PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification.

PURPOSE: To improve the risk stratification of patients with rhabdomyosarcoma (RMS) through the use of clinical and molecular biologic data. PATIENTS AND METHODS: Two independent data sets of gene-expression profiling for 124 and 101 patients with RMS were used to derive prognostic gene signatures by using a meta-analysis. These and a previously published metagene signature were evaluated by using cross validation analyses. A combined clinical and molecular risk-stratification scheme that incorporated the PAX3/FOXO1 fusion gene status was derived from 287 patients with RMS and evaluated. RESULTS: We showed that our prognostic gene-expression signature and the one previously published performed well with reproducible and significant effects. However, their effect was reduced when cross validated or tested in independent data and did not add new prognostic information over the fusion gene status, which is simpler to assay. Among nonmetastatic patients, patients who were PAX3/FOXO1 positive had a significantly poorer outcome compared with both alveolar-negative and PAX7/FOXO1-positive patients. Furthermore, a new clinicomolecular risk score that incorporated fusion gene status (negative and PAX3/FOXO1 and PAX7/FOXO1 positive), Intergroup Rhabdomyosarcoma Study TNM stage, and age showed a significant increase in performance over the current risk-stratification scheme. CONCLUSION: Gene signatures can improve current stratification of patients with RMS but will require complex assays to be developed and extensive validation before clinical application. A significant majority of their prognostic value was encapsulated by the fusion gene status. A continuous risk score derived from the combination of clinical parameters with the presence or absence of PAX3/FOXO1 represents a robust approach to improving current risk-adapted therapy for RMS.

International bioenergy trade- scenario study on international biomass market in 2020

The markets of biomass for energy are developing rapidly and becoming more international. A remarkable increase in the use of biomass for energy needs parallel and positive development in several areas, and there will be plenty of challenges to overcome. The main objective of the study was to clarify the alternative future scenarios for the international biomass market until the year 2020, and based on the scenario process, to identify underlying steps needed towards the vital working and sustainable biomass market for energy purposes. Two scenario processes were conducted for this study. The first was carried out with a group of Finnish experts and thesecond involved an international group. A heuristic, semi-structured approach, including the use of preliminary questionnaires as well as manual and computerised group support systems (GSS), was applied in the scenario processes.The scenario processes reinforced the picture of the future of international biomass and bioenergy markets as a complex and multi-layer subject. The scenarios estimated that the biomass market will develop and grow rapidly as well as diversify in the future. The results of the scenario process also opened up new discussion and provided new information and collective views of experts for the purposes of policy makers. An overall view resulting from this scenario analysis are the enormous opportunities relating to the utilisation of biomass as a resource for global energy use in the coming decades. The scenario analysis shows the key issues in the field: global economic growth including the growing need for energy, environmental forces in the global evolution, possibilities of technological development to solve global problems, capabilities of the international community to find solutions for global issues and the complex interdependencies of all these driving forces. The results of the scenario processes provide a starting point for further research analysing the technological and commercial aspects related the scenarios and foreseeing the scales and directions of biomass streams.

Techniques de gastrostomie chez l'enfant et expérience lausannoise avec le bouton de gastrostomie à ballonnet (Mic-Key)

