Differential Activity of the KRAS Oncogene by Method of Activation: Implications for Signaling and Therapeutic Intervention

Despite having been identified over thirty years ago and definitively established as having a critical role in driving tumor growth and predicting for resistance to therapy, the KRAS oncogene remains a target in cancer for which there is no effective treatment. KRas is activated b y mutations at a few sites, primarily amino acid substitutions at codon 12 which promote a constitutively active state. I have found that different amino acid substitutions at codon 12 can activate different KRas downstream signaling pathways, determine clonogenic growth potential and determine patient response to molecularly targeted therapies. Computer modeling of the KRas structure shows that different amino acids substituted at the codon 12 position influences how KRas interacts with its effecters. In the absence of a direct inhibitor of mutant KRas several agents have recently entered clinical trials alone and in combination directly targeting two of the common downstream effecter pathways of KRas, namely the Mapk pathway and the Akt pathway. These inhibitors were evaluated for efficacy against different KRAS activating mutations. An isogenic panel of colorectal cells with wild type KRas replaced with KRas G12C, G12D, or G12V at the endogenous loci differed in sensitivity to Mek and Akt inhibition. In contrast, screening was performed in a broad panel of lung cell lines alone and no correlation was seen between types of activating KRAS mutation due to concurrent oncogenic lesions. To find a new method to inhibit KRAS driven tumors, siRNA screens were performed in isogenic lines with and without active KRas. The knockdown of CNKSR1 (CNK1) showed selective growth inhibition in cells with an oncogenic KRAS. The deletion of CNK1 reduces expression of mitotic cell cycle proteins and arrests cells with active KRas in the G1 phase of the cell cycle similar to the deletion of an activated KRas regardless of activating substitution. CNK1 has a PH domain responsible for localizing it to membrane lipids making KRas potentially amenable to inhibition with small molecules. The work has identified a series of small molecules capable of binding to this PH domain and inhibiting CNK1 facilitated KRas signaling.

BIOMEDICAL LANGUAGE UNDERSTANDING AND EXTRACTION (BLUE-TEXT): A MINIMAL SYNTACTIC, SEMANTIC METHOD

Clinical text understanding (CTU) is of interest to health informatics because critical clinical information frequently represented as unconstrained text in electronic health records are extensively used by human experts to guide clinical practice, decision making, and to document delivery of care, but are largely unusable by information systems for queries and computations. Recent initiatives advocating for translational research call for generation of technologies that can integrate structured clinical data with unstructured data, provide a unified interface to all data, and contextualize clinical information for reuse in multidisciplinary and collaborative environment envisioned by CTSA program. This implies that technologies for the processing and interpretation of clinical text should be evaluated not only in terms of their validity and reliability in their intended environment, but also in light of their interoperability, and ability to support information integration and contextualization in a distributed and dynamic environment. This vision adds a new layer of information representation requirements that needs to be accounted for when conceptualizing implementation or acquisition of clinical text processing tools and technologies for multidisciplinary research. On the other hand, electronic health records frequently contain unconstrained clinical text with high variability in use of terms and documentation practices, and without commitmentto grammatical or syntactic structure of the language (e.g. Triage notes, physician and nurse notes, chief complaints, etc). This hinders performance of natural language processing technologies which typically rely heavily on the syntax of language and grammatical structure of the text. This document introduces our method to transform unconstrained clinical text found in electronic health information systems to a formal (computationally understandable) representation that is suitable for querying, integration, contextualization and reuse, and is resilient to the grammatical and syntactic irregularities of the clinical text. We present our design rationale, method, and results of evaluation in processing chief complaints and triage notes from 8 different emergency departments in Houston Texas. At the end, we will discuss significance of our contribution in enabling use of clinical text in a practical bio-surveillance setting.

Modeling Techniques for the High-Resolution Interpretation of Cryo-Electron Microscopy Reconstructions

