Microarrays in Molecular Profiling of Ewing Sarcoma Family of Tumors and CDKN2A Aberrations

Background: The Ewing sarcoma family of tumors (ESFT) are rare but highly malignant neoplasms that occur mainly in bone or but also in soft tissue. ESFT affects patients typically in their second decade of life, whereby children and adolescents bear the heaviest incidence burden. Despite recent advances in the clinical management of ESFT patients, their prognosis and survival are still disappointingly poor, especially in cases with metastasis. No targeted therapy for ESFT patients is currently available. Moreover, based merely on current clinical and biological characteristics, accurate classification of ESFT patients often fails at the time of diagnosis. Therefore, there is a constant need for novel molecular biomarkers to be applied in tandem with conventional parameters to further intensify ESFT risk-stratification and treatment selection, and ultimately to develop novel targeted therapies. In this context, a greater understanding of the genetics and immune characteristics of ESFT is needed. Aims: This study sought to open novel insights into gene copy number changes and gene expression in ESFT and, further, to enlighten the role of inflammation in ESFT. For this purpose, microarrays were used to provide gene-level information on a genomewide scale. In addition, this study focused on screening of 9p21.3 deletion sizes and frequencies in ESFT and, in another pediatric cancer, acute lymphocytic leukemia (ALL), in order to define more exact criteria for highrisk patient selection and to provide data for developing a more reliable diagnostic method to detect CDKN2A deletions. Results: In study I, 20 novel ESFT-associated suppressor genes and oncogenes were pinpointed using combined array CGH and expression analysis. In addition, interesting chromosomal rearrangements were identified: (1) Duplication of derivative chromosome der(22)(11;22) was detected in three ESFT patients. This duplication included the EWSR1-FLI1 fusion gene leading to increase in its copy number; (2) Cryptic amplifications on chromosomes 20 and 22 were detected, suggesting a novel translocation between chromosomes 20 and 22, which most probably produces a fusion between EWSR1 and NFATC2. In study II, bioinformatic analysis of ESFT expression profiles showed that inflammatory gene activation is detectable in ESFT patient samples and that the activation is characterized by macrophage gene expression. Most interestingly, ESFT patient samples were shown to express certain inflammatory genes that were prognostically significant. High local expression of C5 and JAK1 at the tumor site was shown to associate with favorable clinical outcome, whereas high local expression of IL8 was shown to be detrimental. Studies III and IV showed that the smallest overlapping region of deletion in 9p21.3 includes CDKN2A in all cases and that the length of this region is 12.2 kb in both Ewing sarcoma and ALL. Furthermore, our results showed that the most widely used commercial CDKN2A FISH probe creates false negative results in the narrowest microdeletion cases (<190 kb). Therefore, more accurate methods should be developed for the detection of deletions in the CDKN2A locus. Conclusions: This study provides novel insights into the genetic changes involved in the biology of ESFT, in the interaction between ESFT cells and immune system, and in the inactivation of CDKN2A. Novel ESFT biomarker genes identified in this study serve as a useful resource for future studies and in developing novel therapeutic strategies to improve the survival of patients with ESFT.

Mittauslaitteiston suunnittelu piidiodien vuotovirtamittauksiin matalissa lämpötiloissa

Tässä työssä on suunniteltu mittauslaitteisto ja toteutettu diodien vuotovirtamittaukset matalissa lämpötiloissa. Suunnittelun pääpaino oli tuottaa mittauslaitteisto, joka kestäisi mittausolosuhteitten matalan lämpötilan (80 K) ja toisaalta myös lämpötilavaihtelut huoneen lämpötilasta mataliin lämpötiloihin. Lisäksi mittauslaitteiston oli kestettävä myös tutkimusprojektin myöhemmissä vaiheissa mukaan tulevaa protonisäteilytystä, mikä asetti omat valintaperusteensa materiaaleille. Mittauslaitteiston kohinaa pyrittiin vaimentamaan kontaktipintojen kultapinnoitteilla ja kiinnittämällä huomiota virtajohtimien eristyksiin. Työssä mitattiin erilailla prosessoitujen piidiodien vuotovirtoja eri lämpötiloissa. Mitatut diodit olivat sekä etukäteen säteilytettyjä että säteilyttämättömiä ja työn yhtenä päämääränä oli verrata säteilytyksen vaikutuksia vuotovirran lämpötilakorrelaatioon. Diodien piimateriaaleja oli valmistettu magneettisella Czochralski-menetelmällä sekä Float Zone-menetelmällä, lisäksi osaa diodeista oli muokattu erilaisilla lämpökäsittelyillä parempien säteilynkesto-ominaisuuksien aikaansaamiseksi. Mittauksissa diodin lämpötila laskettiin jäähdytyslaitteistolla systeemin minimilämpötilaan ja diodin ominaiskäyrä mitattiin välillä 0-450 V. Lämpötilaa nostettiin asteittain ja ominaiskäyrät mitattiin määrätyissä lämpötiloissa, minkä jälkeen tuloksia verrattiin teoreettisiin arvioihin vuotovirran lämpötilakäyttäytymisestä. Tulosten perusteella voidaan todeta teoreettisten arvojen vastaavan kokeellisia, mittauslaitteiston erottelukyvyn kynnykselle asti (10-11A), mutta tämän jälkeen mahdollinen lämpötilan laskun aiheuttama virranlasku hukkuu mittalaitteiston kohinan sekaan. Säteilytettyjen diodien kohdalla lämpötilan laskeminen madalsi vuotovirtaa 6 dekadia huoneenlämmöstä 190 K lämpötilaan, kunnes mittauskynnys ylittyi. Säteilyttämättömillä diodeilla vuotovirta oli jo huoneenlämpötilassa erittäin pientä ja lämpötilan laskiessa minimiarvoonsa vuotovirta pieneni n. 2 dekadia, kunnes mittalaitteiston mittatarkkuus tuli vastaan.

