Infectivity of Lactobacillus rhamnosus and Lactobacillus paracasei isolates in a rat model of experimental endocarditis.

The potential pathogenicity of selected (potentially) probiotic and clinical isolates of Lactobacillus rhamnosus and Lactobacillus paracasei was investigated in a rat model of experimental endocarditis. In addition, adhesion properties of the lactobacilli for fibrinogen, fibronectin, collagen and laminin, as well as the killing activity of the platelet-microbicidal proteins fibrinopeptide A (FP-A) and connective tissue activating peptide 3 (CTAP-3), were assessed. The 90 % infective dose (ID(90)) of the L. rhamnosus endocarditis isolates varied between 10(6) and 10(7) c.f.u., whereas four of the six (potentially) probiotic L. rhamnosus isolates showed an ID(90) that was at least 10-fold higher (10(8) c.f.u.) (P<0.001). In contrast, the two other probiotic L. rhamnosus isolates exhibited an ID(90) (10(6) and 10(7) c.f.u.) comparable to the ID(90) of the clinical isolates of this species investigated (P>0.05). Importantly, these two probiotic isolates shared the same fluorescent amplified fragment length polymorphism cluster type as the clinical isolate showing the lowest ID(90) (10(6) c.f.u.). L. paracasei tended to have a lower infectivity than L. rhamnosus (ID(90) of 10(7) to > or =10(8) c.f.u.). All isolates had comparable bacterial counts in cardiac vegetations (P>0.05). Except for one L. paracasei strain adhering to all substrates, all tested lactobacilli adhered only weakly or not at all. The platelet peptide FP-A did not show any microbicidal activity against the tested lactobacilli, whereas CTAP-3 killed the majority of the isolates. In general, these results indicate that probiotic lactobacilli display a lower infectivity in experimental endocarditis compared with true endocarditis pathogens. However, the difference in infectivity between L. rhamnosus endocarditis and (potentially) probiotic isolates could not be explained by differences in adherence or platelet microbicidal protein susceptibility. Other disease-promoting factors may exist in these organisms and warrant further investigation.

Growth promoting signaling by tenascin-C [corrected].

Tenascin-C is an adhesion-modulating extracellular matrix molecule that is highly expressed in tumor stroma and stimulates tumor cell proliferation. Adhesion of T98G glioblastoma cells to a fibronectin substratum is inhibited by tenascin-C. To address the mechanism of action, we performed a RNA expression analysis of T89G cells grown in the presence or absence of tenascin-C and found that tenascin-C down-regulates tropomyosin-1. Upon overexpression of tropomyosin-1, cell spreading on a fibronectin/tenascin-C substratum was restored, indicating that tenascin-C destabilizes actin stress fibers through down-regulation of tropomyosin-1. Tenascin-C also increased the expression of the endothelin receptor type A and stimulated the corresponding mitogen-activated protein kinase signaling pathway, which triggers extracellular signal-regulated kinase 1/2 phosphorylation and c-Fos expression. Tenascin-C additionally caused down-regulation of the Wnt inhibitor Dickkopf 1. In consequence, Wnt signaling was enhanced through stabilization of beta-catenin and stimulated the expression of the beta-catenin target Id2. Finally, our in vivo data derived from astrocytoma tissue arrays link increased tenascin-C and Id2 expression with high malignancy. Because increased endothelin and Wnt signaling, as well as reduced tropomyosin-1 expression, are closely linked to transformation and tumorigenesis, we suggest that tenascin-C specifically modulates these signaling pathways to enhance proliferation of glioma cells.