Essential biological processes are governed by organized, dynamic interactions between multiple biomolecular systems. Complexes are thus formed to enable the biological function and get dissembled as the process is completed. Examples of such processes include the translation of the messenger RNA into protein by the ribosome, the folding of proteins by chaperonins or the entry of viruses in host cells. Understanding these fundamental processes by characterizing the molecular mechanisms that enable then, would allow the (better) design of therapies and drugs. Such molecular mechanisms may be revealed trough the structural elucidation of the biomolecular assemblies at the core of these processes. Various experimental techniques may be applied to investigate the molecular architecture of biomolecular assemblies. High-resolution techniques, such as X-ray crystallography, may solve the atomic structure of the system, but are typically constrained to biomolecules of reduced flexibility and dimensions. In particular, X-ray crystallography requires the sample to form a three dimensional (3D) crystal lattice which is technically di‑cult, if not impossible, to obtain, especially for large, dynamic systems. Often these techniques solve the structure of the different constituent components within the assembly, but encounter difficulties when investigating the entire system. On the other hand, imaging techniques, such as cryo-electron microscopy (cryo-EM), are able to depict large systems in near-native environment, without requiring the formation of crystals. The structures solved by cryo-EM cover a wide range of resolutions, from very low level of detail where only the overall shape of the system is visible, to high-resolution that approach, but not yet reach, atomic level of detail. In this dissertation, several modeling methods are introduced to either integrate cryo-EM datasets with structural data from X-ray crystallography, or to directly interpret the cryo-EM reconstruction. Such computational techniques were developed with the goal of creating an atomic model for the cryo-EM data. The low-resolution reconstructions lack the level of detail to permit a direct atomic interpretation, i.e. one cannot reliably locate the atoms or amino-acid residues within the structure obtained by cryo-EM. Thereby one needs to consider additional information, for example, structural data from other sources such as X-ray crystallography, in order to enable such a high-resolution interpretation. Modeling techniques are thus developed to integrate the structural data from the different biophysical sources, examples including the work described in the manuscript I and II of this dissertation. At intermediate and high-resolution, cryo-EM reconstructions depict consistent 3D folds such as tubular features which in general correspond to alpha-helices. Such features can be annotated and later on used to build the atomic model of the system, see manuscript III as alternative. Three manuscripts are presented as part of the PhD dissertation, each introducing a computational technique that facilitates the interpretation of cryo-EM reconstructions. The first manuscript is an application paper that describes a heuristics to generate the atomic model for the protein envelope of the Rift Valley fever virus. The second manuscript introduces the evolutionary tabu search strategies to enable the integration of multiple component atomic structures with the cryo-EM map of their assembly. Finally, the third manuscript develops further the latter technique and apply it to annotate consistent 3D patterns in intermediate-resolution cryo-EM reconstructions. The first manuscript, titled An assembly model for Rift Valley fever virus, was submitted for publication in the Journal of Molecular Biology. The cryo-EM structure of the Rift Valley fever virus was previously solved at 27Å-resolution by Dr. Freiberg and collaborators. Such reconstruction shows the overall shape of the virus envelope, yet the reduced level of detail prevents the direct atomic interpretation. High-resolution structures are not yet available for the entire virus nor for the two different component glycoproteins that form its envelope. However, homology models may be generated for these glycoproteins based on similar structures that are available at atomic resolutions. The manuscript presents the steps required to identify an atomic model of the entire virus envelope, based on the low-resolution cryo-EM map of the envelope and the homology models of the two glycoproteins. Starting with the results of the exhaustive search to place the two glycoproteins, the model is built iterative by running multiple multi-body refinements to hierarchically generate models for the different regions of the envelope. The generated atomic model is supported by prior knowledge regarding virus biology and contains valuable information about the molecular architecture of the system. It provides the basis for further investigations seeking to reveal different processes in which the virus is involved such as assembly or fusion. The second manuscript was recently published in the of Journal of Structural Biology (doi:10.1016/j.jsb.2009.12.028) under the title Evolutionary tabu search strategies for the simultaneous registration of multiple atomic structures in cryo-EM reconstructions. This manuscript introduces the evolutionary tabu search strategies applied to enable a multi-body registration. This technique is a hybrid approach that combines a genetic algorithm with a tabu search strategy to promote the proper exploration of the high-dimensional search space. Similar to the Rift Valley fever virus, it is common that the structure of a large multi-component assembly is available at low-resolution from cryo-EM, while high-resolution structures are solved for the different components but lack for the entire system. Evolutionary tabu search strategies enable the building of an atomic model for the entire system by considering simultaneously the different components. Such registration indirectly introduces spatial constrains as all components need to be placed within the assembly, enabling the proper docked in the low-resolution map of the entire assembly. Along with the method description, the manuscript covers the validation, presenting the benefit of the technique in both synthetic and experimental test cases. Such approach successfully docked multiple components up to resolutions of 40Å. The third manuscript is entitled Evolutionary Bidirectional Expansion for the Annotation of Alpha Helices in Electron Cryo-Microscopy Reconstructions and was submitted for publication in the Journal of Structural Biology. The modeling approach described in this manuscript applies the evolutionary tabu search strategies in combination with the bidirectional expansion to annotate secondary structure elements in intermediate resolution cryo-EM reconstructions. In particular, secondary structure elements such as alpha helices show consistent patterns in cryo-EM data, and are visible as rod-like patterns of high density. The evolutionary tabu search strategy is applied to identify the placement of the different alpha helices, while the bidirectional expansion characterizes their length and curvature. The manuscript presents the validation of the approach at resolutions ranging between 6 and 14Å, a level of detail where alpha helices are visible. Up to resolution of 12 Å, the method measures sensitivities between 70-100% as estimated in experimental test cases, i.e. 70-100% of the alpha-helices were correctly predicted in an automatic manner in the experimental data. The three manuscripts presented in this PhD dissertation cover different computation methods for the integration and interpretation of cryo-EM reconstructions. The methods were developed in the molecular modeling software Sculptor (http://sculptor.biomachina.org) and are available for the scientific community interested in the multi-resolution modeling of cryo-EM data. The work spans a wide range of resolution covering multi-body refinement and registration at low-resolution along with annotation of consistent patterns at high-resolution. Such methods are essential for the modeling of cryo-EM data, and may be applied in other fields where similar spatial problems are encountered, such as medical imaging.

