The Effects of Estradiol, Androgens and the Selective Estrogen Modulators: Ospemifene, Raloxifene and Tamoxifen on Explant Cultures of Human Breast Tissue

The impact of menopausal hormone therapy (MHT) on increasing the risk for breast cancer (BC) remains controversial. To understand MHT-elicited cellular breast effects and the potential risks, included with using this therapy, a further investigation into this controversy is the subject of this thesis. In this thesis, to study the effects of estrogen, progestin, androgens and selective estrogen receptor modulators (SERMs), a modified tissue explant culture system was used. The different types of human breast tissues (HBTs) used in this study were normal HBTs, obtained from reduction mammoplasties of premenopausal women (prem-HBTs) or postmenopausal (postm-HBTs) women and peritumoral HBTs (peritum-HBTs) which were obtained from surgeries on postmenopausal BC patients. The explants were cultured up to three weeks in the presence or absence of estradiol (E2), medroxyprogesterone acetate (MPA), testosterone (T), dihydrotestosterone (DHT) and SERMs - ospemifene (OSP), raloxifene (RAL) and tamoxifen (TAM). The cultured HBTs maintained morphological integrity and responded to hormonal treatment in vitro. E2, MPA or E2/MPA increased proliferative activity and was associated with increased cyclin-D1 and caused changes in the cell cycle inhibitors p21 and p27, whereas the androgens T and DHT inhibited proliferation and increased apoptosis in HBT epithelia and opposed E2-stimulated proliferation and cell survival. The postm-HBTs were more sensitive to E2 than prem-HBTs. The effects of OSP, RAL and TAM on HBT epithelium were antiproliferative. E2, androgens and SERMs were associated with marked changes in the proportions of epithelial cells expressing steroid hormone receptors: E2 increased ERα expressing cells and decreased androgen receptor (AR) positive cells, whereas T and DHT had opposite effects. The OSP, RAL and TAM, also decreased a proportion of ERα positive cells in HBT epithelium. At 100 nM, these compounds maintained the relative number of AR positive cells, present at control level, which may partly explain proliferative inhibition. In conclusion, the proliferative activity of E2, in the epithelium of postm-HBTs, is opposed by T and DHT, which suggests that the inclusion of androgens in MHT may decrease the risk for developing BC.

Cost-plus-loss analyses of forest inventory strategies based on kNN-assigned reference sample plot data

Abstract

Osuuspankkiryhmän OP 100 Plus –ryhmästrategian vaikuttavuus jäsenosuuspankkien menestykseen

Pro gradun tavoitteena on selvittää Osuuspankkiryhmän OP 100 Plus –ryhmästrategian vaikuttavuus jäsenosuuspankkien menestykseen. Tutkielma perustuu kvantitatiivisten analyysimenetelmien käyttöön. Aineistona on 66:n jäsenpankin kvantitatiiviset tiedot niiden taloudesta ja kvalitatiivinen luokiteltu tieto näiden pankkien ryhmästrategian implementoinnista. Käytännössä regression avulla voidaan löytää matemaattinen malli, joka soveltuu likimääräisesti kuvaamaan edellä mainittujen tekijöiden välistä riippuvuutta. Jotta regressiota on voitu käyttää, sekä pankin menestykselle että strategian implementoitumiselle on määritelty määrää kuvaavat mittarit. Molemmat mittarit ovat suhteellisia ja ne mahdollistavat vain 66:n tutkitun pankin keskinäisen vertailun.