Local optima networks of hard combinatorial landscapes

Combinatorial optimization involves finding an optimal solution in a finite set of options; many everyday life problems are of this kind. However, the number of options grows exponentially with the size of the problem, such that an exhaustive search for the best solution is practically infeasible beyond a certain problem size. When efficient algorithms are not available, a practical approach to obtain an approximate solution to the problem at hand, is to start with an educated guess and gradually refine it until we have a good-enough solution. Roughly speaking, this is how local search heuristics work. These stochastic algorithms navigate the problem search space by iteratively turning the current solution into new candidate solutions, guiding the search towards better solutions. The search performance, therefore, depends on structural aspects of the search space, which in turn depend on the move operator being used to modify solutions. A common way to characterize the search space of a problem is through the study of its fitness landscape, a mathematical object comprising the space of all possible solutions, their value with respect to the optimization objective, and a relationship of neighborhood defined by the move operator. The landscape metaphor is used to explain the search dynamics as a sort of potential function. The concept is indeed similar to that of potential energy surfaces in physical chemistry. Borrowing ideas from that field, we propose to extend to combinatorial landscapes the notion of the inherent network formed by energy minima in energy landscapes. In our case, energy minima are the local optima of the combinatorial problem, and we explore several definitions for the network edges. At first, we perform an exhaustive sampling of local optima basins of attraction, and define weighted transitions between basins by accounting for all the possible ways of crossing the basins frontier via one random move. Then, we reduce the computational burden by only counting the chances of escaping a given basin via random kick moves that start at the local optimum. Finally, we approximate network edges from the search trajectory of simple search heuristics, mining the frequency and inter-arrival time with which the heuristic visits local optima. Through these methodologies, we build a weighted directed graph that provides a synthetic view of the whole landscape, and that we can characterize using the tools of complex networks science. We argue that the network characterization can advance our understanding of the structural and dynamical properties of hard combinatorial landscapes. We apply our approach to prototypical problems such as the Quadratic Assignment Problem, the NK model of rugged landscapes, and the Permutation Flow-shop Scheduling Problem. We show that some network metrics can differentiate problem classes, correlate with problem non-linearity, and predict problem hardness as measured from the performances of trajectory-based local search heuristics.

