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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Phase 1 Study Of A Sequence Selective Minor Groove DNA Binding Agent (SJG-136) with Pharmacokinetic and Pharmacodynamic Measurements in Patients with Advanced Solid Tumours.

Hochhauser, Daniel, Meyer, Timothy, Spanswick, Victoria J., Wu, Jenny, Clingen, Peter H., Loadman, Paul M., Cobb, Margaret, Gumbrell, Lindsey, Begent, Richard H., Hartley, J.A., Jodrell, Duncan January 2009 (has links)
PURPOSE: This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data. EXPERIMENTAL DESIGN: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 microg/m(2)) given as a 10-minute i.v. infusion every 21 days. The dose was subsequently reduced in incremental steps to 45 microg/m(2) due to unexpected toxicity. RESULTS: The maximum tolerated dose of SJG-136 was 45 microg/m(2). The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive gamma-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested. CONCLUSIONS: SJG-136 was associated with dose-limiting VLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.
2

Development of an eco- and material-efficient pellet production chain—a chemical study

Kuokkanen, M. (Matti) 16 April 2013 (has links)
Abstract According to the EU’s strategy and the corresponding Finnish national strategy on waste materials, all kinds of waste must be utilised primarily as material (reuse, recycling) and secondarily as energy, and at the lowest level of waste hierarchy is their disposal using environmentally friendly methods. Today material efficiency is an essential topic in promoting sustainable use of natural resources, industrial by-products and waste material. The present goal proposed by the EU sets the target for the total proportion of renewable energy as high as 38% by 2020 in Finland. Up to 20 million tonnes of waste wood biomass per year are left unused in Finland, mainly in the forests during forestry operations, because supply and demand do not meet. As a consequence of high heat energy prices, the looming threat of climate change, the greenhouse effect and global as well as national demands to considerably increase the proportion of renewable energy, Finland currently has a tremendous interest in increasing decentralised pellet production alongside of large-scale factories. The aim of this thesis is to promote the development of eco-, material- and cost-efficient Nordic wood-based pellet production and utilisation of pellet bio-ash by means of chemical research. Using Finnish wood (sawdust and shavings) as a model raw material, the total functionality of a pilot-scale pellet facility combined with an extensive chemical toolbox was tested in this study to promote development of an eco-, material- and cost-efficient wood-based pellet production chain. The chemical toolbox includes measurements of moisture content, density, heat value, mechanical durability and particle size distribution, TG analysis and elementary analysis, as well as new applications for pellet biodegradation using BOD OxiTop equipment and optical microscopic staining methods. To improve the quality of pellets, considering the profitability of production and occupational safety factors (wood dust exposure, fire and explosion risk), it is profitable to use different binding agents, especially industrial by-products and locally utilisable residuals. Thus, lignosulphonate, residual potato flour and potato peel residue were used and tested as model adhesive binding agents. The results showed that binding agents increased the quality of pellets and changed their inorganic characteristics, but did not have a significant effect on their calorimetric heat values. Lignosulphonate even increased the rate of production. To characterise different starch-containing binding agents, a new specific optical microscopic staining method was developed and tested, and the initial results are presented in this thesis. Wood pellet ash has potential as a liming agent, in soil remediation, as a soil fertilizer, and in granulated form, in new applications such as road construction and waste water purification. Valuable information about raw materials, binding agents and the pelletizing process is necessary when developing good-quality pellets—a prime biofuel—from non-utilised low-value and/or moist biomass that has undergone a cost-efficient