The effects of selective estrogen receptor modulators on the death of breast cancer cells and osteoblastic cells

Selektiivisten estrogeenireseptorin muuntelijoiden (serm) vaikutus rintasyöpäsolujen ja luun solujen kuolemaan Selektiiviset estrogeenireseptorin muuntelijat (SERMit) ovat ryhmä kemialliselta rakenteeltaan erilaisia yhdisteitä jotka sitoutuvat solunsisäisiin estrogeenireseptoreihin toimien joko estrogeenin kaltaisina yhdisteinä tai estrogeenin vastavaikuttajina. Tamoksifeeni on SERM –yhdiste, jota on jo pitkään käytetty estrogeenireseptoreita (ER) ilmentävän rintasyövän lääkehoidossa. Tamoksifeeni sekä estää rintasyöpäsolujen jakaantumista että toisaalta aikaansaa niiden apoptoosin eli ohjelmoidun solukuoleman muuntelemalla ER-välitteisesti kohdesolun geenien ilmentymistä. Viimeaikaiset tutkimustulokset ovat kuitenkin osoittaneet tamoksifeenilla olevan myös nopeampia, nongenomisia vaikutusmekanismeja. Tässä väitöskirjatyössä tutkimme niitä nopeita vaikutusmekanismeja joiden avulla tamoksifeeni vaikuttaa rintasyöpäsolujen elinkykyyn. Osoitamme että tamoksifeeni farmakologisina pitoisuuksina aikaansaa nopean mitokondriaalisen solukuolemaan johtavan signallointireitin aktivoitumisen rintasyöpäsoluissa. Tämän lisäksi tutkimme myös tamoksifeenin aiheuttamaan mitokondriovaurioon johtavia tekijöitä. Tutkimustuloksemme osoittavat että ER-positiivisissa rintasyöpäsoluissa tamoksifeeni indusoi pitkäkestoisen ERK-kinaasiaktivaation, joka voidaan estää 17-beta-estradiolilla. Tamoksifeenin aikaansaama nopea solukuolema on pääosin ER:sta riippumaton tapahtuma, mutta siihen voidaan vaikuttaa myös ER-välitteisin mekanismein. Sen sijaan epidermaalisen kasvutekijäreseptorin (EGFR) voitiin osoittaa osallistuvan tamoksifeenin nopeiden vaikutusten välittämiseen. Tämän lisäksi vertailimme myös estradiolin ja eri SERM-yhdisteiden kykyä suojata apoptoosilta käyttämällä osteoblastiperäisiä soluja. Pytyäksemme vertailemaan ER-isotyyppien roolia eri yhdisteiden suojavaikutuksissa, transfektoimme U2OS osteosarkoomasolulinjan ilmentämään pysyvästi joko ERalfaa tai ERbetaa. Tulostemme mukaan sekä estradioli että uusi SERM-yhdiste ospemifeeni suojaavat osteoblastin kaltaisia soluja etoposidi-indusoidulta apoptoosilta. Sekä ERalfa että ERbeta pystyivät välittämään suojavaikutusta, joskin vaikutukset erosivat toisistaan. Lisäksi havaitsimme edellä mainitun suojavaikutuksen olevan yhteydessä muutoksiin solujen sytokiiniekspressiossa. Tietoa SERM-yhdisteiden anti-ja proapoptoottisten vaikutusmekanismeista eri kohdekudoksissa voidaan mahdollisesti hyödyntää kehiteltäessä uusia kudosspesifisiä SERM-yhdisteitä.

Bone Mineral Accrual in Physically Active Girls. With Special Reference to Reduction in Physical Activity Level and Use of Oral Contraceptives

