improved a lot their knowledge in many key areas as human function and human diseases. However there is one human organ that is still barely understood compared with the rest: The human brain. The understanding of the human brain is one of the main challenges of the XXI century. In this regard, it is considered a strategic research field for the European Union and the USA. Thus, there is a big interest in applying new experimental techniques for the study of brain function. Magnetoencephalography (MEG) is one of these novel techniques that are currently applied for mapping the brain activity1. This technique has important advantages compared to the metabolic-based brain imagining techniques like Functional Magneto Resonance Imaging2 (fMRI). The main advantage is that MEG has a higher time resolution than fMRI. Another benefit of MEG is that it is a patient friendly clinical technique. The measure is performed with a wireless set up and the patient is not exposed to any radiation. Although MEG is widely applied in clinical studies, there are still open issues regarding data analysis. The present work deals with the solution of the inverse problem in MEG, which is the most controversial and uncertain part of the analysis process3. This question is addressed using several variations of a new solving algorithm based in a heuristic method. The performance of those methods is analyzed by applying them to several test cases with known solutions and comparing those solutions with the ones provided by our methods.

An approach to a model of the visual cortex: disorders of vision

One of the most challenging problems that must be solved by any theoretical model purporting to explain the competence of the human brain for relational tasks is the one related with the analysis and representation of the internal structure in an extended spatial layout of múltiple objects. In this way, some of the problems are related with specific aims as how can we extract and represent spatial relationships among objects, how can we represent the movement of a selected object and so on. The main objective of this paper is the study of some plausible brain structures that can provide answers in these problems. Moreover, in order to achieve a more concrete knowledge, our study will be focused on the response of the retinal layers for optical information processing and how this information can be processed in the first cortex layers. The model to be reported is just a first trial and some major additions are needed to complete the whole vision process.

A system of systems engineering approach to design new smarter and energy efficient products

The concept of smartness of energy efficient products and systems from a business perspective has been investigated by several authors. The problem of understanding, designing, engineering and governing these technologies requires new concepts. The emergence of these modern technologies causes a myriad of interconnected systems, which are working together to satisfy the necessities of modern life. The problem of understanding, designing, engineering, and governing these technologies requires new concepts. Development of System of System Engineering (SoSE) is an attempt by the systems engineering and science community to fulfill this requirement.