Studies of new inorganic species using relativistic quantum chemistry

In the present work the methods of relativistic quantum chemistry have been applied to a number of small systems containing heavy elements, for which relativistic effects are important. First, a thorough introduction of the methods used is presented. This includes some of the general methods of computational chemistry and a special section dealing with how to include the effects of relativity in quantum chemical calculations. Second, after this introduction the results obtained are presented. Investigations on high-valent mercury compounds are presented and new ways to synthesise such compounds are proposed. The methods described were applied to certain systems containing short Pt-Tl contacts. It was possible to explain the interesting bonding situation in these compounds. One of the most common actinide compounds, uranium hexafluoride was investigated and a new picture of the bonding was presented. Furthermore the rareness of uranium-cyanide compounds was discussed. In a foray into the chemistry of gold, well known for its strong relativistic effects, investigations on different gold systems were performed. Analogies between Au$^+$ and platinum on one hand and oxygen on the other were found. New systems with multiple bonds to gold were proposed to experimentalists. One of the proposed systems was spectroscopically observed shortly afterwards. A very interesting molecule, which was theoretically predicted a few years ago is WAu$_{12}$. Some of its properties were calculated and the bonding situation was discussed. In a further study on gold compounds it was possible to explain the substitution pattern in bis[phosphane-gold(I)] thiocyanate complexes. This is of some help to experimentalists as the systems could not be crystallised and the structure was therefore unknown. Finally, computations on one of the heaviest elements in the periodic table were performed. Calculation on compounds containing element 110, darmstadtium, showed that it behaves similarly as its lighter homologue platinum. The extreme importance of relativistic effects for these systems was also shown.

The kinetics and reactivity of several polyatomic free radicals in reactions with NO2, O2, Cl2, and HCl

In this thesis, the kinetics of several alkyl, halogenated alkyl, and alkenyl free radical reactions with NO2, O2, Cl2, and HCl reactants were studied over a wide temperature range in time resolved conditions. Laser photolysis photoionisation mass spectrometer coupled to a flow reactor was the experimental method employed and this thesis present the first measurements performed with the experimental system constructed. During this thesis a great amount of work was devoted to the designing, building, testing, and improving the experimental apparatus. Carbon-centred free radicals were generated by the pulsed 193 or 248 nm photolysis of suitable precursors along the tubular reactor. The kinetics was studied under pseudo-first-order conditions using either He or N2 buffer gas. The temperature and pressure ranges employed were between 190 and 500 K, and 0.5 45 torr, respectively. The possible role of heterogeneous wall reactions was investigated employing reactor tubes with different sizes, i.e. to significantly vary the surface to volume ratio. In this thesis, significant new contributions to the kinetics of carbon-centred free radical reactions with nitrogen dioxide were obtained. Altogether eight substituted alkyl (CH2Cl, CHCl2, CCl3, CH2I, CH2Br, CHBr2, CHBrCl, and CHBrCH3) and two alkenyl (C2H3, C3H3) free radical reactions with NO2 were investigated as a function of temperature. The bimolecular rate coefficients of all these reactions were observed to possess negative temperature dependencies, while pressure dependencies were not noticed for any of these reactions. Halogen substitution was observed to moderately reduce the reactivity of substituted alkyl radicals in the reaction with NO2, while the resonance stabilisation of the alkenyl radical lowers its reactivity with respect to NO2 only slightly. Two reactions relevant to atmospheric chemistry, CH2Br + O2 and CH2I + O2, were also investigated. It was noticed that while CH2Br + O2 reaction shows pronounced pressure dependence, characteristic of peroxy radical formation, no such dependence was observed for the CH2I + O2 reaction. Observed primary products of the CH2I + O2 reaction were the I-atom and the IO radical. Kinetics of CH3 + HCl, CD3 + HCl, CH3 + DCl, and CD3 + DCl reactions were also studied. While all these reactions possess positive activation energies, in contrast to the other systems investigated in this thesis, the CH3 + HCl and CD3 + HCl reactions show a non-linear temperature dependency on the Arrhenius plot. The reactivity of substituted methyl radicals toward NO2 was observed to increase with decreasing electron affinity of the radical. The same trend was observed for the reactions of substituted methyl radicals with Cl2. It is proposed that interactions of frontier orbitals are responsible to these observations and Frontier Orbital Theory could be used to explain the observed reactivity trends of these highly exothermic reactions having reactant-like transition states.