Tapping the innovation potential of corporate engagement with stakeholders

Summary This dissertation explores how stakeholder dialogue influences corporate processes, and speculates about the potential of this phenomenon - particularly with actors, like non-governmental organizations (NGOs) and other representatives of civil society, which have received growing attention against a backdrop of increasing globalisation and which have often been cast in an adversarial light by firms - as a source of teaming and a spark for innovation in the firm. The study is set within the context of the introduction of genetically-modified organisms (GMOs) in Europe. Its significance lies in the fact that scientific developments and new technologies are being generated at an unprecedented rate in an era where civil society is becoming more informed, more reflexive, and more active in facilitating or blocking such new developments, which could have the potential to trigger widespread changes in economies, attitudes, and lifestyles, and address global problems like poverty, hunger, climate change, and environmental degradation. In the 1990s, companies using biotechnology to develop and offer novel products began to experience increasing pressure from civil society to disclose information about the risks associated with the use of biotechnology and GMOs, in particular. Although no harmful effects for humans or the environment have been factually demonstrated even to date (2008), this technology remains highly-contested and its introduction in Europe catalysed major companies to invest significant financial and human resources in stakeholder dialogue. A relatively new phenomenon at the time, with little theoretical backing, dialogue was seen to reflect a move towards greater engagement with stakeholders, commonly defined as those "individuals or groups with which. business interacts who have a 'stake', or vested interest in the firm" (Carroll, 1993:22) with whom firms are seen to be inextricably embedded (Andriof & Waddock, 2002). Regarding the organisation of this dissertation, Chapter 1 (Introduction) describes the context of the study, elaborates its significance for academics and business practitioners as an empirical work embedded in a sector at the heart of the debate on corporate social responsibility (CSR). Chapter 2 (Literature Review) traces the roots and evolution of CSR, drawing on Stakeholder Theory, Institutional Theory, Resource Dependence Theory, and Organisational Learning to establish what has already been developed in the literature regarding the stakeholder concept, motivations for engagement with stakeholders, the corporate response to external constituencies, and outcomes for the firm in terms of organisational learning and change. I used this review of the literature to guide my inquiry and to develop the key constructs through which I viewed the empirical data that was gathered. In this respect, concepts related to how the firm views itself (as a victim, follower, leader), how stakeholders are viewed (as a source of pressure and/or threat; as an asset: current and future), corporate responses (in the form of buffering, bridging, boundary redefinition), and types of organisational teaming (single-loop, double-loop, triple-loop) and change (first order, second order, third order) were particularly important in building the key constructs of the conceptual model that emerged from the analysis of the data. Chapter 3 (Methodology) describes the methodology that was used to conduct the study, affirms the appropriateness of the case study method in addressing the research question, and describes the procedures for collecting and analysing the data. Data collection took place in two phases -extending from August 1999 to October 2000, and from May to December 2001, which functioned as `snapshots' in time of the three companies under study. The data was systematically analysed and coded using ATLAS/ti, a qualitative data analysis tool, which enabled me to sort, organise, and reduce the data into a manageable form. Chapter 4 (Data Analysis) contains the three cases that were developed (anonymised as Pioneer, Helvetica, and Viking). Each case is presented in its entirety (constituting a `within case' analysis), followed by a 'cross-case' analysis, backed up by extensive verbatim evidence. Chapter 5 presents the research findings, outlines the study's limitations, describes managerial implications, and offers suggestions for where more research could elaborate the conceptual model developed through this study, as well as suggestions for additional research in areas where managerial implications were outlined. References and Appendices are included at the end. This dissertation results in the construction and description of a conceptual model, grounded in the empirical data and tied to existing literature, which portrays a set of elements and relationships deemed important for understanding the impact of stakeholder engagement for firms in terms of organisational learning and change. This model suggests that corporate perceptions about the nature of stakeholder influence the perceived value of stakeholder contributions. When stakeholders are primarily viewed as a source of pressure or threat, firms tend to adopt a reactive/defensive posture in an effort to manage stakeholders and protect the firm from sources of outside pressure -behaviour consistent with Resource Dependence Theory, which suggests that firms try to get control over extemal threats by focussing on the relevant stakeholders on whom they depend for critical resources, and try to reverse the control potentially exerted by extemal constituencies by trying to influence and manipulate these valuable stakeholders. In situations where stakeholders are viewed as a current strategic asset, firms tend to adopt a proactive/offensive posture in an effort to tap stakeholder contributions and connect the organisation to its environment - behaviour consistent with Institutional Theory, which suggests that firms try to ensure the continuing license to operate by internalising external expectations. In instances where stakeholders are viewed as a source of future value, firms tend to adopt an interactive/innovative posture in an effort to reduce or widen the embedded system and bring stakeholders into systems of innovation and feedback -behaviour consistent with the literature on Organisational Learning, which suggests that firms can learn how to optimize their performance as they develop systems and structures that are more adaptable and responsive to change The conceptual model moreover suggests that the perceived value of stakeholder contribution drives corporate aims for engagement, which can be usefully categorised as dialogue intentions spanning a continuum running from low-level to high-level to very-high level. This study suggests that activities aimed at disarming critical stakeholders (`manipulation') providing guidance and correcting misinformation (`education'), being transparent about corporate activities and policies (`information'), alleviating stakeholder concerns (`placation'), and accessing stakeholder opinion ('consultation') represent low-level dialogue intentions and are experienced by stakeholders as asymmetrical, persuasive, compliance-gaining activities that are not in line with `true' dialogue. This study also finds evidence that activities aimed at redistributing power ('partnership'), involving stakeholders in internal corporate processes (`participation'), and demonstrating corporate responsibility (`stewardship') reflect high-level dialogue intentions. This study additionally finds evidence that building and sustaining high-quality, trusted relationships which can meaningfully influence organisational policies incline a firm towards the type of interactive, proactive processes that underpin the development of sustainable corporate strategies. Dialogue intentions are related to type of corporate response: low-level intentions can lead to buffering strategies; high-level intentions can underpin bridging strategies; very high-level intentions can incline a firm towards boundary redefinition. The nature of corporate response (which encapsulates a firm's posture towards stakeholders, demonstrated by the level of dialogue intention and the firm's strategy for dealing with stakeholders) favours the type of learning and change experienced by the organisation. This study indicates that buffering strategies, where the firm attempts to protect itself against external influences and cant' out its existing strategy, typically lead to single-loop learning, whereby the firm teams how to perform better within its existing paradigm and at most, improves the performance of the established system - an outcome associated with first-order change. Bridging responses, where the firm adapts organisational activities to meet external expectations, typically leads a firm to acquire new behavioural capacities characteristic of double-loop learning, whereby insights and understanding are uncovered that are fundamentally different from existing knowledge and where stakeholders are brought into problem-solving conversations that enable them to influence corporate decision-making to address shortcomings in the system - an outcome associated with second-order change. Boundary redefinition suggests that the firm engages in triple-loop learning, where the firm changes relations with stakeholders in profound ways, considers problems from a whole-system perspective, examining the deep structures that sustain the system, producing innovation to address chronic problems and develop new opportunities - an outcome associated with third-order change. This study supports earlier theoretical and empirical studies {e.g. Weick's (1979, 1985) work on self-enactment; Maitlis & Lawrence's (2007) and Maitlis' (2005) work and Weick et al's (2005) work on sensegiving and sensemaking in organisations; Brickson's (2005, 2007) and Scott & Lane's (2000) work on organisational identity orientation}, which indicate that corporate self-perception is a key underlying factor driving the dynamics of organisational teaming and change. Such theorizing has important implications for managerial practice; namely, that a company which perceives itself as a 'victim' may be highly inclined to view stakeholders as a source of negative influence, and would therefore be potentially unable to benefit from the positive influence of engagement. Such a selfperception can blind the firm from seeing stakeholders in a more positive, contributing light, which suggests that such firms may not be inclined to embrace external sources of innovation and teaming, as they are focussed on protecting the firm against disturbing environmental influences (through buffering), and remain more likely to perform better within an existing paradigm (single-loop teaming). By contrast, a company that perceives itself as a 'leader' may be highly inclined to view stakeholders as a source of positive influence. On the downside, such a firm might have difficulty distinguishing when stakeholder contributions are less pertinent as it is deliberately more open to elements in operating environment (including stakeholders) as potential sources of learning and change, as the firm is oriented towards creating space for fundamental change (through boundary redefinition), opening issues to entirely new ways of thinking and addressing issues from whole-system perspective. A significant implication of this study is that potentially only those companies who see themselves as a leader are ultimately able to tap the innovation potential of stakeholder dialogue.

