Final Report (SPR Project 90-00-RB10-012) on the Maintenance Asset Management Project Phase I, 2012

This project resulted in the development of a proof of concept for a features inventory process to be used by field staff. The resulting concept is adaptable for different asset classes (e.g. culverts, guardrail) and able to leverage existing DOT resources such as the videolog and LRS and our current technology platforms including Oracle and our GIS web infrastructure. The concept examined the feasibility of newly available technologies, such as mobile devices, while balancing ease of use in the field. Implementation and deployment costs were also important considerations in evaluating the success of the project. These project funds allowed the pilot to address the needs of two DOT districts. A report of findings was prepared, including recommendations for or against full deployment of the pilot solution.

Final Report (SPR Project 90-00-RB10-012) on the Maintenance Asset Management Project Phase II, 2013

This project resulted in the development of a proof of concept for a features inventory process to be used by field staff. The resulting concept is adaptable for different asset classes (e.g. culverts, guardrail) and able to leverage existing DOT resources such as the videolog and LRS and our current technology platforms including Oracle and our GIS web infrastructure. The concept examined the feasibility of newly available technologies, such as mobile devices, while balancing ease of use in the field. Implementation and deployment costs were also important considerations in evaluating the success of the project. These project funds allowed the pilot to address the needs of two DOT districts. A report of findings was prepared, including recommendations for a full deployment of a field data collection.

Multiplex targeted high-throughput sequencing for Mendelian cardiac disorders.

Mendelian cardiomyopathies and arrhythmias are characterized by an important genetic heterogeneity, rendering Sanger sequencing very laborious and expensive. As a proof of concept, we explored multiplex targeted high-throughput sequencing (HTS) as a fast and cost-efficient diagnostic method for individuals suffering from Mendelian cardiac disorders. We designed a DNA capture assay including all exons from 130 genes involved in cardiovascular Mendelian disorders and analysed simultaneously four samples by multiplexing. Two patients had familial hypertrophic cardiomyopathy (HCM) and two patients suffered from long QT syndrome (LQTS). In patient 1 with HCM, we identified two known pathogenic missense variants in the two most frequently mutated sarcomeric genes MYH7 and MYBPC. In patient 2 with HCM, a known acceptor splice site variant in MYBPC3 was found. In patient 3 with LQTS, two missense variants in the genes SCN5A and KCNQ were identified. Finally, in patient 4 with LQTS a known missense variant was found in MYBPC3, which is usually mutated in patients with cardiomyopathy. Our results showed that multiplex targeted HTS works as an efficient and cost-effective tool for molecular diagnosis of heterogeneous disorders in clinical practice and offers new insights in the pathogenesis of these complex diseases.

Which factors influence glycemic control in the intensive care unit?

PURPOSE OF REVIEW: Intensive insulin therapy titrated to restore and maintain blood glucose between 80 and 110 mg/dl (4.4-6.1 mmol/l) was found to improve survival of critically ill patients in one pioneering proof-of-concept study performed in a surgical intensive care unit. The external validity of these findings was investigated. RECENT FINDINGS: Six independent prospective randomized controlled trials, involving 9877 patients in total, were unable to confirm the survival benefit reported in the pioneering trial. Several hypotheses were proposed to explain this discrepancy, including the case-mix, the features of the usual care, the quality of glucose control and the risks associated with hypoglycemia. SUMMARY: Before a better understanding and delineation of the conditions associated with and improved outcome by tight glycemic control, the choice of an intermediate glycemic target appears as a safe and effective solution.

Software Process Modeling with Eclipse Process Framework

The software development industry is constantly evolving. The rise of the agile methodologies in the late 1990s, and new development tools and technologies require growing attention for everybody working within this industry. The organizations have, however, had a mixture of various processes and different process languages since a standard software development process language has not been available. A promising process meta-model called Software & Systems Process Engineering Meta- Model (SPEM) 2.0 has been released recently. This is applied by tools such as Eclipse Process Framework Composer, which is designed for implementing and maintaining processes and method content. Its aim is to support a broad variety of project types and development styles. This thesis presents the concepts of software processes, models, traditional and agile approaches, method engineering, and software process improvement. Some of the most well-known methodologies (RUP, OpenUP, OpenMethod, XP and Scrum) are also introduced with a comparison provided between them. The main focus is on the Eclipse Process Framework and SPEM 2.0, their capabilities, usage and modeling. As a proof of concept, I present a case study of modeling OpenMethod with EPF Composer and SPEM 2.0. The results show that the new meta-model and tool have made it possible to easily manage method content, publish versions with customized content, and connect project tools (such as MS Project) with the process content. The software process modeling also acts as a process improvement activity.