Adolescence is an important time for acquiring high peak bone mass. Physical activity is known to be beneficial to bone development. The effect of estrogen-progestin contraceptives (EPC) is still controversial. Altogether 142 (52 gymnasts, 46 runners, and 42 controls) adolescent women participated in this study, which is based on two 7-year (n =142), one 6-year (n =140) and one 4-year (n =122) follow-ups. Information on physical activity, menstrual history, sexual maturation, nutrition, living habits and health status was obtained through questionnaires and interviews. The bone mineral density (BMD) and content (BMC) of lumbar spine (LS) and femoral neck (FN) were measured by dual- energy X-ray absoptiometry. Calcaneal sonographic measurements were also made. The physical activity of the athletes participating in this study decreased after 3-year follow-up. High-impact exercise was beneficial to bones. LS and FN BMC was higher in gymnasts than in controls during the follow-up. Reduction in physical activity had negative effects on bone mass. LS and FN BMC increased less in the group having reduced their physical activity more than 50%, compared with those continuing at the previous level (1.69 g, p=0.021; 0.14 g, p=0.015, respectively). The amount of physical activity was the only significant parameter accounting for the calcaneal sonography measurements at 6-year follow-up (11.3%) and reduced activity level was associated with lower sonographic values. Long-term low-dose EPC use seemed to prevent normal bone mass acquisition. There was a significant trend towards a smaller increase in LS and FN BMC among long-term EPC users. In conclusion, this study confirms that high-impact exercise is beneficial to bones and that the benefits are partly maintained even after a clear reduction in training level at least for 4 years. Continued exercise is needed to retain all acquired benefits. The bone mass gained and maintained can possibly be maximized in adolescence by implementing high-impact exercise for youngsters. The peak bone mass of the young women participating in the study may be reached before the age of 20. Use of low-dose EPCs seems to suppress normal bone mass acquisition.

D’abord, ensuite, enfin et 0, De plus: Organisation textuelle par des séries linéaires dans les articles de recherche

The study examines the signalling of text organisation in research articles (RA) in French. The work concentrates on a particular type of organisation provided by text sequences, i.e. structures organising text to items of which at least some are signalled by markers of addition or order: First… 0… The third point… In addition… / Premièrement… 0… Le troisième point… De plus… By indicating the way the text is organised, these structures guide the reader in the reading process so that he doesn’t need to interpret the text structure himself. The aim of the work is to study factors affecting the marking of text sequences. Why is their structure sometimes signalled explicitly by markers such as secondly, whereas in other places such markers are not used? The corpus is manually XML-annotated and consists of 90 RAs (~800 000 words) in French from the fields of linguistics, education and history. The analysis highlights several factors affecting the marking of text sequences. First, exact markers (such as fist ) seem to be more frequent in sequences where all the items are explicitly signalled by a marker, whereas additive markers (such as moreover) are used in sequences with both explicitly signalled and unmarked items. The marking of explicitly signalled sequences seems thus to be precise and even repetitive, whereas the signalling of sequences with unmarked items is altogether more vague. Second, the marking of text sequences seems to depend on the length of the text. The longer the text segment, the more vague the marking. Additive markers and unmarked items are more frequent in longer sequences possibly covering several pages, whereas shorter sequences are often signalled explicitly by exact markers. Also the marker types vary according to the sequence length. Anaphoric expressions, such as first, are fairly close to their referents and are used in short sequences, connectors, such as secondly, are frequently used in sequences of intermediate length, whereas the longest sequences are often signalled by constructions composed of an ordinal and a noun acting as a subject of the sentence: The first item is… Finally, the marking of text organisation depends also on the discipline the RA belongs to. In linguistics, the marking is fairly frequent and precise; exact markers such as second are the most used, and structures with unmarked items are less common. Similarly, the marking is fairly frequent in education. In this field, however, it is also less precise than in linguistics, with frequent unmarked items and additive markers. History, on the other hand, is characterised by less frequent marking. In addition, when used, the marking in this field is also less precise and less explicit.

Simulation of Solid Processes by Aspen Plus

Solid processes are used for obtaining the valuable minerals. Due to their worth, it is obligatory to perform different experiments to determine the different values of these minerals. With the passage of time, it is becoming more difficult to carry out these experiments for each mineral for different characteristics due to high labor costs and consumption of time. Therefore, scientists and engineers have tried to overcome this issue. They made different software to handle this problem. Aspen is one of those software for the calculation of different parameters. Therefore, the aim of this report was to do simulation for solid processes to observe different effect for minerals. Different solid processes like crushing, screening; filtration and crystallization were simulated by Aspen Plus. The simulation results are obtained by using this simulation software and they are described in this thesis. It was noticed that the results were acceptable for all solid processes. Therefore, this software can be used for the designing of crushers by calculating the power consumption of crushers, can design the filter and for the calculation of material balance for all processes.