Regulation of the vitellogenin gene B1 promoter after transfer into hepatocytes in primary cultures.

The estrogen-dependent and tissue-specific regulation of the Xenopus laevis vitellogenin gene B1 promoter has been studied by lipid-mediated DNA transfer into Xenopus hepatocytes in primary culture. Hepatocytes achieve an efficient hormonal control of this promoter through a functional interaction between the estrogen responsive elements and a promoter proximal region upstream of the TATA box, which is characterized by a high density of binding sites for the transcription factors CTF/NF-1, C/EBP and HNF3. DNA accessibility to restriction enzymes within the chromosomal copy of the vitellogenin gene B1 promoter shows that the estrogen responsive unit and the promoter proximal region are sensitive to digestion in uninduced and estrogen-induced hepatocytes but not in erythrocyte nuclei. Together, these findings support the notion that chromatin configuration as well as the interplay of promoter elements mediate proper hormone-dependent and tissue-specific expression of the B1 vitellogenin gene.

c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.

The activity of adult stem cells is essential to replenish mature cells constantly lost due to normal tissue turnover. By a poorly understood mechanism, stem cells are maintained through self-renewal while concomitantly producing differentiated progeny. Here, we provide genetic evidence for an unexpected function of the c-Myc protein in the homeostasis of hematopoietic stem cells (HSCs). Conditional elimination of c-Myc activity in the bone marrow (BM) results in severe cytopenia and accumulation of HSCs in situ. Mutant HSCs self-renew and accumulate due to their failure to initiate normal stem cell differentiation. Impaired differentiation of c-Myc-deficient HSCs is linked to their localization in the differentiation preventative BM niche environment, and correlates with up-regulation of N-cadherin and a number of adhesion receptors, suggesting that release of HSCs from the stem cell niche requires c-Myc activity. Accordingly, enforced c-Myc expression in HSCs represses N-cadherin and integrins leading to loss of self-renewal activity at the expense of differentiation. Endogenous c-Myc is differentially expressed and induced upon differentiation of long-term HSCs. Collectively, our data indicate that c-Myc controls the balance between stem cell self-renewal and differentiation, presumably by regulating the interaction between HSCs and their niche.