Résumé : Ce travail comprend deux parties : La première partie a pour but de présenter une revue des techniques de gastrostomie chez l'enfant. La gastrostomie est, par définition, un tractus fistuleux entre l'estomac et la paroi abdominale. Le but de la gastrostomie est de permettre la décompression gastrique, la nutrition entérale et l'apport médicamenteux. Les indications et contre-indications à la confection et utilisation de la gastrostomie sont détaillées dans ce travail. Historiquement, les premières gastrostomies étaient d'origine accidentelle ou infectieuse (fistule gastro-cutanée), incompatibles avec la vie. Sedillot, en 1845 décrivit la première gastrostomie chirurgicale sans cathéter, qui avait comme désavantage la présence de fuites. Depuis, les techniques se sont multipliées en évoluant vers la continence et l'utilisation de cathéters. En 1979 Gauderer décrivit pour la première fois une technique percutanée, réalisée sur un enfant âgé de 5 mois. Cette technique est appelée « Percutaneous Endoscopic Gastrostomy » (PEG). Elle a ensuite été élargie à la population adulte. Actuellement, il existe une grande multiplicité de techniques par abord « laparotomique », laparoscopique ou percutanée (endoscopique ou radiologique). Ces techniques peuvent être combinées. Toutes ces techniques nécessitent la présence intermittente ou continue d'un dispositif, qui permet le maintient de la gastrostomie ouverte et évite les fuites gastriques. Ces dispositifs sont multiples; initialement il s'agissait de cathéters rigides (bois, métal, caoutchouc). Ensuite ils ont été fabriqués en silicone, ce qui les rend plus souples et mieux tolérés par le patient. Pour éviter leur dislocation, ils possèdent un système d'amarrage intra-gastrique tel que : un champignon (Bard®), un ballonnet (Foley®, Mic-Key®), ou une forme spiralée du cathéter (« pig-tail ») et possèdent un système d'amarrage extra-gastrique (« cross-bar »). En 1982, Gauderer créa le premier dispositif à fleur de peau : le bouton de gastrostomie (BG). Actuellement, il en existe deux types : à champignon (Bard®) et à ballonnet (Mic-Key®). Il existe plusieurs types de complications liées à la technique opératoire, à la prise en charge et au matériel utilisé. Une comparaison des différentes techniques, matériaux utilisés et coûts engendrés est détaillée dans ce travail. La deuxième partie de ce travail est dédiée aux BG et plus spécifiquement au BG à ballonnet (Mic-Key®). Nous présentons les différents boutons et les techniques spécifiques. Le BG est inséré soit dans une gastrostomie préformée, soit directement lors de la confection d'une gastrostomie par laparotomie, laparoscopie ou de façon percutanée. Les complications liées au BG sont rapportées. D'autres utilisations digestives ou urologiques sont décrites. Nous présentons ensuite notre expérience avec 513 BG à ballonnet (Mic-Key®) dans une revue de 73 enfants. La pose du BG est effectuée dans une gastrostomie préformée sans recours à une anesthésie générale. La technique choisie pour la confection de la gastrostomie dépend de la pathologie de base, de l'état général du patient, de la nécessité d'une opération concomitante et du risque anesthésique. Nous apportons des précisions sur le BG telles que la dimension en fonction de l'âge, la durée de vie, et les causes qui ont amené au changement du BG. Nos résultats sont comparés à ceux de la littérature. Sur la base de notre expérience et après avoir passé en revue la littérature spécialisée, nous proposons des recommandations sur le choix de la technique et le choix du matériel. Ce travail se termine avec une réflexion sur le devenir de la gastrostomie. Si le futur consiste à améliorer et innover les techniques et les matériaux, des protocoles destinés à la standardisation des techniques, à la sélection des patients et à l'enseignement des soins devraient s'en suivre. La prise en charge de l'enfant ne se limite pas à la sélection appropriée de la technique et des matériaux, mais il s'agit avant tout d'une approche multidisciplinaire. La collaboration entre le personnel soignant, la famille et l'enfant est essentielle pour que la prise en charge soit optimale et sans risques.

Data-parallel computation in parallel and distributed environments

The past few decades have seen a considerable increase in the number of parallel and distributed systems. With the development of more complex applications, the need for more powerful systems has emerged and various parallel and distributed environments have been designed and implemented. Each of the environments, including hardware and software, has unique strengths and weaknesses. There is no single parallel environment that can be identified as the best environment for all applications with respect to hardware and software properties. The main goal of this thesis is to provide a novel way of performing data-parallel computation in parallel and distributed environments by utilizing the best characteristics of difference aspects of parallel computing. For the purpose of this thesis, three aspects of parallel computing were identified and studied. First, three parallel environments (shared memory, distributed memory, and a network of workstations) are evaluated to quantify theirsuitability for different parallel applications. Due to the parallel and distributed nature of the environments, networks connecting the processors in these environments were investigated with respect to their performance characteristics. Second, scheduling algorithms are studied in order to make them more efficient and effective. A concept of application-specific information scheduling is introduced. The application- specific information is data about the workload extractedfrom an application, which is provided to a scheduling algorithm. Three scheduling algorithms are enhanced to utilize the application-specific information to further refine their scheduling properties. A more accurate description of the workload is especially important in cases where the workunits are heterogeneous and the parallel environment is heterogeneous and/or non-dedicated. The results obtained show that the additional information regarding the workload has a positive impact on the performance of applications. Third, a programming paradigm for networks of symmetric multiprocessor (SMP) workstations is introduced. The MPIT programming paradigm incorporates the Message Passing Interface (MPI) with threads to provide a methodology to write parallel applications that efficiently utilize the available resources and minimize the overhead. The MPIT allows for communication and computation to overlap by deploying a dedicated thread for communication. Furthermore, the programming paradigm implements an application-specific scheduling algorithm. The scheduling algorithm is executed by the communication thread. Thus, the scheduling does not affect the execution of the parallel application. Performance results achieved from the MPIT show that considerable improvements over conventional MPI applications are achieved.