Mean dynamic topography and oceanographic parameters estimated from an inverse model and satellite geodesy, with link to model result in one single NetCDF file (392 MB), including the inverse data error covariance

Geostrophic surface velocities can be derived from the gradients of the mean dynamic topography-the difference between the mean sea surface and the geoid. Therefore, independently observed mean dynamic topography data are valuable input parameters and constraints for ocean circulation models. For a successful fit to observational dynamic topography data, not only the mean dynamic topography on the particular ocean model grid is required, but also information about its inverse covariance matrix. The calculation of the mean dynamic topography from satellite-based gravity field models and altimetric sea surface height measurements, however, is not straightforward. For this purpose, we previously developed an integrated approach to combining these two different observation groups in a consistent way without using the common filter approaches (Becker et al. in J Geodyn 59(60):99-110, 2012, doi:10.1016/j.jog.2011.07.0069; Becker in Konsistente Kombination von Schwerefeld, Altimetrie und hydrographischen Daten zur Modellierung der dynamischen Ozeantopographie, 2012, http://nbn-resolving.de/nbn:de:hbz:5n-29199). Within this combination method, the full spectral range of the observations is considered. Further, it allows the direct determination of the normal equations (i.e., the inverse of the error covariance matrix) of the mean dynamic topography on arbitrary grids, which is one of the requirements for ocean data assimilation. In this paper, we report progress through selection and improved processing of altimetric data sets. We focus on the preprocessing steps of along-track altimetry data from Jason-1 and Envisat to obtain a mean sea surface profile. During this procedure, a rigorous variance propagation is accomplished, so that, for the first time, the full covariance matrix of the mean sea surface is available. The combination of the mean profile and a combined GRACE/GOCE gravity field model yields a mean dynamic topography model for the North Atlantic Ocean that is characterized by a defined set of assumptions. We show that including the geodetically derived mean dynamic topography with the full error structure in a 3D stationary inverse ocean model improves modeled oceanographic features over previous estimates.