Use of preclinical and early clinical data for dose selection of a selective estrogen receptor modulator toremifene in treatment of breast cancer

In development of human medicines, it is important to predict early and accurately enough the disease and patient population to be treated as well as the effective and safe dose range of the studied medicine. This is pursued by using preclinical research models, clinical pharmacology and early clinical studies with small sample sizes. When successful, this enables effective development of medicines and reduces unnecessary exposure of healthy subjects and patients to ineffectice or harmfull doses of experimental compounds. Toremifene is a selective estrogen receptor modulator (SERM) used for treatment of breast cancer. Its development was initiated in 1980s when selection of treatment indications and doses were based on research in cell and animal models and on noncomparative clinical studies including small number of patients. Since the early development phase, the treatment indication, the patient population and the dose range were confirmed in large comparative clinical studies in patients. Based on the currently available large and long term clinical study data the aim of this study was to investigate how the early phase studies were able to predict the treatment indication, patient population and the dose range of the SERM. As a conclusion and based on the estrogen receptor mediated mechanism of action early studies were able to predict the treatment indication, target patient population and a dose range to be studied in confirmatory clinical studies. However, comparative clinical studies are needed to optimize dose selection of the SERM in treatment of breast cancer.

Beethoven Plus 3 : Beethoven: Sonaatit viululle ja pianolle, 1900- luvun viulu-pianoteoksia

Esitetty myös: Hämeenlinna: Raatihuone, Tampere: Pyynikkisali

Kohdentamalla suurin hyöty maatalouden ympäristönsuojeluun : TEHO Plus -hankkeen (2011-2014) loppuraportti

TEHO Plus, Maatalouden vesiensuojelun tehostaminen -hanke jatkoi TEHO-hankkeen aloittamaa työtä vuosina 2011–2014. Hankkeen toiminnan painopistealueina ovat olleet maatalouden ympäristöneuvojien koulutuspaketin luonti ja koulutuksen kokeileminen, tilakohtainen neuvonta ja neuvonnasta saatujen kokemusten hyödyntäminen, tietopaketin kokoaminen maatalouden ympäristöasioista, tilatason kokeilutoiminta ja vedenlaadun seurannan kehittäminen. Ympäristötoimia on neuvonnassa suositeltu kohdennettavaksi paikkatietoaineistoja ja ravinnetaseita hyödyntäen. Hanke toteutettiin Varsinais-Suomen ELY-keskuksen, MTK-Satakunnan ja MTK-Varsinais-Suomen yhteistyönä. Hanketta rahoittivat maa- ja metsätalousministeriö sekä ympäristöministeriö. Tärkeänä kumppanina hankkeessa olivat yhteistyöviljelijät, joiden kanssa kehitettiin ympäristöneuvontaa ja toteutettiin kokeilutoimintaa. Hankkeen toiminta-alueena oli Satakunta ja Varsinais-Suomi, mutta hankkeen tulokset ovat valtakunnallisesti hyödynnettävissä. Valtakunnallista näkemystä haettiin tiiviillä yhteistyöllä eri maakuntien toimijoiden kanssa. Tähän loppuraporttiin on koottu hankkeen kokemuksia ja tuloksia ympäristöneuvonnasta, ympäristöneuvojien koulutuksesta, tilakäynnistä ja viljelijöiden antamasta palautteesta ympäristöneuvonnasta, vedenlaadun seurannan kehittämisestä, kokeilutoiminnasta sekä hanketyöstä.

Amérique méridionale : dressée sur les mémoires les plus récents et assujétie aux observations astronomique[s]

Julkaisussa: Atlas universel

Carte générale du globe terrestre dressée sur les mémoires les plus approuvés et les observations les plus exactes

Julkaisussa: Nouvel atlas du globe terrestre representé en une carte générale et XII cartes particulières avec une courte description