Role of ErbB2 and ErbB4 in Cancer Growth, Prognosis and as Targets for Immunotherapy

ErbB receptors (EGFR, ErbB2, ErbB3 and ErbB4) are growth factor receptors that regulate signals of cell differentiation, proliferation, migration and survival. Inappropriate activation of these receptors is associated with the development and severity of many cancers and has prognostic and predictive value in cancer therapy. Drugs, such as therapeutic antibodies, targeted against EGFR and ErbB2, are currently used in therapy of breast, colorectal and head and neck cancers. The role of ErbB4 in tumorigenesis has remained relatively poorly understood. Alternative splicing produces four different isoforms of one ErbB4 gene. These isoforms (JM-a, JM-b, CYT-1 and CYT-2) are functionally dissimilar and proposed to have different roles in carcinogenesis. The juxtamembrane form JM-a undergoes regulated intramembrane proteolysis producing a soluble receptor ectodomain and an intracellular domain that translocates into the nucleus and regulates transcription. Nuclear signaling via JM-a isoform stimulates cancer cell proliferation. This study aimed to develop antibodies targeting the proposed oncogenic ErbB4 JM-a isoform that show potential in inhibiting ErbB4 dependent tumorigenesis. Also, the clinical relevance of ErbB4 shedding in cancer was studied. The currently used monoclonal antibody trastuzumab, targeting ErbB2, has shown efficacy in breast cancer therapy. In this study novel tissues with ErbB2 amplification and trastuzumab sensitivity were analyzed. The results of this study indicated that a subpopulation of breast cancer patients demonstrate increased shedding and cleavage of ErbB4. A JM-a isoform-specific antibody that inhibited ErbB4 shedding and consequent activation of ErbB4 had anti-tumor activity both in vitro and in vivo. Thus, ErbB4 shedding associates with tumor growth and specific targeting of the cleavable JM-a isoform could be considered as a strategy for developing novel ErbB-based cancer drugs. In addition, it was demonstrated that ErbB2 amplification is common in intestinal type gastric cancers with poor clinical outcome. Trastuzumab inhibited growth of gastric and breast cancer cells with equal efficacy. Thus, ErbB2 may be a useful target in gastric cancer.

Studies on the Multifaceted Interaction of Atoms and an Electromagnetic Field

In this Thesis the interaction of an electromagnetic field and matter is studied from various aspects in the general framework of cold atoms. Our subjects cover a wide spectrum of phenomena ranging from semiclassical few-level models to fully quantum mechanical interaction with structured reservoirs leading to non-Markovian open quantum system dynamics. Within closed quantum systems, we propose a selective method to manipulate the motional state of atoms in a time-dependent double-well potential and interpret the method in terms of adiabatic processes. Also, we derive a simple wave-packet model, based on distributions of generalized eigenstates, explaining the finite visibility of interference in overlapping continuous-wave atom lasers. In the context of open quantum systems, we develop an unraveling of non-Markovian dynamics in terms of piecewise deterministic quantum jump processes confined in the Hilbert space of the reduced system - the non-Markovian quantum jump method. As examples, we apply it for simple 2- and 3-level systems interacting with a structured reservoir. Also, in the context of ion-cavity QED we study the entanglement generation based on collective Dicke modes in experimentally realistic conditions including photonic losses and an atomic spontaneous decay.

Nuclear Matrix in Apoptotic Cell Death and Cell Proliferation. The role of Nuclear Mitotic Apparatus (NuMA) Protein