Turbulent flux and meteorological measurements during ARCTEX-2006 campaign

This dataset present result from the DFG- funded Arctic-Turbulence-Experiment (ARCTEX-2006) performed by the University of Bayreuth on the island of Svalbard, Norway, during the winter/spring transition 2006. From May 5 to May 19, 2006 turbulent flux and meteorological measurements were performed on the monitoring field near Ny-Ålesund, at 78°55'24'' N, 11°55'15'' E Kongsfjord, Svalbard (Spitsbergen), Norway. The ARCTEX-2006 campaign site was located about 200 m southeast of the settlement on flat snow covered tundra, 11 m to 14 m above sea level. The permanent sites used for this study consisted of the 10 m meteorological tower of the Alfred Wegener Institute for Polar- and Marine Research (AWI), the international standardized radiation measurement site of the Baseline Surface Radiation Network (BSRN), the radiosonde launch site and the AWI tethered balloon launch sites. The temporary sites - set up by the University of Bayreuth - were a 6 m meteorological gradient tower, an eddy-flux measurement complex (EF), and a laser-scintillometer section (SLS). A quality assessment and data correction was applied to detect and eliminate specific measurement errors common at a high arctic landscape. In addition, the quality checked sensible heat flux measurements are compared with bulk aerodynamic formulas that are widely used in atmosphere-ocean/land-ice models for polar regions as described in Ebert and Curry (1993, doi:10.1029/93JC00656) and Launiainen and Cheng (1995). These parameterization approaches easily allow estimation of the turbulent surface fluxes from routine meteorological measurements. The data show: - the role of the intermittency of the turbulent atmospheric fluctuation of momentum and scalars, - the existence of a disturbed vertical temperature profile (sharp inversion layer) close to the surface, - the relevance of possible free convection events for the snow or ice melt in the Arctic spring at Svalbard, and - the relevance of meso-scale atmospheric circulation pattern and air-mass advection for the near-surface turbulent heat exchange in the Arctic spring at Svalbard. Recommendations and improvements regarding the interpretation of eddy-flux and laser-scintillometer data as well as the arrangement of the instrumentation under polar distinct exchange conditions and (extreme) weather situations could be derived.

Direct visualization of solute locations in laboratory ice samples, links to videos

Many important chemical reactions occur in polar snow, where solutes may be present in several reservoirs, including at the air-ice interface and in liquid-like regions within the ice matrix. Some recent laboratory studies suggest chemical reaction rates may differ in these two reservoirs. While investigations have examined where solutes are found in natural snow and ice, similar research has not identified solute locations in laboratory samples, nor the possible factors controlling solute segregation. To address this, we examined solute locations in ice samples prepared from either aqueous cesium chloride (CsCl) or Rose Bengal solutions that were frozen using several different methods. Samples frozen in a laboratory freezer had the largest liquid-like inclusions and air bubbles, while samples frozen in a custom freeze chamber had somewhat smaller air bubbles and inclusions; in contrast, samples frozen in liquid nitrogen showed much smaller concentrated inclusions and air bubbles, only slightly larger than the resolution limit of our images (~2 µm). Freezing solutions in plastic versus glass vials had significant impacts on the sample structure, perhaps because the poor heat conductivity of plastic vials changes how heat is removed from the sample as it cools. Similarly, the choice of solute had a significant impact on sample structure, with Rose Bengal solutions yielding smaller inclusions and air bubbles compared to CsCl solutions frozen using the same method. Additional experiments using higher-resolution imaging of an ice sample show that CsCl moves in a thermal gradient, supporting the idea that the solutes in ice are present in liquid-like regions. Our work shows that the structure of laboratory ice samples, including the location of solutes, is sensitive to freezing method, sample container, and solute characteristics, requiring careful experimental design and interpretation of results.

Direct effects of increased CO2 concentrations in seawater on the net primary production of charophytes in a shallow, coastal, brackish-water ecosystem

Charophytes are found in fresh and brackish waters across the globe and play key roles in coastal ecosystems. However, their response to increasing CO2 is not well understood. The aim of the study was to detect the effects of elevated CO2 on the physiology of charophyte species growing in the brackish Baltic Sea by measuring net primary production. Mesocosm experiments were conducted in the Kõiguste Bay (N Gulf of Riga) during the field season of 2012. Separate mesocosms were maintained at different pCO2 levels: 2000, 1000 and 200 µatm. The experiments were carried out with three species of charophytes: Chara aspera, C. tomentosa and C. horrida. The short-term photosynthetic responses of charophytes to different treatments were measured by the oxygen method. The results show that elevated CO2 levels in brackish water may enhance the photosynthetic activity of charophyte species and suggest that increasing CO2 in the Baltic Sea could have implications for interspecific competition and community structure in a future high CO2 world.

3D Direct Simulation Monte Carlo Modelling of the Inner Gas Coma of Comet 67P/Churyumov-Gerasimenko: A Parameter Study

Direct Simulation Monte Carlo (DSMC) is a powerful numerical method to study rarefied gas flows such as cometary comae and has been used by several authors over the past decade to study cometary outflow. However, the investigation of the parameter space in simulations can be time consuming since 3D DSMC is computationally highly intensive. For the target of ESA's Rosetta mission, comet 67P/Churyumov-Gerasimenko, we have identified to what extent modification of several parameters influence the 3D flow and gas temperature fields and have attempted to establish the reliability of inferences about the initial conditions from in situ and remote sensing measurements. A large number of DSMC runs have been completed with varying input parameters. In this work, we present the simulation results and conclude on the sensitivity of solutions to certain inputs. It is found that among cases of water outgassing, the surface production rate distribution is the most influential variable to the flow field.