Suunnittelun tunnusluvut

Diplomityön tavoitteena oli kehittää Andritzin Kuitulinja-divisioonalle tunnuslukuja, työkaluja sekä menetelmiä projektin johdon jasuunnittelun eri osa-alueiden arviointiin, hinnoitteluun ja seurantaan Työn teoriaosuudessa käsiteltiin projektiliiketoimintaa, suunnitteluaja sen hankintaa, tunnuslukuja sekä mittaamista projektiympäristössä. Työn pääpaino oli kuitenkin empiriaosuudella, jossa aluksi tutustuttiin yksityiskohtaisesti työssä tutkittaviin osa-alueisiin. Tiedonkeruuvaiheessa kerättiin suuri määrätunnuslukujen laskemiseksi tarvittavaa tietoa toteutetuista tai vielä hieman keskeneräisistä projekteista. Työn kirjallinen osuus ja kerätty numeerinen tieto yhdistettiin tunnuslukujen analysointivaiheessa, jossa tutkittiin eri tunnuslukujen soveltuvuutta mittaamiseen. Tunnusluvut soveltuivat hyvin joidenkin osa-alueiden kuten prosessi- ja putkistosuunnittelun mittaamiseen. Joidenkin osa-alueiden, kuten rakennussuunnittelun mittaaminen tunnuslukujen avulla oli vaikeampaa tunnuslukujen suuresta hajonnasta johtuen. Eri osa-alueille saatiin kuitenkin määritettyä parhaat tunnusluvut, projektien luokitteluperusteet ja standardiarvot. Työn lopputuloksina saatiin päätavoitteena ollut tunnuslukumittaristo sekä mittaamisen yhtenäistämiseksi luotu tiedonkeruulomake. Mittaamisen tehostamiseksi ja kehittämiseksi tehtiin useita jatkotutkimus- ja kehitysehdotuksia. Lisäksi työssä esitettiin uusi menetelmä projektinohjauksen ja resurssisuunnittelun tueksi.

ERP- järjestelmän tukiprosessin nykytilan analyysi ja prosessin kehittäminen

Diplomityön tavoitteena oli tunnistaa kohdeyrityksessä kehitysmahdollisuuksia. Kehitysmahdollisuuksien etsiminen käyttäjätukiprosessin aloitettiin prosessin nykytilan analysoinnilla, jolla pyrittiin tunnistamaan prosessin ominaisuuksia sekä ongelma-alueita, joita korjaamalla prosessia voitiin tehostaa. Tutkimus on jaettu teoria ja empiria osaan.Teorian alussa käsitellään tietotekniikkapalveluiden organisointia, jotta ymmärretään toiminnanohjausjärjestelmien ja niihin liittyvien tukiprosessien merkitys yrityksissä. Tämän jälkeen perehdytään prosessijohtamiseen ja sen keinoihin liiketoimintaprosessien kehittämiseen. Tuloksena voidaan sanoa, että prosessien virtaviivaistaminen on nopea ja edullinen tapa tehostaa prosessin toimintaa ja päivittää vanha prosessi vastaamaan yrityksen nykyisiä tarpeita. Prosessien virtaviivaistamisella ei saada suuria kustannussäästöjä, vaan hyödyt liittyvät prosessin tehostumiseen. Virtaviivaistetusta prosessista on poistettu turhat toiminnot ja se on suunniteltu vastaamaan tarkoitustaan parhaalla mahdollisella tavalla. Näin prosessin virtaviivaistaminen lisää myös asiakkaan kokemaa arvoa.