Assessing dystrophies and other muscle diseases at the nanometer scale by atomic force microscopy.

AIM: Atomic force microscopy nanoindentation of myofibers was used to assess and quantitatively diagnose muscular dystrophies from human patients. MATERIALS & METHODS: Myofibers were probed from fresh or frozen muscle biopsies from human dystrophic patients and healthy volunteers, as well as mice models, and Young's modulus stiffness values were determined. RESULTS: Fibers displaying abnormally low mechanical stability were detected in biopsies from patients affected by 11 distinct muscle diseases, and Young's modulus values were commensurate to the severity of the disease. Abnormal myofiber resistance was also observed from consulting patients whose muscle condition could not be detected or unambiguously diagnosed otherwise. DISCUSSION & CONCLUSION: This study provides a proof-of-concept that atomic force microscopy yields a quantitative read-out of human muscle function from clinical biopsies, and that it may thereby complement current muscular dystrophy diagnosis.

Touching the void: exploring virtual objects through a vibrotactile glove

This paper describes a simple low-cost approach toadding an element of haptic interaction within a virtualenvironment. Using off-the-shelf hardware and software wedescribe a simple setup that can be used to explore physically virtual objects in space. This setup comprises of a prototype glove with a number of vibrating actuators to provide the haptic feedback, a Kinect camera for the tracking of the user's hand and a virtual reality development environment. As proof of concept and to test the efficiency of the system as well as its potential applications, we developed a simple application where we created 4 different shapes within a virtual environment in order to try toexplore them and guess their shape through touch alone.

A single epidermal stem cell strategy for safe ex vivo gene therapy.

There is a widespread agreement from patient and professional organisations alike that the safety of stem cell therapeutics is of paramount importance, particularly for ex vivo autologous gene therapy. Yet current technology makes it difficult to thoroughly evaluate the behaviour of genetically corrected stem cells before they are transplanted. To address this, we have developed a strategy that permits transplantation of a clonal population of genetically corrected autologous stem cells that meet stringent selection criteria and the principle of precaution. As a proof of concept, we have stably transduced epidermal stem cells (holoclones) obtained from a patient suffering from recessive dystrophic epidermolysis bullosa. Holoclones were infected with self-inactivating retroviruses bearing a COL7A1 cDNA and cloned before the progeny of individual stem cells were characterised using a number of criteria. Clonal analysis revealed a great deal of heterogeneity among transduced stem cells in their capacity to produce functional type VII collagen (COLVII). Selected transduced stem cells transplanted onto immunodeficient mice regenerated a non-blistering epidermis for months and produced a functional COLVII. Safety was assessed by determining the sites of proviral integration, rearrangements and hit genes and by whole-genome sequencing. The progeny of the selected stem cells also had a diploid karyotype, was not tumorigenic and did not disseminate after long-term transplantation onto immunodeficient mice. In conclusion, a clonal strategy is a powerful and efficient means of by-passing the heterogeneity of a transduced stem cell population. It guarantees a safe and homogenous medicinal product, fulfilling the principle of precaution and the requirements of regulatory affairs. Furthermore, a clonal strategy makes it possible to envision exciting gene-editing technologies like zinc finger nucleases, TALENs and homologous recombination for next-generation gene therapy.

Hepatitis C virus variants resistant to macrocyclic NS3-4A inhibitors subvert IFN-β induction by efficient MAVS cleavage.

BACKGROUND & AIMS: The hepatitis C virus (HCV) NS3-4A protease is essential for the HCV life cycle and a prime target of antiviral treatment strategies. Protease inhibitors, however, are limited by emergence of resistance-associated amino acid variants (RAVs). The capacity to cleave and inactivate mitochondrial antiviral-signaling protein (MAVS) in the RIG-I-signaling pathway is a cardinal feature of NS3-4A, by which HCV blocks induction of interferon-(IFN)-β, thereby promoting viral persistence. Here, we aimed to investigate the impact of NS3-4A RAVs on MAVS cleavage. METHODS: The impact of NS3-4A RAVs on MAVS cleavage was assessed using immunoblot analyses, luciferase reporter assays and molecular dynamics simulations to study the underlying molecular principles. IFN-β was quantified in serum from patients with different NS3-4A RAVs. RESULTS: We show that macrocyclic NS3-4A RAVS with substitutions at residue D168 of the protease result in an increased capacity of NS3-4A to cleave MAVS and suppress IFN-β induction compared with a comprehensive panel of RAVs and wild type HCV. Mechanistically, we show the reconstitution of a tight network of electrostatic interactions between protease and the peptide substrate that allows much stronger binding of MAVS to D168 RAVs than to the wild-type protease. Accordingly, we could show IFN-β serum levels to be lower in patients with treatment failure due to the selection of D168 variants compared to R155 RAVs. CONCLUSIONS: Our data constitutes a proof of concept that the selection of RAVs against specific classes of direct antivirals can lead to the predominance of viral variants with possibly adverse pathogenic characteristics.