Inferring the Effects of Vertical Integration from Entry Games : An Analysis of the Generic Pharmaceutical Industry

This paper introduces a novel method for examining the effects of vertical integration. The basic idea is to estimate the parameters of a vertical entry game. By carefully specifying firms' payoff equations and constructing appropriate tests, it is possible to use estimates on rival profit effects to make inferences about the existence of vertical foreclosure. I estimate the vertical entry model using data from the US generic pharmaceutical industry. The estimates indicate that vertical integration is unlikely to generate anticompetitive foreclosure effects. On the other hand, significant efficiency effects are found to arise from vertical integration. I use the parameter estimates to simulate a policy that bans vertically integrated entry. The simulation results suggest that such a ban is counterproductive; it is likely to reduce entry into smaller markets.

Chapter 1 Economic Integration and Industry Location: Theories, Empirical Results, and Implications for CLMV

Trade affects the internal location of industry in two ways: it induces firms to specialize and it expands the set of markets that firms serve. If there are industry-specific external economies, firms in related industries will spatially agglomerate (Hanson 1996a). In the context of economic integration, diminished barriers to trade affect industry location particularly in less developed countries. As described below, regional agreements in North America and Europe have caused frontier regions to expand. These regions, which include border regions and port cities, have advantages over internal regions in terms of access to foreign markets. Since trade liberalization induces many firms in developing countries to participate in production networks and to specialize in labor-intensive activities such as assembling and processing of foreign-made components, their inputs as well as final products need to be carried across borders. Therefore, the best industry location, one that minimizes transport costs, is likely to shift to frontier regions. In East Asia, China has developed rapidly since it opened up to international trade. Simultaneously, a large amount of foreign direct investment (FDI) has been attracted and industry agglomerations have been formed in coastal regions, that is, frontier regions linked to the global market by sea, leaving many internal regions behind. Similarly, Cambodia, Laos, Myanmar, and Vietnam (CLMV) have joined AFTA and/or the WTO and liberalized international trade since the 1990s. Moreover, transport infrastructures such as the East-West Economic Corridor, the Southern Economic Corridor, and the North-South Economic Corridor have been built and narrowed economic distances in the Greater Mekong Subregion (GMS). As a result, frontier regions are likely to increase their location advantages and lure labor-intensive operations from neighboring countries. It is expected that, as has happened in North America and Europe, economic integration in East Asia will significantly affect internal geography in CLMV. In this study, I first review theories relevant to economic integration and industry location within a country. In particular, emphasis is placed on the new economic geography (NEG). Secondly, empirical results for North America and Europe are surveyed since they have preceded East Asia in regional integration and a substantial number of studies have been conducted on these regions. The final section summarizes and discusses implications for internal geography in CLMV.

Measuring global value chains and regional economic integration : an international input-output approach

Firms that are expanding their cross-border activities, such as vertical specialization trade, outsourcing, and fragmentation productions, have brought dramatic changes to the global economy during the last two decades. In an attempt to understand the evolution of the interaction among countries or country groups, many trade-statistics-based indicators have been developed. However, most of these statistics focus on showing the direct trade-specific-relationship among countries, rather than considering the roles that intercountry and interindustrial production networks play in a global economy. This paper uses the concepts of trade in value added as measured by the input–output tables of OECD and IDE-JETRO to provide alternative indicators that show the evolution of regional economic integration and global value chains for more than 50 economies. In addition, this paper provides thoughts on how to evaluate comparative advantages on the basis of value added using an international input–output model.

Export platform foreign direct investment : theory and evidence

This paper proposes a model that accounts for “export platform” FDI – a form of FDI that is common in the data but rarely discussed in the theoretical literature. Unlike the previous literature, this paper’s theory nests all the typical modes of supply, including exports, horizontal and vertical FDI, horizontal and vertical export platform FDI. The theory yields the testable hypothesis that a decrease in either inter-regional or intra-regional trade costs induces firms to choose export platform FDI. The empirical analysis provides descriptive statistics which point to large proportions of third country exports of US FDI, and an econometric analysis, whose results are in line with the model’s predictions. The last section suggests policy implications for nations seeking to attract FDI.