Developing Processes and Learning in a Project-based Firm

Tämän diplomityön tavoitteena on kuvata tiedonkulkua projektiliiketoimintaa harjoittavassa yrityksessä sekä analysoida kuvausta määrittäen mahdolliset kehityskohdat. Työssätuotetut kuvaukset ja kehityskohtien määrittäminen toimivat pohjana yrityksen kehittäessä projektien hallintaansa tulevaisuudessa. Työssä valitaan tietojohtamisen näkökulma sopivaksi lähestymistavaksi yrityksen toiminnananalysointiin. Haastatteluin kerätyn tutkimusmateriaalin perusteella luodaan prosessikuvaukset jotka mallintavat tietovirtoja yrityksen projektien aikana tapahtuvien prosessien välillä. Kuvausta peilataan tietämyksen luomisen sekä projektien tietojohtamisen teoriaan ja määritetään kehityskohteita. Kehityskohteiden määrittämisen lisäksi ehdotetaan mahdollisia toimenpiteitä tiedon ja tietämyksen hallinnan kehittämiseksi. Kokemusten ja opittujen asioiden sekäpalautteen kerääminen projektien aikana sekä niiden jälkeen havaittiin tärkeimmäksi kehityskohdaksi. Näiden keräämisen voidaan todeta vaativan järjestelmällisyyttä jotta projektien onnistumiset sekä niissä saavutetut parannukset voidaan toistaa jatkossa ja virheet sekä epäonnistumiset sitä vastoin välttää.

Implementing theLean Manufacturing System

Tuottavuuden ja tehokkuuden parantaminen on keskeisimpiä menestystekijöitä glo-baaleilla markkinoilla. Yksi kehittämisen toimintamalli on lean manufacturing -ajattelutapa, joka perustuu imuohjaukseen. Sen lähtökohtana on asiakasarvo ja keskit-tyminen arvoa lisäävien toimintojen maksimointiin. Tutkimuksen tavoitteena oli parantaa Strömfors Electric Oy:n materiaalivirtauksia yhdellä tuotantolinjalla. Projektin oli tarkoitus olla pilotti lean-implementointiin koko tehtaalla. Projektissa otettiin käyttöön kanban-imuohjausjärjestelmä, jota varten teh-tiin analyysejä ja laskelmia arvovirtoihin, varastoihin ja ohjaukseen. Lean-ajattelutapaan ja -työkaluihin perustuvaa kirjallisuutta käytettiin pohjatietona pilotti-projektissa sekätulevien kehitysprojektien suunnittelussa. Pilottiprojektin tuloksena materiaalinohjaus tehostui ja keskeneräisen tuotannon va-rasto tasoittui käyttötarpeen mukaiseksi. Työntekijät ja työnjohtajat tutustuivat leanin perusteisiin osallistuessaan pilottiprojektiin. Pidemmän aikavälin suunnitelmissa ontoimitusvarmuuden ja laadun parantuminen ensin pilottiprojektia koskevalla linjalla ja myöhemmin koko tehtaalla imuohjauksen kokonaisvaltaisen käyttöönoton myötä.