The nucleus is a membrane enclosed organelle containing most of the genetic information of the cell in the form of chromatin. The nucleus, which can be divided into many sub-organelles such as the nucleoli, the Cajal bodies and the nuclear lamina, is the site for several essential cellular functions such as the DNA replication and its regulation and most of the RNA synthesis and processing. The nucleus is often affected in disease: the size and the shape of the nucleus, the chromatin distribution and the size of the nucleoli have remained the basis for the grading of several cancers. The maintenance of the vertebrate body shape depends on the skeleton. Similarly, in a smaller context, the shape of the cell and the nucleus are mainly regulated by the cytoskeletal and nucleoskeletal elements. The nuclear matrix, which by definition is a detergent, DNase and salt resistant proteinaceous nuclear structure, has been suggested to form the nucleoskeleton responsible for the nuclear integrity. Nuclear mitotic apparatus protein, NuMA, a component of the nuclear matrix, is better known for its mitotic spindle organizing function. NuMA is one of the nuclear matrix proteins suggested to participate in the maintenance of the nuclear integrity during interphase but its interphase function has not been solved to date. This thesis study concentrated on the role of NuMA and the nuclear matrix as structural and functional components of the interphase nucleus. The first two studies clarified the essential role of caspase-3 in the disintegration of the nuclear structures during apoptosis. The second study also showed NuMA and chromatin to co-elute from cells in significant amounts and the apoptotic cleavage of NuMA was clarified to have an important role in the dissociation of NuMA from the chromatin. The third study concentrated on the interphase function of NuMA showing NuMA depletion to result in cell cycle arrest and the cytoplasmic relocalization of NuMA interaction partner GAS41. We suggest that the relocalization of the transcription factor GAS41 may mediate the cell cycle arrest. Thus, this study has given new aspects in the interactions of NuMA, chromatin and the nuclear matrix.

The potential of social networking sites in inpatriate adjustment

People make up one of the most important resources for a corporation and therefore it has to continuously seek an ever more diverse and international workforce. Inpatriation is another way of utilizing foreign expertise in a corporation. An inpatriate refers to a person that is on an international assignment at the headquarters of a corporation, where they have been sent either from a subsidiary abroad or from a third country outside the corporation. Strengthening the social network of the inpatriate and their family contributes to the adjustment process and furthermore the success of the work assignment. As social networking sites are currently the fastest developing personal networking tools in the world, it is interesting to see how they can help in inpatriate adjustment. The objective of this thesis is to explore the potential of social networking sites (SNS) in inpatriate adjustment. The main objective can be divided into three sub objectives: 1. What is SNS used for during the inpatriate assignment? 2. What are the inpatriates’ motivations to use SNS? 3. Could the three facets of adjustment (work, interaction and general) be gained through SNS? This qualitative study utilizes the theme interview data collection method and the thematic analysis approach for analysing the interview data. From the interviews with five Indian inpatriates in Finland the most mentioned uses of SNS were related to participating (sharing opinions, recommendations and discussing things and connecting to friends, family and colleagues) and consuming (collecting information for work and free time), the least mentioned use of SNS was producing (posting videos, photos and updates). An interesting finding was that the five interviewees did not use SNS for purely entertainment motives at all during their assignment. This thesis found that all three facets of adjustment could potentially be gained through SNS.

An interaction framework for deploying the knowledge of diasporas: Using Finland as an example

This study discusses the importance of diasporas’ knowledge with regard to the national competitive advantage of Finland. The purpose of this study is to suggest an interaction framework, which illustrates how diasporas can benefit the host country via intentional knowledge spillovers, with two sub-objectives: to seek which features are crucial for productive interaction between a host government and diasporas, and to scrutinize the modes of interaction currently effective in Finland. The theoretical background of the study consists of literature relating to the concepts of diaspora and knowledge. The empirical research conducted for this study is based on expert interviews. The interview data was collected between September and November 2013. Eight interviews were made; five with representatives of expert organizations, and three with immigrants. Thematic analysis was used to categorize and interpret the interview data. In addition, thematic networks were built to act as a basis of analysis. This study finds that knowledge, especially new combinations of knowledge, is a significant input in innovation. Innovation is found to be the basis of national competitive advantage. Thus the means through which knowledge is transferred are of key importance. Diasporas are found a good source of new knowledge, and thus may aid the innovative process. Host country stance and policy are found to have a major impact on the ability of the host country to benefit from diasporas’ knowledge. As a host country, this study finds Finland to have a very fragmented strategy field and a prejudiced attitude, which currently make it difficult to utilize the potential of diasporas. The interaction framework based on these findings suggests ways in which Finland can improve its national competitive advantage through acquiring the innovative potential of diasporas. Strategy revision and increased promotion are discussed as means towards improved interaction. In addition, the importance of learning is emphasized. The findings of this study enhance understanding of the relationship between the concepts of diaspora and knowledge. In addition, this study ties the relationship to economic benefit. Future research is, however, necessary in order to fully understand the meaning of the relationship, as well as to increase understanding of the generalizability of the interaction framework.