Atomic Layer Deposition of Multicomponent Oxide Materials

Atomic layer deposition (ALD) is a method for thin film deposition which has been extensively studied for binary oxide thin film growth. Studies on multicomponent oxide growth by ALD remain relatively few owing to the increased number of factors that come into play when more than one metal is employed. More metal precursors are required, and the surface may change significantly during successive stages of the growth. Multicomponent oxide thin films can be prepared in a well-controlled way as long as the same principle that makes binary oxide ALD work so well is followed for each constituent element: in short, the film growth has to be self-limiting. ALD of various multicomponent oxides was studied. SrTiO3, BaTiO3, Ba(1-x)SrxTiO3 (BST), SrTa2O6, Bi4Ti3O12, BiTaO4 and SrBi2Ta2O9 (SBT) thin films were prepared, many of them for the first time by ALD. Chemistries of the binary oxides are shown to influence the processing of their multicomponent counterparts. The compatibility of precursor volatilities, thermal stabilities and reactivities is essential for multicomponent oxide ALD, but it should be noted that the main reactive species, the growing film itself, must also be compatible with self-limiting growth chemistry. In the cases of BaO and Bi2O3 the growth of the binary oxide was very difficult, but the presence of Ti or Ta in the growing film made self-limiting growth possible. The application of the deposited films as dielectric and ferroelectric materials was studied. Post-deposition annealing treatments in different atmospheres were used to achieve the desired crystalline phase or, more generally, to improve electrical properties. Electrode materials strongly influenced the leakage current densities in the prepared metal insulator metal (MIM) capacitors. Film permittivities above 100 and leakage current densities below 110-7 A/cm2 were achieved with several of the materials.

Imaging of knee injuries with special focus on tibial plateau fractures

Acute knee injury is a common event throughout life, and it is usually the result of a traffic accident, simple fall, or twisting injury. Over 90% of patients with acute knee injury undergo radiography. An overlooked fracture or delayed diagnosis can lead to poor patient outcome. The major aim of this thesis was retrospectively to study imaging of knee injury with a special focus on tibial plateau fractures in patients referred to a level-one trauma center. Multi-detector computed tomography (MDCT) findings of acute knee trauma were studied and compared to radiography, as well as whether non-contrast MDCT can detect cruciate ligaments with reasonable accuracy. The prevalence, type, and location of meniscal injuries in magnetic resonance imaging (MRI) were evaluated, particularly in order to assess the prevalence of unstable meniscal tears in acute knee trauma with tibial plateau fractures. The possibility to analyze with conventional MRI the signal appearance of menisci repaired with bioabsorbable arrows was also studied. The postoperative use of MDCT was studied in surgically treated tibial plateau fractures: to establish the frequency and indications of MDCT and to assess the common findings and their clinical impact in a level-one trauma hospital. This thesis focused on MDCT and MRI of knee injuries, and radiographs were analyzed when applica-ble. Radiography constitutes the basis for imaging acute knee injury, but MDCT can yield information beyond the capabilities of radiography. Especially in severely injured patients , sufficient radiographs are often difficult to obtain, and in those patients, radiography is unreliable to rule out fractures. MDCT detected intact cruciate ligaments with good specificity, accuracy, and negative predictive value, but the assessment of torn ligaments was unreliable. A total of 36% (14/39) patients with tibial plateau fracture had an unstable meniscal tear in MRI. When a meniscal tear is properly detected preoperatively, treatment can be combined with primary fracture fixation, thus avoiding another operation. The number of meniscal contusions was high. Awareness of the imaging features of this meniscal abnormality can help radiologists increase specificity by avoiding false-positive findings in meniscal tears. Postoperative menisci treated with bioabsorbable arrows showed no difference, among different signal intensities in MRI, among menisci between patients with operated or intact ACL. The highest incidence of menisci with an increased signal intensity extending to the meniscal surface was in patients whose surgery was within the previous 18 months. The results may indicate that a rather long time is necessary for menisci to heal completely after arrow repair. Whether the menisci with an increased signal intensity extending to the meniscal surface represent improper healing or re-tear, or whether this is just the earlier healing feature in the natural process remains unclear, and further prospective studies are needed to clarify this. Postoperative use of MDCT in tibial plateau fractures was rather infrequent even in this large trauma center, but when performed, it revealed clinically significant information, thus benefitting patients in regard to treatment.