Efficient Model-based 3D Tracking by Using Direct Image Registration

This thesis deals with the problem of efficiently tracking 3D objects in sequences of images. We tackle the efficient 3D tracking problem by using direct image registration. This problem is posed as an iterative optimization procedure that minimizes a brightness error norm. We review the most popular iterative methods for image registration in the literature, turning our attention to those algorithms that use efficient optimization techniques. Two forms of efficient registration algorithms are investigated. The first type comprises the additive registration algorithms: these algorithms incrementally compute the motion parameters by linearly approximating the brightness error function. We centre our attention on Hager and Belhumeur’s factorization-based algorithm for image registration. We propose a fundamental requirement that factorization-based algorithms must satisfy to guarantee good convergence, and introduce a systematic procedure that automatically computes the factorization. Finally, we also bring out two warp functions to register rigid and nonrigid 3D targets that satisfy the requirement. The second type comprises the compositional registration algorithms, where the brightness function error is written by using function composition. We study the current approaches to compositional image alignment, and we emphasize the importance of the Inverse Compositional method, which is known to be the most efficient image registration algorithm. We introduce a new algorithm, the Efficient Forward Compositional image registration: this algorithm avoids the necessity of inverting the warping function, and provides a new interpretation of the working mechanisms of the inverse compositional alignment. By using this information, we propose two fundamental requirements that guarantee the convergence of compositional image registration methods. Finally, we support our claims by using extensive experimental testing with synthetic and real-world data. We propose a distinction between image registration and tracking when using efficient algorithms. We show that, depending whether the fundamental requirements are hold, some efficient algorithms are eligible for image registration but not for tracking.

Si(100) versus Ge(100): Watching the interface formation for the growth of III-V-based solar cells on abundant substrates

We investigated the atomic surface properties of differently prepared silicon and germanium (100) surfaces during metal-organic vapour phase epitaxy/chemical vapour deposition (MOVPE/MOCVD), in particular the impact of the MOVPE ambient, and applied reflectance anisotropy/difference spectroscopy (RAS/RDS) in our MOVPE reactor to in-situ watch and control the preparation on the atomic length scale for subsequent III-V-nucleation. The technological interest in the predominant opto-electronic properties of III-V-compounds drives the research for their heteroepitaxial integration on more abundant and cheaper standard substrates such as Si(100) or Ge(100). In these cases, a general task must be accomplished successfully, i.e. the growth of polar materials on non-polar substrates and, beyond that, very specific variations such as the individual interface formation and the atomic step structure, have to be controlled. Above all, the method of choice to grow industrial relevant high-performance device structures is MOVPE, not normally compatible with surface and interface sensitive characterization tools, which are commonly based on ultrahigh vacuum (UHV) ambients. A dedicated sample transfer system from MOVPE environment to UHV enabled us to benchmark the optical in-situ spectra with results from various surfaces science instruments without considering disruptive contaminants. X-ray photoelectron spectroscopy (XPS) provided direct observation of different terminations such as arsenic and phosphorous and verified oxide removal under various specific process parameters. Absorption lines in Fourier-transform infrared (FTIR) spectra were used to identify specific stretch modes of coupled hydrides and the polarization dependence of the anti-symmetric stretch modes distinguished different dimer orientations. Scanning tunnelling microscopy (STM) studied the atomic arrangement of dimers and steps and tip-induced H-desorption proved the saturation of dangling bonds after preparati- n. In-situ RAS was employed to display details transiently such as the presence of H on the surface at lower temperatures (T <; 800°C) and the absence of Si-H bonds at elevated annealing temperature and also surface terminations. Ge buffer growth by the use of GeH4 enables the preparation of smooth surfaces and leads to a more pronounced amplitude of the features in the spectra which indicates improvements of the surface quality.

Patient-based Literature Retrieval and Integration: A Use Case for Diabetes and arterial Hypertension

Specialized search engines such as PubMed, MedScape or Cochrane have increased dramatically the visibility of biomedical scientific results. These web-based tools allow physicians to access scientific papers instantly. However, this decisive improvement had not a proportional impact in clinical practice due to the lack of advanced search methods. Even queries highly specified for a concrete pathology frequently retrieve too many information, with publications related to patients treated by the physician beyond the scope of the results examined. In this work we present a new method to improve scientific article search using patient information. Two pathologies have been used within the project to retrieve relevant literature to patient data and to be integrated with other sources. Promising results suggest the suitability of the approach, highlighting publications dealing with patient features and facilitating literature search to physicians.