The supermassive binary black hole system OJ287

Abstract This doctoral thesis concerns the active galactic nucleus (AGN) most often referred to with the catalogue number OJ287. The publications in the thesis present new discoveries of the system in the context of a supermassive binary black hole model. In addition, the introduction discusses general characteristics of the OJ287 system and the physical fundamentals behind these characteristics. The place of OJ287 in the hierarchy of known types of AGN is also discussed. The introduction presents a large selection of fundamental physics required to have a basic understanding of active galactic nuclei, binary black holes, relativistic jets and accretion disks. Particularly the general relativistic nature of the orbits of close binaries of supermassive black holes is explored with some detail. Analytic estimates of some of the general relativistic effects in such a binary are presented, as well as numerical methods to calculate the effects more precisely. It is also shown how these results can be applied to the OJ287 system. The binary orbit model forms the basis for models of the recurring optical outbursts in the OJ287 system. In the introduction, two physical outburst models are presented in some detail and compared. The radiation hydrodynamics of the outbursts are discussed and optical light curve predictions are derived. The precursor outbursts studied in Paper III are also presented, and tied into the model of OJ287. To complete the discussion of the observable features of OJ287, the nature of the relativistic jets in the system, and in active galactic nuclei in general, is discussed. Basic physics of relativistic jets are presented, with additional detail added in the form of helical jet models. The results of Papers II, IV and V concerning the jet of OJ287 are presented, and their relation to other facets of the binary black hole model is discussed. As a whole, the introduction serves as a guide, though terse, for the physics and numerical methods required to successfully understand and simulate a close binary of supermassive black holes. For this purpose, the introduction necessarily combines a large number of both fundamental and specific results from broad disciplines like general relativity and radiation hydrodynamics. With the material included in the introduction, the publications of the thesis, which present new results with a much narrower focus, can be readily understood. Of the publications, Paper I presents newly discovered optical data points for OJ287, detected on archival astronomical plates from the Harvard College Observatory. These data points show the 1900 outburst of OJ287 for the first time. In addition, new data points covering the 1913 outburst allowed the determination of the start of the outburst with more precision than was possible before. These outbursts were then successfully numerically modelled with an N-body simulation of the OJ287 binary and accretion disc. In Paper II, mechanisms for the spin-up of the secondary black hole in OJ287 via interaction with the primary accretion disc and the magnetic fields in the system are discussed. Timescales for spin-up and alignment via both processes