Introducing massively parallel computers into operational weather forecasting

Numerical weather prediction and climate simulation have been among the computationally most demanding applications of high performance computing eversince they were started in the 1950's. Since the 1980's, the most powerful computers have featured an ever larger number of processors. By the early 2000's, this number is often several thousand. An operational weather model must use all these processors in a highly coordinated fashion. The critical resource in running such models is not computation, but the amount of necessary communication between the processors. The communication capacity of parallel computers often fallsfar short of their computational power. The articles in this thesis cover fourteen years of research into how to harness thousands of processors on a single weather forecast or climate simulation, so that the application can benefit as much as possible from the power of parallel high performance computers. The resultsattained in these articles have already been widely applied, so that currently most of the organizations that carry out global weather forecasting or climate simulation anywhere in the world use methods introduced in them. Some further studies extend parallelization opportunities into other parts of the weather forecasting environment, in particular to data assimilation of satellite observations.

Converter-flux-based current control of voltage source PWM rectifiers - analysis and implementation

Pulsewidth-modulated (PWM) rectifier technology is increasingly used in industrial applications like variable-speed motor drives, since it offers several desired features such as sinusoidal input currents, controllable power factor, bidirectional power flow and high quality DC output voltage. To achieve these features,however, an effective control system with fast and accurate current and DC voltage responses is required. From various control strategies proposed to meet these control objectives, in most cases the commonly known principle of the synchronous-frame current vector control along with some space-vector PWM scheme have been applied. Recently, however, new control approaches analogous to the well-established direct torque control (DTC) method for electrical machines have also emerged to implement a high-performance PWM rectifier. In this thesis the concepts of classical synchronous-frame current control and DTC-based PWM rectifier control are combined and a new converter-flux-based current control (CFCC) scheme is introduced. To achieve sufficient dynamic performance and to ensure a stable operation, the proposed control system is thoroughly analysed and simple rules for the controller design are suggested. Special attention is paid to the estimationof the converter flux, which is the key element of converter-flux-based control. Discrete-time implementation is also discussed. Line-voltage-sensorless reactive reactive power control methods for the L- and LCL-type line filters are presented. For the L-filter an open-loop control law for the d-axis current referenceis proposed. In the case of the LCL-filter the combined open-loop control and feedback control is proposed. The influence of the erroneous filter parameter estimates on the accuracy of the developed control schemes is also discussed. A newzero vector selection rule for suppressing the zero-sequence current in parallel-connected PWM rectifiers is proposed. With this method a truly standalone and independent control of the converter units is allowed and traditional transformer isolation and synchronised-control-based solutions are avoided. The implementation requires only one additional current sensor. The proposed schemes are evaluated by the simulations and laboratory experiments. A satisfactory performance and good agreement between the theory and practice are demonstrated.

Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis.

Poly (ADP-ribose) polymerase 1 (PARP-1) is a constitutive enzyme, the major isoform of the PARP family, which is involved in the regulation of DNA repair, cell death, metabolism, and inflammatory responses. Pharmacological inhibitors of PARP provide significant therapeutic benefits in various preclinical disease models associated with tissue injury and inflammation. However, our understanding the role of PARP activation in the pathophysiology of liver inflammation and fibrosis is limited. In this study we investigated the role of PARP-1 in liver inflammation and fibrosis using acute and chronic models of carbon tetrachloride (CCl4 )-induced liver injury and fibrosis, a model of bile duct ligation (BDL)-induced hepatic fibrosis in vivo, and isolated liver-derived cells ex vivo. Pharmacological inhibition of PARP with structurally distinct inhibitors or genetic deletion of PARP-1 markedly attenuated CCl4 -induced hepatocyte death, inflammation, and fibrosis. Interestingly, the chronic CCl4 -induced liver injury was also characterized by mitochondrial dysfunction and dysregulation of numerous genes involved in metabolism. Most of these pathological changes were attenuated by PARP inhibitors. PARP inhibition not only prevented CCl4 -induced chronic liver inflammation and fibrosis, but was also able to reverse these pathological processes. PARP inhibitors also attenuated the development of BDL-induced hepatic fibrosis in mice. In liver biopsies of subjects with alcoholic or hepatitis B-induced cirrhosis, increased nitrative stress and PARP activation was noted. CONCLUSION: The reactive oxygen/nitrogen species-PARP pathway plays a pathogenetic role in the development of liver inflammation, metabolism, and fibrosis. PARP inhibitors are currently in clinical trials for oncological indications, and the current results indicate that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential.