Computer simulation of H and He effects in fusion reactor materials

Fusion power is an appealing source of clean and abundant energy. The radiation resistance of reactor materials is one of the greatest obstacles on the path towards commercial fusion power. These materials are subject to a harsh radiation environment, and cannot fail mechanically or contaminate the fusion plasma. Moreover, for a power plant to be economically viable, the reactor materials must withstand long operation times, with little maintenance. The fusion reactor materials will contain hydrogen and helium, due to deposition from the plasma and nuclear reactions because of energetic neutron irradiation. The first wall divertor materials, carbon and tungsten in existing and planned test reactors, will be subject to intense bombardment of low energy deuterium and helium, which erodes and modifies the surface. All reactor materials, including the structural steel, will suffer irradiation of high energy neutrons, causing displacement cascade damage. Molecular dynamics simulation is a valuable tool for studying irradiation phenomena, such as surface bombardment and the onset of primary damage due to displacement cascades. The governing mechanisms are on the atomic level, and hence not easily studied experimentally. In order to model materials, interatomic potentials are needed to describe the interaction between the atoms. In this thesis, new interatomic potentials were developed for the tungsten-carbon-hydrogen system and for iron-helium and chromium-helium. Thus, the study of previously inaccessible systems was made possible, in particular the effect of H and He on radiation damage. The potentials were based on experimental and ab initio data from the literature, as well as density-functional theory calculations performed in this work. As a model for ferritic steel, iron-chromium with 10% Cr was studied. The difference between Fe and FeCr was shown to be negligible for threshold displacement energies. The properties of small He and He-vacancy clusters in Fe and FeCr were also investigated. The clusters were found to be more mobile and dissociate more rapidly than previously assumed, and the effect of Cr was small. The primary damage formed by displacement cascades was found to be heavily influenced by the presence of He, both in FeCr and W. Many important issues with fusion reactor materials remain poorly understood, and will require a huge effort by the international community. The development of potential models for new materials and the simulations performed in this thesis reveal many interesting features, but also serve as a platform for further studies.

Search for new color-octet vector particle decaying to t tbar in p pbar collisions at sqrt{s} = 1.96 TeV

We present the result of a search for a massive color-octet vector particle, (e.g. a massive gluon) decaying to a pair of top quarks in proton-antiproton collisions with a center-of-mass energy of 1.96 TeV. This search is based on 1.9 fb$^{-1}$ of data collected using the CDF detector during Run II of the Tevatron at Fermilab. We study $t\bar{t}$ events in the lepton+jets channel with at least one $b$-tagged jet. A massive gluon is characterized by its mass, decay width, and the strength of its coupling to quarks. These parameters are determined according to the observed invariant mass distribution of top quark pairs. We set limits on the massive gluon coupling strength for masses between 400 and 800 GeV$/c^2$ and width-to-mass ratios between 0.05 and 0.50. The coupling strength of the hypothetical massive gluon to quarks is consistent with zero within the explored parameter space.

A model Integrating the Facilities Management Process with the Building End User’s Business Process (ProFacil)

The ProFacil model is a generic process model defined as a framework model showing the links between the facilities management process and the building end user’s business process. The purpose of using the model is to support more detailed process modelling. The model has been developed using the IDEF0 modelling method. The ProFacil model describes business activities from the generalized point of view as management-, support-, and core processes and their relations. The model defines basic activities in the provision of a facility. Examples of these activities are “operate facilities”, “provide new facilities”, “provide re-build facilities”, “provide maintained facilities” and “perform dispose of facilities”. These are all generic activities providing a basis for a further specialisation of company specific FM activities and their tasks. A facilitator can establish a specialized process model using the ProFacil model and interacting with company experts to describe their company’s specific processes. These modelling seminars or interviews will be done in an informal way, supported by the high-level process model as a common reference.