are estimated. It is found that the secondary black hole likely has a high spin. Paper III reports a new outburst of OJ287 in March 2013. The outburst was found to be rather similar to the ones reported in 1993 and 2004. All these outbursts happened just before the main outburst season, and are called precursor outbursts. In this paper, a mechanism was proposed for the precursor outbursts, where the secondary black hole collides with a gas cloud in the primary accretion disc corona. From this, estimates of brightness and timescales for the precursor were derived, as well as a prediction of the timing of the next precursor outburst. In Paper IV, observations from the 2004–2006 OJ287 observing program are used to investigate the existence of short periodicities in OJ287. The existence of a _50 day quasiperiodic component is confirmed. In addition, statistically significant 250 day and 3.5 day periods are found. Primary black hole accretion of a spiral density wave in the accretion disc is proposed as the source of the 50 day period, with numerical simulations supporting these results. Lorentz contracted jet re-emission is then proposed as the reason for the 3.5 day timescale. Paper V fits optical observations and mm and cm radio observations of OJ287 with a helical jet model. The jet is found to have a spine–sheath structure, with the sheath having a much lower Lorentz gamma factor than the spine. The sheath opening angle and Lorentz factor, as well as the helical wavelength of the jet are reported for the first time. Tiivistelmä Tässä väitöskirjatutkimuksessa on keskitytty tutkimaan aktiivista galaksiydintä OJ287. Väitöskirjan osana olevat tieteelliset julkaisut esittelevät OJ287-systeemistä saatuja uusia tuloksia kaksoismusta-aukkomallin kontekstissa. Väitöskirjan johdannossa käsitellään OJ287:n yleisiä ominaisuuksia ja niitä fysikaalisia perusilmiöitä, jotka näiden ominaisuuksien taustalla vaikuttavat. Johdanto selvittää myös OJ287-järjestelmän sijoittumisen aktiivisten galaksiytimien hierarkiassa. Johdannossa käydään läpi joitakin perusfysiikan tuloksia, jotka ovat tarpeen aktiivisten galaksiydinten, mustien aukkojen binäärien, relativististen suihkujen ja kertymäkiekkojen ymmärtämiseksi. Kahden toisiaan kiertävän mustan aukon keskinäisen radan suhteellisuusteoreettiset perusteet käydään läpi yksityiskohtaisemmin. Johdannossa esitetään joitakin analyyttisiä tuloksia tällaisessa binäärissä havaittavista suhteellisuusteoreettisista ilmiöistä. Myös numeerisia menetelmiä näiden ilmiöiden tarkempaan laskemiseen esitellään. Tuloksia sovelletaan OJ287-systeemiin, ja verrataan havaintoihin. OJ287:n mustien aukkojen ratamalli muodostaa pohjan systeemin toistuvien optisten purkausten malleille. Johdannossa esitellään yksityiskohtaisemmin kaksi fysikaalista purkausmallia, ja vertaillaan niitä. Purkausten säteilyhydrodynamiikka käydään läpi, ja myös ennusteet purkausten valokäyrille johdetaan. Johdannossa esitellään myös Julkaisussa III johdettu prekursoripurkausten malli, ja osoitetaan sen sopivan yhteen OJ287:n binäärimallin kanssa. Johdanto esittelee myös relativististen suihkujen fysiikkaa sekä OJ287- systeemiin liittyen että aktiivisten galaksiydinten kontekstissa yleisesti. Relativististen