Solution scanning as a key policy tool: identifying management interventions to help maintain and enhance regulating ecosystem services

The major task of policy makers and practitioners when confronted with a resource management problem is to decide on the potential solution(s) to adopt from a range of available options. However, this process is unlikely to be successful and cost effective without access to an independently verified and comprehensive available list of options. There is currently burgeoning interest in ecosystem services and quantitative assessments of their importance and value. Recognition of the value of ecosystem services to human well-being represents an increasingly important argument for protecting and restoring the natural environment, alongside the moral and ethical justifications for conservation. As well as understanding the benefits of ecosystem services, it is also important to synthesize the practical interventions that are capable of maintaining and/or enhancing these services. Apart from pest regulation, pollination, and global climate regulation, this type of exercise has attracted relatively little attention. Through a systematic consultation exercise, we identify a candidate list of 296 possible interventions across the main regulating services of air quality regulation, climate regulation, water flow regulation, erosion regulation, water purification and waste treatment, disease regulation, pest regulation, pollination and natural hazard regulation. The range of interventions differs greatly between habitats and services depending upon the ease of manipulation and the level of research intensity. Some interventions have the potential to deliver benefits across a range of regulating services, especially those that reduce soil loss and maintain forest cover. Synthesis and applications: Solution scanning is important for questioning existing knowledge and identifying the range of options available to researchers and practitioners, as well as serving as the necessary basis for assessing cost effectiveness and guiding implementation strategies. We recommend that it become a routine part of decision making in all environmental policy areas.

Identification and mutational analyses of phosphorylation sites of the calcineurin-binding protein CbpA and the identification of domains required for calcineurin binding in Aspergillus fumigatus.

Calcineurin is a key protein phosphatase required for hyphal growth and virulence in Aspergillus fumigatus, making it an attractive antifungal target. However, currently available calcineurin inhibitors, FK506 and cyclosporine A, are immunosuppressive, limiting usage in the treatment of patients with invasive aspergillosis. Therefore, the identification of endogenous inhibitors of calcineurin belonging to the calcipressin family is an important parallel strategy. We previously identified the gene cbpA as the A. fumigatus calcipressin member and showed its involvement in hyphal growth and calcium homeostasis. However, the mechanism of its activation/inhibition through phosphorylation and its interaction with calcineurin remains unknown. Here we show that A. fumigatus CbpA is phosphorylated at three distinct domains, including the conserved SP repeat motif (phosphorylated domain-I; PD-I), a filamentous fungal-specific domain (PD-II), and the C-terminal CIC motif (Calcipressin Inhibitor of Calcineurin; PD-III). While mutation of three phosphorylated residues (Ser208, Ser217, Ser223) in the PD-II did not affect CbpA function in vivo, mutation of the two phosphorylated serines (Ser156, Ser160) in the SP repeat motif caused reduced hyphal growth and sensitivity to oxidative stress. Mutational analysis in the key domains in calcineurin A (CnaA) and proteomic interaction studies confirmed the requirement of PxIxIT motif-binding residues (352-NIR-354) and the calcineurin B (CnaB)-binding helix residue (V371) for the binding of CbpA to CnaA. Additionally, while the calmodulin-binding residues (442-RVF-444) did not affect CbpA binding to CnaA, three mutations (T359P, H361L, and L365S) clustered between the CnaA catalytic and the CnaB-binding helix were also required for CbpA binding. This is the first study to analyze the phosphorylation status of calcipressin in filamentous fungi and identify the domains required for binding to calcineurin.

A wolf in sheep"s clothing: carnivory in dominant sea urchins in the Mediterranean

Arbacia lixula and Paracentrotus lividus are the dominant sea urchins in the Mediterranean sublittoral, where they are key structuring species due to their grazing activity. It has been commonly accepted that competition between both species is minimized by specializing in different algal foods. A. lixula is considered to feed mainly on encrusting coralline algae, while P. lividus prefers fleshy macroalgae. We used stable isotope analysis to test if these species occupy different trophic positions at 3 locations in the western Mediterranean and one in Macaronesia. Our results show unambiguously that A. lixula always occupies a higher trophic level than P. lividus, with a δ15N comparable in some locations to strict carnivores such as Actinia schmidti or Marthasterias glacialis. A temporal monitoring at one locality showed that this signature of a higher trophic level is consistent throughout the year. These results are incompatible with the current belief of an herbivorous diet for A. lixula and suggest that it must be considered an omnivore tending to carnivory in Mediterranean ecosystems, feeding at least partially on sessile animals such as Cirripedia, Hydrozoa or Bryozoa. A parallel analysis of gut contents showed a predominance of vegetal items in both species, although A. lixula consistently had a higher abundance of animal components than P. lividus. Our results challenge the validity of using gut content observations alone for characterizing the trophic behaviour of omnivorous marine invertebrates that feed on a variety of food sources with different digestibility.