Centralized password management in a global enterprise

Käyttäjien tunnistaminen tietojärjestelmissä on ollut yksi tietoturvan kulmakivistä vuosikymmenten ajan. Ajatus käyttäjätunnuksesta ja salasanasta on kaikkein kustannustehokkain ja käytetyin tapa säilyttää luottamus tietojärjestelmän ja käyttäjien välillä. Tietojärjestelmien käyttöönoton alkuaikoina, jolloin yrityksissä oli vain muutamia tietojärjestelmiä ja niitä käyttivät vain pieni ryhmä käyttäjiä, tämä toimintamalli osoittautui toimivaksi. Vuosien mittaan järjestelmien määrä kasvoi ja sen mukana kasvoi salasanojen määrä ja monimuotoisuus. Kukaan ei osannut ennustaa, kuinka paljon salasanoihin liittyviä ongelmia käyttäjät kohtaisivat ja kuinka paljon ne tulisivat ruuhkauttamaan yritysten käyttäjätukea ja minkälaisia tietoturvariskejä salasanat tulisivat aiheuttamaan suurissa yrityksissä. Tässä diplomityössä tarkastelemme salasanojen aiheuttamia ongelmia suuressa, globaalissa yrityksessä. Ongelmia tarkastellaan neljästä eri näkökulmasta; ihmiset, teknologia, tietoturva ja liiketoiminta. Ongelmat osoitetaan esittelemällä tulokset yrityksen työntekijöille tehdystä kyselystä, joka toteutettiin osana tätä diplomityötä. Ratkaisu näihin ongelmiin esitellään keskitetyn salasanojenhallintajärjestelmän muodossa. Järjestelmän eri ominaisuuksia arvioidaan ja kokeilu -tyyppinen toteutus rakennetaan osoittamaan tällaisen järjestelmän toiminnallisuus.

The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.

UNLABELLED: Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7-7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4-5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46-103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1-2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir. TRIAL REGISTRATION: clinicaltrials.gov NTC02092116.

Targeting the undruggable: immunotherapy meets personalized oncology in the genomic era.

Owing to recent advances in genomic technologies, personalized oncology is poised to fundamentally alter cancer therapy. In this paradigm, the mutational and transcriptional profiles of tumors are assessed, and personalized treatments are designed based on the specific molecular abnormalities relevant to each patient's cancer. To date, such approaches have yielded impressive clinical responses in some patients. However, a major limitation of this strategy has also been revealed: the vast majority of tumor mutations are not targetable by current pharmacological approaches. Immunotherapy offers a promising alternative to exploit tumor mutations as targets for clinical intervention. Mutated proteins can give rise to novel antigens (called neoantigens) that are recognized with high specificity by patient T cells. Indeed, neoantigen-specific T cells have been shown to underlie clinical responses to many standard treatments and immunotherapeutic interventions. Moreover, studies in mouse models targeting neoantigens, and early results from clinical trials, have established proof of concept for personalized immunotherapies targeting next-generation sequencing identified neoantigens. Here, we review basic immunological principles related to T-cell recognition of neoantigens, and we examine recent studies that use genomic data to design personalized immunotherapies. We discuss the opportunities and challenges that lie ahead on the road to improving patient outcomes by incorporating immunotherapy into the paradigm of personalized oncology.