suihkujen perusfysiikka esitellään, kuten myös malleja kierteisistä suihkuista. Julkaisujen II, IV ja V OJ287-systeemin suihkuja koskevat tulokset esitellään binäärimallin kontekstissa. Kokonaisuutena johdanto palvelee suppeana oppaana, joka esittelee tarvittavan fysiikan ja tarpeelliset numeeriset menetelmät mustien aukkojen binäärijärjestelmän ymmärtämiseen ja simulointiin. Tätä tarkoitusta varten johdanto yhdistää sekä perustuloksia että joitakin syvällisempiä tuloksia laajoilta fysiikan osa-alueilta kuten suhteellisuusteoriasta ja säteilyhydrodynamiikasta. Johdannon sisältämän materiaalin avulla väitöskirjan julkaisut, ja niiden esittämät tulokset, ovat hyvin ymmärrettävissä. Väitöskirjan julkaisuista ensimmäinen esittelee uusia OJ287-systeemistä saatuja havaintopisteitä, jotka on paikallistettu Harvardin yliopiston observatorion arkiston valokuvauslevyiltä. OJ287:n vuonna 1900 tapahtunut purkaus nähdään ensimmäistä kertaa näissä havaintopisteissä. Uudet havaintopisteet mahdollistivat myös vuoden 1913 purkauksen alun ajoittamisen tarkemmin kuin aiemmin oli mahdollista. Havaitut purkaukset mallinnettiin onnistuneesti simuloimalla OJ287-järjestelmän mustien aukkojen paria ja kertymäkiekkoa. Julkaisussa II käsitellään mekanismeja OJ287:n sekundäärisen mustan aukon spinin kasvamiseen vuorovaikutuksessa primäärin kertymäkiekon ja systeemin magneettikenttien kanssa. Julkaisussa arvioidaan maksimispinin saavuttamisen ja spinin suunnan vakiintumisen aikaskaalat kummallakin mekanismilla. Tutkimuksessa havaitaan sekundäärin spinin olevan todennäköisesti suuri. Julkaisu III esittelee OJ287-systeemissä maaliskuussa 2013 tapahtuneen purkauksen. Purkauksen havaittiin muistuttavan vuosina 1993 ja 2004 tapahtuneita purkauksia, joita kutsutaan yhteisnimityksellä prekursoripurkaus (precursor outburst). Julkaisussa esitellään purkauksen synnylle mekanismi, jossa OJ287-systeemin sekundäärinen musta aukko osuu primäärisen mustan aukon kertymäkiekon koronassa olevaan kaasupilveen. Mekanismin avulla johdetaan arviot prekursoripurkausten kirkkaudelle ja aikaskaalalle. Julkaisussa johdetaan myös ennuste seuraavan prekursoripurkauksen ajankohdalle. Julkaisussa IV käytetään vuosina 2004–2006 kerättyjä havaintoja OJ287- systeemistä lyhyiden jaksollisuuksien etsintään. Julkaisussa varmennetaan systeemissä esiintyvä n. 50 päivän kvasiperiodisuus. Lisäksi tilastollisesti merkittävät 250 päivän ja 3,5 päivän jaksollisuudet havaitaan. Julkaisussa esitetään malli, jossa primäärisen mustan aukon kertymäkiekossa oleva spiraalitiheysaalto aiheuttaa 50 päivän jaksollisuuden. Mallista tehty numeerinen simulaatio tukee tulosta. Systeemin relativistisen suihkun emittoima aikadilatoitunut säteily esitetään aiheuttajaksi 3,5 päivän jaksollisuusaikaskaalalle. Julkaisussa V sovitetaan kierresuihkumalli OJ287-systeemistä tehtyihin optisiin havaintoihin ja millimetri- sekä senttimetriaallonpituuden radiohavaintoihin. Suihkun rakenteen havaitaan olevan kaksijakoinen ja koostuvan ytimestä ja kuoresta. Suihkun kuorella on merkittävästi pienempi Lorentzin gamma-tekijä kuin suihkun ytimellä. Kuoren avautumiskulma ja Lorentztekijä sekä suihkun kierteen aallonpituus raportoidaan julkaisussa ensimmäistä kertaa.