Code Generator for Key Management Protocols - Design and Implementation

Key management has a fundamental role in secure communications. Designing and testing of key management protocols is tricky. These protocols must work flawlessly despite of any abuse. The main objective of this work was to design and implement a tool that helps to specify the protocol and makes it possible to test the protocol while it is still under development. This tool generates compile-ready java code from a key management protocol model. A modelling method for these protocols, which uses Unified Modeling Language (UML) was also developed. The protocol is modelled, exported as an XMI and read by the code generator tool. The code generator generates java code that is immediately executable with a test software after compilation.

Key Account Management in Paper and Board Industry- Identification of Key Accounts for Stora Enso Graphical Boards

Tutkimuksen tarkoituksena oli tunnistaa nykyiset sekä potentiaaliset avainasiakkaat case yritykselle. Avainasiakkaat tunnistettiin Chevertonin tunnistamis- ja valintamatriisin avulla, jossa asiakkaan sijoittumista matriisiin arvioidaan asiakkaan houkuttelevuuden sekä toimittajan suhteellisten vahvuuksien avulla. Kriteereiksi avainasiakkaiden tunnistamiseen valittiin asiakkaan vuotuinen ostovolyymi, asiakkaan business-potentiaali sekä case-yrityksen toimittajaosuus. Asiakkaat luokiteltiin avainasiakkaisiin, kehitettäviin avainasiakkaisiin, ylläpidettäviin asiakkaisiin sekä satunnaisiin asiakkaisiin. Tutkimus tarjosi lähtökohdan case-yrityksen uusille avainasiakaspäälliköille sekä osoitti suunnan tulevaisuuden tutkimustarpeille. Aktiivisen tiedonvaihdannan kautta eri myyntikonttoreiden johtohenkilöstön sekä myös yrityksen eri funktionaalisten divisioonien välillä voidaan saavuttaa kilpailuetua kun lähestytään asiakasta toimintojaan järkiperäisesti koordinoineena toimittajana samalla kun asiakkaat keskittävät ostojaan. Jotta yrityksen tavoitteet, markkinamahdollisuudet sekä resurssit olisivat hyvin tasapainossa, tulisi myös asiakaskannattavuutta sekä asiakkaiden strategista merkittävyyttä arvioida ja mitata säännöllisesti tässä tutkimuksessa käytettyjen tunnistuskriteereiden lisäksi.

Is syndecan-2 a key angiogenic element?

Angiogenesis is a tightly regulated process in vertebrates that leads to the formation of new blood vessels from pre-existing vessels or by the recruitment of bone marrow-derived endothelial precursor cells[1]. During embryogenesis, after stimulation by proangiogenic factors, such as VEGF or FGF, it contributes to the maturation of the vascular plexus. In adults, it is important in some physiologic conditions, such as wound healing or the reproductive cycle in females, although most of the time it is"switched off" by endogenous inhibitors, such as endostatin or angiostatin. Furthermore, its misregulation is the cause of many pathological situations, as it contributes to tumor development[2], diabetic retinopathy[3], rheumatoid arthritis[4], psoriasis[5], but also cardiovascular disorders[6] and obesity[7]

Parallel feedback loops control the basal activity of the HOG MAPK signaling cascade.

Tight regulation of the MAP kinase Hog1 is crucial for survival under changing osmotic conditions. Interestingly, we found that Hog1 phosphorylates multiple upstream components, implying feedback regulation within the signaling cascade. Taking advantage of an unexpected link between glucose availability and Hog1 activity, we used quantitative single cell measurements and computational modeling to unravel feedback regulation operating in addition to the well-known adaptation feedback triggered by glycerol accumulation. Indeed, we found that Hog1 phosphorylates its activating kinase Ssk2 on several sites, and cells expressing a non-phosphorylatable Ssk2 mutant are partially defective for feedback regulation and proper control of basal Hog1 activity. Together, our data suggest that Hog1 activity is controlled by intertwined regulatory mechanisms operating with varying kinetics, which together tune the Hog1 response to balance basal Hog1 activity and its steady-state level after adaptation to high osmolarity.