Wide Area Network Acceleration in Corporate Networks

There are several factors affecting network performance. Some of these can be controlled whereas the others are more fixed. These factors are studied in this thesis from the wide area network (WAN) perspective and the focus is on corporate networks. Another area of interest is the behavior of application protocols when used through WAN. The aim is to study the performance of commonly used application protocols in corporate networks. After identifying the performance problems in corporate WANs the thesis concentrates on methods for improving WAN performance. WAN acceleration is presented as a possible solution. The different acceleration methods are discussed in order to give the reader a theoretical view on how the accelerators can improve WAN performance. Guidelines on the installation of accelerators into a network are also discussed. After a general overview on accelerators is given, one accelerator vendor currently on market is selected for a further analysis. The work is also a case study where two accelerators are installed into a target company network for testing purposes. The tests are performed with three different application protocols that have been identified as critical applications for the target corporation. The aim of the tests is to serve as a proof of concept for WAN acceleration in the target network.

Master data quality management in a global enterprise

In a networked business environment the visibility requirements towards the supply operations and customer interface has become tighter. In order to meet those requirements the master data of case company is seen as an enabler. However the current state of master data and its quality are not seen good enough to meet those requirements. In this thesis the target of research was to develop a process for managing master data quality as a continuous process and find solutions to cleanse the current customer and supplier data to meet the quality requirements defined in that process. Based on the theory of Master Data Management and data cleansing, small amount of master data was analyzed and cleansed using one commercial data cleansing solution available on the market. This was conducted in cooperation with the vendor as a proof of concept. In the proof of concept the cleansing solution’s applicability to improve the quality of current master data was proved. Based on those findings and the theory of data management the recommendations and proposals for improving the quality of data were given. In the results was also discovered that the biggest reasons for poor data quality is the lack of data governance in the company, and the current master data solutions and its restrictions.

Viitearkkitehtuuri Windows-sovelluksen käyttöliittymän modernisoimiseksi web-sovellukseksi

IT-järjestelmillä on tärkeä rooli organisaation liiketoiminnassa. Koska organisaation liiketoimintavaatimukset ja strategia muuttuvat ympäröivän maailman mukaan, täytyy järjestelmän arkkitehtuurin sopeutua vallitsevaan tilanteeseen sekä mahdollisiin muutoksiin lyhyellä ja pitkällä aikavälillä. Modernin web-sovelluksen arkkitehtuuri sopeutuu organisaation liiketoiminnan haasteisiin. Erityisesti hallinnolliseksi ongelmaksi organisaatiossa muodostuvat Windows-sovellukset, koska niiden ylläpito sitoo henkilöresursseja ja niiden käyttökonteksti on rajallinen. Tästä syystä organisaatiot ovat käyneet etsimään ratkaisuja kuinka korvata Windows-sovellukset web-sovelluksilla. Kustannustehokas ratkaisu on modernisoida Windows-sovelluksen käyttöliittymä web-sovellukseksi. Tämän diplomityön tavoitteena oli laatia Logica Suomi Oy yritykselle viitearkkitehtuuri Win-dows-sovelluksen käyttöliittymän modernisoimiseksi web-sovellukseksi. Työ suoritettiin Proof of Concept projektissa, jossa modernisointiin Logican pääkäyttäjäsovellus. Työn tarkoituksena oli tunnistaa laajalti käytetyt arkkitehtuurimallit ja menetelmät jotka mahdollistavat modernisoinnin toteutuksen. Lisäksi tarkoitus oli tunnistaa menetelmät ja ohjelmistot jotka mahdollistavat kustannustehokkaan ja laadukkaan web-sovelluksen kehittämisen ja toteuttamisen. Työn osatavoitteena oli laatia modernisoitavan pääkäyttäjäsovelluksen kokonaisarkkitehtuuri. Työn tuloksena saatiin viitearkkitehtuuri jota voidaan käyttää ja hyödyntää ohjelmistokehitysprojekteissa, asiakkaan dokumentaatiossa, myynnissä ja markkinoinnissa. Viitearkkitehtuurissa on esitelty modernit web-teknologiat joilla on mahdollista toteuttaa web-sovellus jonka käyttökokemus vastaa Windows-sovellusta. Lisäksi tuloksena saatiin pääkäyttäjäsovelluksen kokonaisarkkitehtuuri, jonka tärkeimpiä tuloksia ovat modernisoinnin tavoitetila ja sovellusarkkitehtuuri. Tärkeimpiä jatkotoimenpiteitä ovat viitearkkitehtuuriin pohjautuvan modernisointiviitekehyksen laadinta sekä modernisointiprojektin arviointiin käytettävien mittareiden määrittely, suunnittelu ja toteutus. Relevanttien mittareiden avulla voidaan todeta, vastaako modernisoitu sovellus organisaation liiketoimintavaatimuksia ja strategiaa.