Alpha- and gamma-melanocyte stimulating hormones in obesity. A study of the key central areas of metabolic regulation

The melanocortin system is an important regulator of feeding, energy metabolism,and cardiovascular function and it consists of the pro-opiomelanocortin (POMC) derived melanocyte stimulating hormones (α-, β- and γ-MSH) and their endogenous melanocortin receptors, MC1R to MC5R. In the hypothalamus, α-MSH reduces food intake, and increases energy expenditure and sympathetic tone by binding to MC4R. Mutations affecting the MC4R gene lead to obesity in mammals. On the other hand, the metabolic effects of MC3R stimulation using agonists such as the endogenously expressed γ-MSH have been less extensively explored. The main objective of this study was to investigate the long-term effects of increased melanocortin tone in key areas of metabolic regulation in the central nervous system (CNS) in order to investigate the sitespecific roles of both α-MSH and γ-MSH. The aim was to stereotaxically induce local overexpression of single melanocortin peptides using lentiviral vectors expressing α-MSH (LVi-α-MSH-EGFP) and γ-MSH (LVi-γ-MSH-EGFP). The lentiviral vectors were shown to produce a long-term overexpression and biologically active peptides in cell-based assays. The LVi-α-MSHEGFP was targeted to the arcuate nucleus in the hypothalamus of diet induced obese mice where it reduced weight gain and adiposity independently of food intake. When the nucleus tractus solitarus in the brainstem was targeted, the LVi-α-MSH-EGFP treatment was shown to cause a small decrease in adiposity, which did not impact weight development. However, the α-MSH treatment increased heart rate, which was attenuated by adrenergic receptor blockade indicative of increased sympathetic activity. The LVi-γ-MSH-EGFP was targeted to the hypothalamus where it decreased fat mass in mice eating the standard diet, but the effect was abated if animals consumed a high-fat Western type diet. When the diet induced obese mice were subjected again to the standard diet, the LVi-γ-MSH-EGFP treated animals displayed increased weight loss and reduced adiposity. These results indicate that the long-term central anti-obesity effects of α-MSH are independent of food intake. In addition, overexpression of α-MSH in the brain stem efficiently blocked the development of adiposity, but increased sympathetic tone. The evidence presented in this thesis also indicates that selective MC3R agonists such as γ-MSH could be potential therapeutics in combination with low fat diets.

Plant-Herbivore Interaction in a Fragmented Landscape: Local Adaptation and Inbreeding

Reciprocal selection between interacting species is a major driver of biodiversity at both the genetic and the species level. This reciprocal selection, or coevolution, has led to the diversification of two highly diverse and abundant groups of organisms, flowering plants and their insect herbivores. In heterogeneous environments, the outcome of coevolved species interactions is influenced by the surrounding community and/or the abiotic environment. The process of adaptation allows species to adapt to their local conditions and to local populations of interacting species. However, adaptation can be disrupted or slowed down by an absence of genetic variation or by increased inbreeding, together with the following inbreeding depression, both of which are common in small and isolated populations that occur in fragmented environments. I studied the interaction between a long-lived plant Vincetoxicum hirundinaria and its specialist herbivore Abrostola asclepiadis in the southwestern archipelago of Finland. I focused on mutual local adaptation of plants and herbivores, which is a demonstration of reciprocal selection between species, a prerequisite for coevolution. I then proceeded to investigate the processes that could potentially hamper local adaptation, or species interaction in general, when the population size is small. I did this by examining how inbreeding of both plants and herbivores affects traits that are important for interaction, as well as among-population variation in the effects of inbreeding. In addition to bi-parental inbreeding, in plants inbreeding can arise from self-fertilization which has important implications for mating system evolution. I found that local adaptation of the plant to its herbivores varied among populations. Local adaptation of the herbivore varied among populations and years, being weaker in populations that were most connected. Inbreeding caused inbreeding depression in both plants and herbivores. In some populations inbreeding depression in herbivore biomass was stronger in herbivores feeding on inbred plants than in those feeding on outbred ones. For plants it was the other way around: inbreeding depression in anti-herbivore resistance decreased when the herbivores were inbred. Underlying some of the among-population variation in the effects of inbreeding is variation in plant phenolic compounds. However, variation in the modification of phenolic compounds in the digestive tract of the herbivore did not explain the inbreeding depression in herbivore biomass. Finally, adult herbivores had a preference for outbred host plants for egg deposition, and herbivore inbreeding had a positive effect on egg survival when the eggs were exposed to predators and parasitoids. These results suggest that plants and herbivores indeed exert reciprocal selection, as demonstrated by the significant local adaptation of V. hirundinaria and A. asclepiadis to one another. The most significant cause of disruption of the local adaptation of herbivore populations was population connectivity, and thus probably gene flow. In plants local adaptation tended to increase with increasing genetic variation. Whether or not inbreeding depression occurred varied according to the life-history stage of the herbivore and/or the plant trait in question. In addition, the effects of inbreeding strongly depended on the population. Taken together, inbreeding modified plant-herbivore interactions at several different levels, and can thus affect the strength of reciprocal selection between species. Thus inbreeding has the potential to affect the outcome of coevolution.