Innovaation kehittäminen yritysverkostolle, Case: Projektihallinta

Työn tavoitteena on kehittää arvoinnovaatio yritysverkostolle. Arvoinnovaation teoreettisen viitekehyksen konkretisoimiseksi ja arvioimiseksi käytetään työssä kohteena ProPortfolio - ohjelmistotuotetta sekä sen kehittämistyössä saatuja kokemuksia. ProPortfolio on vuosina 2001-2004 kehitetty mobiiliin teknologiaan perustuva ohjelmistosovellus. ProPortfolio ohjelmisto on liikkeenjohdon konsulttiyritys Tuloskunto Oy:n johdolla ja TEKES:n rahoittamassa hankkeessa kehitetty pientaloprojektien toteuttajaverkoston toiminnanohjausjärjestelmä. Pitkäaikaisen kilpailuedun saavuttaminen erottumalla kilpailijoiden massasta on kasvava haaste yrityksille. Tutkijoiden Kimin ja Mauborgnen kehittämän arvoinnovaation ja strategisen suunnittelun prosessin lähtökohtana on kilpailun kiertäminen differoitumalla kilpailijoista ja uusien markkinoiden luominen. Perinteisen strategisen ajattelutavan mukaan yritykset voivat tuottaa korkeampaa arvoaasiakkaille korkeammin kustannuksin tai kohtuullista arvoa pienemmin kustannuksin. Eli strateginen asemointi perustuu valintaan differoitumisen ja kustannusjohtajuuden välillä (Porter,1985). Arvoinnovaatioon perustuvassa asemoinnissa tavoitellaan sekä differoitumista että kustannusjohtajuutta samanaikaisesti. Arvoinnovaation keskeisimmät kriteerit täyttyivät kehityshankkeen lopputuloksena syntyneessä ProPortfolio -ohjelmistotuotteessa. Tämän työn pohjalta voidaan todeta, että Kimin ja Mauborgnen kehittämä strategian suunnitteluprosessi on laaja ja vaativa. Arvoinnovaatio syntyy harvoin hetkellisenä oivalluksena, vaan kehittyy järjestelmällisen työskentelyn tuloksena. ProPortfolio -ohjelmistotuotteen arvoinnovaation muodostuminen perustui kehityshankkeen onnistuneeseen asiakastarpeiden tunnistamiseen ja ennakoimiseen. Selkeän kuvan hahmottuminen ratkaistavista ongelmista auttoi asemoimaan hankkeen jatkokehitystyön oikein ja loi edellytykset arvoinnovaation muodostumiselle. Tutkijat Kim jaMauborgne ovat haastaneet perinteiset strategiatyöskentelyn mallit. Tutkimustuloksiinsa pohjautuen he ovat kehittäneet uuden arvoinnovaatioon perustuvan strategisen suunnittelun teoreettisen viitekehikon ja prosessin. Nämä mallit tulevat varmasti jättämään pysyvän jäljen strategiatyöskentelyn nykykäytäntöihin.

Phosphorylation of phosphatidylinositol-3-kinase-protein kinase B and extracellular signal-regulated kinases 1/2 mediate reoxygenation-induced cardioprotection during hypoxia.

In vivo exposure to chronic hypoxia (CH) depresses myocardial performance and tolerance to ischemia, but daily reoxyenation during CH (CHR) confers cardioprotection. To elucidate the underlying mechanism, we tested the role of phosphatidylinositol-3-kinase-protein kinase B (Akt) and p42/p44 extracellular signal-regulated kinases (ERK1/2), which are known to be associated with protection against ischemia/reperfusion (I/R). Male Sprague-Dawley rats were maintained for two weeks under CH (10% O(2)) or CHR (as CH but with one-hour daily exposure to room air). Then, hearts were either frozen for biochemical analyses or Langendorff-perfused to determine performance (intraventricular balloon) and tolerance to 30-min global ischemia and 45-min reperfusion, assessed as recovery of performance after I/R and infarct size (tetrazolium staining). Additional hearts were perfused in the presence of 15 micromol/L LY-294002 (inhibitor of Akt), 10 micromol/L UO-126 (inhibitor of ERK1/2) or 10 micromol/L PD-98059 (less-specific inhibitor of ERK1/2) given 15 min before ischemia and throughout the first 20 min of reperfusion. Whereas total Akt and ERK1/2 were unaffected by CH and CHR in vivo, in CHR hearts the phosphorylation of both proteins was higher than in CH hearts. This was accompanied by better performance after I/R (heart rate x developed pressure), lower end-diastolic pressure and reduced infarct size. Whereas the treatment with LY-294002 decreased the phosphorylation of Akt only, the treatment with UO-126 decreased ERK1/2, and that with PD-98059 decreased both Akt and ERK1/2. In all cases, the cardioprotective effect led by CHR was lost. In conclusion, in vivo daily reoxygenation during CH enhances Akt and ERK1/2 signaling. This response was accompanied by a complex phenotype consisting in improved resistance to stress, better myocardial performance and lower infarct size after I/R. Selective inhibition of Akt and ERK1/2 phosphorylation abolishes the beneficial effects of the reoxygenation. Therefore, Akt and ERK1/2 have an important role to mediate cardioprotection by reoxygenation during CH in vivo.

Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen.

Background: Estrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30-40% of ER+ BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings.Results: We developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95% CI: 1.29-3.13; p = 0.002). Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response.Conclusion: We have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen.

Paineellisten reaktoreiden projektitoimituksen optimointi

Diplomityössä tavoitteena on saada selvitys, jonka avulla yritys löytää toimitusprojekteistaan parannusta ja huomiota vaativat osa-alueet projektimuotoisten toimitusten kustannusrakennetta ja optimointia tarkastelemalla. Näin yritys voi tulevaisuudessa kehittää projektitoimituksen osa-alueita niin että se voi vastata asiakkaiden asettamiin vaatimuksiin sekä haasteisiin entistä nopeammin ja tarkemmin. Tutkimuksen lähtökohtana ovat projektiajattelu sekä siihen liittyvän toimitusketjun prosessit, joiden avulla lähestytään tutkimuksen ongelmaa ja selvitetään koko toimitusprojektin kehitystä vaativat alueet. Tutkimuksessa vaaditut tiedot saavutettiin vapaamuotoisten haastattelujen, yrityksen dokumentteja tutkimalla sekä yhteistyökumppanien avulla. Projektitoimituksen kokonaisvaltainen kehitys vaatii yhteistyötä ja huomiota toimitusketjun jokaisessa osa-alueessa aina raaka-ainelähteiltä loppukäyttäjälle asti. Näin voidaan saavuttaa tietojen avoimuus ja täsmällisyys, jotta päästään parhaaseen lopputulokseen projektitoimituksen osalta. Erityisesti kustannusrakenteen jakauma tuleehuomioida tulevaisuudessa tarkasti tehtäessä projektitoimitukseen liittyviä ratkaisuja. Esivalmistusasteen tarkastelu asetettiin työn alussa yhdeksi tärkeimmäksi tutkimuskohteeksi. Tarkastelussa havaittiin, että valmistusasteen valinnalla voidaan vaikuttaa lähes puoleen reaktorin kustannusrakenteen mukaisista kustannuksista kuten työ-, kuljetus- ja asennuskustannukseen. Myös materiaalikustannukset ovat suuressa roolissa reaktorinkustannusrakenteessa, joten tähän tulee kiinnittää myös huomiota. Muita tutkittavia tekijöitä, jotka pääasiassa vaikuttivat materiaali- ja asennuskustannuksiin työssä olivat paineastiastandardin ja paineluokan sekä valmistuspaikan valinta. Lisäksi huomioitiin toteutuneiden toimitusten eroavaisuuksia teoreettisiin ratkaisuihin ja etsittiin näistä mahdollisia kehitys- ja kustannussäästökohteita.

Civil society organisations participating in ISO TC 228 and ISO TC 229: the INTERNORM project and its future

This paper presents the first results of the INTERNORM pilot project funded by the University of Lausanne (2010 - 2014) to support the involvement of civil society organisations (CSO) in two ISO technical committees (TC), the ISO TC 228 on "tourism and related services" and the ISO TC 229 on "nanotechnologies". It analyses how a distinct participatory mechanism can influence the institutional environment of technical diplomacy in which standards are shaped. The project is an attempt to respond to the democratic deficit attested in the field of international standardisation, formally open to civil society participation, but still largely dominated by expert knowledge and market players. Many international standards have direct implications on society as a whole, but CSOs (consumers and environmental associations, trade unions) are largely under-represented in negotiation arenas. The paper draws upon international relations literature on new institutional forms in global governance and studies of participation in science and technology to address three questions: to which extent do CSOs identify participation in standardisation as worth of their mobilisation? How is the pluralisation of knowledge and expertise supporting CSO position during the deliberation? To which extent can CSO access and influence standardisation beyond their consultative role? It argues that there are significant limitations to the rise of civil society participation in such global governance mechanisms. Despite high entry costs into technical diplomacy, participation is not so much a matter of upstream engagement, or of procedure and resources only, than of opportunistic CSOs mobilization, of distinct thematic incentives and concrete outcomes to be expected in standardisation arenas or in the broader use of international standards.