Hur uppkommer värde för kunden?

Värdeforskningen inom marknadsföringen har traditionellt fokuserat på utbyten och det upplevda värdet av företagets produkter. Den gängse synen på värde har därför också utmärkts av en produktions- och transaktionsorienterad syn där värde anses produceras i företagets processer och sedan överlåts till kunden i samband med ett utbyte. I den här studien betraktas värde i stället ur ett kund- och relationsbaserat perspektiv. Utgångspunkten är att värde för kunden är något som företaget vare sig kan producera eller leverera. Kunden betraktas i den här studien därför som subjekt i sin egen värdeskapande process, medan varor, tjänster och kundens relationer till olika företag betraktas som resurser eller objekt i kundens egna värdeskapande aktiviteter. Tyngdpunkten flyttas från företaget som värdeskapare till kunden som värdeskapare vilket innebär en omarbetad logik för värdeskapande. Det relationsbaserade perspektivet på värde vidgar ytterligare synen på hur värde uppkommer för kunden. Studien visar att kundens värdeskapande kontext omfattar mer än enbart produkten och den värdebedömning som görs i en köpsituation. Detta påtalar behovet av att man analyserar hur värde uppkommer för kunden över tiden och ur ett helhetsperspektiv. Studiens syfte är att analysera hur värde uppkommer för kunden – i vilka aktiviteter och med vilka resurser. Målet är att finna en balans i synen på relationen mellan kund och företag och att lära om hur företagets marknadsföringsprocesser kan utvecklas genom att kundens egna värdeskapande aktiviteter analyseras. Studien är inriktad på konsumentmarknaden och den empiriska miljön utgörs av bilägare som intervjuats med en longitudinell ansats. Avhandlingen utmynnar i en teoretisk referensram om hur värde uppkommer för kunden. Olika dimensioner av värdebegreppet identifieras och analyseras och en kund- och relationsbaserad värdeterminologi utvecklas. I stället för att analysera det upplevda värdet av företagets produkt uppmanas marknadsföraren här att analysera hur värde uppkommer för kunden som individ över tiden. Detta uppnås genom att företaget lär känna kundens värdeskapande kontext i syfte att förstå var (i vilka aktiviteter) och hur (under vilka premisser) värde uppkommer för kunden. På basis av denna information kan företaget ta ställning till sin roll i kundens värdeskapande process och även visionera om vilken roll företaget kunde ha.

The Context and Diffusion of Knowledge in the Finnish Jewellery Industry - The role of the House of Fabergé

Researchers within the fields of economic geography and organizational management have extensively studied learning and the prerequisites and impediments for knowledge transfer. This paper combines two discourses within the two subjects: the-communities-of-practice and the learning region approaches, merging them through the so-called ecology of knowledge-approach, which is used to examine the knowledge transfer from the House of Fabergé to the Finnish jewellery industry. We examine the pre-revolution St Petersburg jewellery cluster and the post-revolution Helsinki, and the transfer of knowledge between these two locations through the components of communities of people, institutions and industry. The paper shows that the industrial dynamics of the Finnish modern-day goldsmith industry was inherently shaped both through the transfer and the non-transfer of knowledge. It also contends that the “knowledge-economy” is not anchored in and exclusive for the high technology sector of the late 20th century.

The determinants of sexually transmitted infections among reproductive age women in St. Petersburg, Estonia and Finland

OBJECTIVES: Sexually transmitted infections' (STIs) rate vary in St. Petersburg, Estonia and Finland; the aim was to compare the determinants of self-reported sexually transmitted infections in these areas. METHODS: Data from four population-based questionnaire surveys were used (Finland in 1992 and 1999; St. Petersburg in 2003; Estonia in 2004). With the exception of the 1992 Finnish survey (interview) all were postal surveys, with 1,070 respondents in Finland (78 and 52% response rates), 1,147 (68%) in St. Petersburg, and 5,190 (54%) in Estonia. RESULTS: Risky sexual behaviours were equally common in the three areas and the determinants were the same. Women with an STIs history more often had had their first sexual intercourse when aged under 18, had not used condom during first intercourse, had a high number of lifetime or previous year sexual partners. However, marital status and education were not similar determinants. Cohabiting and well-educated women in Finland were more likely to have STIs while in other areas the associations found were not statistically significant. CONCLUSIONS: Risky behaviour predicts STIs, but does not explain the varying rates of STIs between areas.