drying process. This way pellet production will have more essential importance in energy policy, especially in the European forest belt. / Tiivistelmä Vallitsevan EU:n sekä Suomen kansallisen lainsäädännön mukaan kaikenlainen jäte täytyy hyödyntää ensisijaisesti materiaalina (uudelleenkäyttö, kierrätys), toissijaisesti energiana ja jätehierarkiassa alimpana tasona on sen hävittäminen ympäristöystävällisin keinoin. Materiaalitehokkuus on nykyään välttämätön aihe edistettäessä luonnonvarojen, teollisuuden sivutuotteiden ja jätemateriaalien kestävää käyttöä. EU-strategian mukainen tavoite uusiutuvan energian osuudelle kaikesta energiantuotannosta Suomessa on 38 % vuoteen 2020 mennessä. Jopa 20 miljoonaa tonnia jätepuubiomassaa vuodessa jää käyttämättä Suomessa lähinnä metsänharvennustöiden yhteydessä, koska kysyntä ja tarjonta eivät kohtaa. Seurauksena korkeista lämpöenergiahinnoista, uhkaavasta ilmastonmuutoksesta, kasvihuoneilmiöstä sekä globaalisista ja kansallisista vaatimuksista lisätä uusiutuvan energian osuutta, Suomessa on viime aikoina noussut voimakas kiinnostus lisätä hajautettua pellettituotantoa suurten pellettilaitosten rinnalle. Väitöskirjan tarkoituksena on edistää ja kehittää pohjoismaista eko- ja kustannustehokasta puupellettituotantoa ja pellettibiotuhkan hyötykäyttöä kemiallisen tutkimuksen avulla. Käyttäen suomalaista puuta (sahanpurua ja kutterinlastua) malliraaka-aineina, tässä tutkimuksessa testattiin pilot-mittakaavan pellettilaitoksen toimivuutta yhdistettynä laajaan kemialliseen ”työpakettiin”, edistämään tulevaisuuden eko-, materiaali- ja kustannustehokkaan pellettituotantoketjun kehittämistä. Kemiallinen työpaketti sisältää kosteuden, tiheyden, lämpöarvon, mekaanisen kestävyyden ja partikkelikokojakauman määritykset, TG- ja alkuaineanalyysin, kuten myös uudet sovellukset pellettien ja niiden sideaineiden biohajoavuuden määrittämiseksi BOD OxiTop -laitteistoilla sekä optisen mikroskooppivärjäysmenetelmän. Pellettien laadun kohottamiseksi, ottaen huomioon myös tuotannon kannattavuuden ja työterveydelliset ongelmat (puupölylle altistuminen, tulipalo- ja räjähdysvaara), on perusteltua käyttää sideaineita, erityisesti teollisuuden sivutuotteita ja paikallisesti hyödynnettävissä olevia jätemateriaaleja. Täten lignosulfonaattia, jäteperunajauhoa ja perunankuorijätettä käytettiin ja testattiin liimaavina mallisideaineina. Tulokset osoittivat, että sideaineet nostivat pellettien laatua ja muuttivat niiden epäorgaanisia ominaisuuksia, mutta niillä ei ollut merkittävää vaikutusta määritettyihin lämpöarvoihin. Lignosulfonaatti lisäsi selvästi pelletoinnin tuotantonopeutta. Työssä kehitettiin pelleteille uusi spesifinen optinen mikroskooppivärjäysmenetelmä erilaisten tärkkelystä sisältävien sideaineiden karakterisointiin ja ensimmäiset tulokset on esitetty tässä väitöskirjassa. Puupellettituhka on potentiaalinen kalkitus- ja maanparannusaineena, lannoitteena sekä rakeistettuna uusissa sovelluksissa, kuten tierakentamisessa ja jäteveden puhdistuksessa. Arvokas informaatio raaka-aineista, sideaineista sekä pelletöintiprosessista on välttämätöntä kehitettäessä tulevaisuudessa hyvälaatuisia pellettejä, ”priimaa” biopolttoainetta, hyödyntämättömästä huonolaatuisesta ja/tai kosteasta biomassasta, joka on ennen pelletointia käynyt läpi kustannustehokkaan kuivausprosessin. Täten voidaan olennaisesti lisätä pellettituotannon merkitystä energiapolitiikassa, erityisesti Euroopan metsävyöhykkeellä.
3

Phase I study of sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors

Hochhauser, D., Meyer, T., Spanswick, V.J., Wu, J., Clingen, P.H., Loadman, Paul, Cobb, M., Gumbrell, L., Begent, R.H., Hartley, J.A., Jodrell, D. January 2009 (has links)
No / PURPOSE: This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data. EXPERIMENTAL DESIGN: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 microg/m(2)) given as a 10-minute i.v. infusion every 21 days. The dose was subsequently reduced in incremental steps to 45 microg/m(2) due to unexpected toxicity. RESULTS: The maximum tolerated dose of SJG-136 was 45 microg/m(2). The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive gamma-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested. CONCLUSIONS: SJG-136 was associated with dose-limiting VLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.

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