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A Study of Models for Prediction of Treatment Response in Cancer
Get PDFAbstract in Norwegian
Kreft kjennetegnes av molekylære forandringer som resulterer i unormal og høy celledeling. Opp gjennom årene har et vesentlig antall kjemoterapier rettet mot å hemme denne celledelingen blitt godkjent for bruk i behandling av kreft. Anvendelsen av disse har ført til generelt forbedrede prognoser for kreftpasienter, men fortsatt er det slik at langt fra alle pasienter responderer på slik behandling, og i tillegg opplever mange bivirkninger. For å øke effekten av kreftbehandling, fokuserer mye av dagens forskning på mulighetene for mer målrettet behandling ved å spesifikt angripe de molekylære endringene som gir opphav til sykdommen. Denne behandlingsformen antas å være gunstig av flere grunner, blant annet ved at bivirkningene blir mindre, og ved at mulighetene for persontilpasset behandling blir større. Selv om målrettet behandling i teorien er en lovende strategi, er det også flere utfordringer. En av disse utfordringene er knyttet til plastisiteten til kreftceller, der endringer i kreftcellenes molekylære signalertrafikk ofte gir opphav til behandlingsresistens. Bruken av medikamentkombinasjoner har vist seg å være en effektiv strategi for å omgå resistens, men på grunn av det astronomiske antallet mulige kombinasjoner som må undersøkes eksperimentelt, har relativt få blitt vurdert, godkjent, og nådd klinisk bruk. I tillegg antas mangler i den biologiske likheten mellom mange av dagens eksperimentelle kreftmodeller og virkelige svulster å føre til lite samsvar mellom eksperimentelle og kliniske responser.
Med hovedmål om å øke kunnskapen om hvordan kreftbehandling kan effektiviseres, var arbeidet i denne doktorgraden spesielt rettet mot å undersøke 1) hvordan bruk av mer avanserte eksperimentelle kreftmodeller, med antatt økt klinisk relevans, kan brukes i høykapasitets-utprøving av mange medisiner, og 2) hvordan datamodeller kan brukes som verktøy i søket etter effektive medikamentkombinasjoner. Gjennom en storskala studie som studerte effekten av 21 medikamentkombinasjoner i klassiske (2D) og mer avanserte (3D) eksperimentelle kreftmodeller, ønsket vi å finne forskjellene i medikamentrespons forårsaket av forskjeller i den tredimensjonale oppbyggingen av kreftsvulster. Resultatene fra studien viste signifikante forskjeller i kombinasjonseffekt mellom kreftmodeller, som igjen belyser viktigheten av å nøye vurdere den kliniske relevansen av ulike modeller ved design av eksperimentelle studier. Av de 21 medikamentkombinasjonene som ble testet i studien, ble en betydelig andel funnet å være ineffektiv i begge modellene. For å vise at datakraft kan brukes til å forutsi medikamentrespons og dermed fungere som et verktøy for effektivisering av eksperimentelle studier, designet vi en datamodell basert på medikamentene som er inkludert i kombinasjonsstudien vår. Datamodellen ble oppdatert basert på eksperimentelle funn, og kunne deretter brukes til å identifisere en rekke nye medikamentkombinasjoner med mulig høyere effekt. Alle disse ble bevist riktige i en oppfølgingsstudie, som viser kraften i å bruke datamodeller for å effektivisere eksperimentelle studier av medikamentkombinasjoner. Avslutningsvis, rettet mot å ytterligere øke den kliniske relevansen av eksperimentelle kreftmodeller, utviklet vi en metode for medikamentresponsstudier i primære pasientderiverte kreftmodeller (sfæroider). Denne studien viste klare forskjeller i respons mellom sfæroider fra forskjellige pasienter, som igjen understreker relevansen av persontilpasset behandling av kreft.Abstract
Cancer is characterised by molecular alterations that lead to abnormal and excessive cellular proliferation. Over the years, a considerable number of chemotherapies, aimed to prevent proliferation by inducing cell death, have been approved for treatment of cancer. The use of such therapies has led to an overall increase in the quality of life and survival of cancer patients, but far from all patients respond to treatment. In addition, many patients experience side-effects to therapies. Seeking to increase the effect of cancer therapies, today’s research has turned towards the possibility of treating cancer using strategies that more specifically target the molecular alterations that are the assumed cause of the disease. Treating cancer by specific targeting of aberrant molecular mechanisms is believed to be beneficial from several points of view. As treatments are designed to specifically target cancer cells, the risk for side-effects is supposedly lower. Also, based on evidence of large molecular heterogeneity between cancer patients, targeted therapy is a promising strategy for personalising cancer treatment. Although a promising strategy in theory, the reality of targeted therapy however faces multiple challenges, including, 1) molecular signalling of cancer cells, which is highly adaptive and often results in treatment resistance. While resistance may be circumvented by administrating drugs in combinations 2) identifying such combinations is challenging due to the large combinatorial space that experimentally needs to be explored. In addition, 3) biological discrepancies between in vitro cultures and tumours in vivo are large, which may contribute to low clinical translatability of therapies identified as successful in vitro.
Ultimately seeking to contribute to increased knowledge on how to improve cancer treatment, the work of this thesis was aimed at investigating 1) how drug response can be assayed in more complex culture models that more closely mimic a clinical setting, and 2) how computational models can be employed in the search for synergistic drug combinations.
By performing an unbiased high-throughput screen of 21 drug combinations in planar (2D) and spheroid (3D) cultures of colorectal cancer cell lines, we studied the impact of culture complexity on drug combination effects. We found that drug synergy in general was more pronounced in 2D-cultivated cells, but also noticed that 3D-cultivated cells were more sensitive and showed greater synergistic response to specific combinations. Altogether the results from the study hence indicated that already at the cell line level, culture complexity has a significant impact on drug response, which in turn highlights the importance of careful selection of the most clinically relevant in vitro culture system when seeking to make the most possible out of drug response data. To take 3D models as a tool for in vitro screening one step closer to a clinical scenario we also developed a procedure for drug testing in patient derived tumour spheroids. Doing so, we were able to show that by studying just a small group of samples we could capture sample-heterogeneity in terms of growth rate and drug response. These results highlight the relevance of tailoring cancer treatment to individual patients. Both the combination screen and evaluation of response in patient-derived tumour spheroids were performed in an exhaustive design testing all potential drug combinations. To show that computational modelling can be used for prediction of drug response and hence guiding of drug screens, we constructed a mechanistic computational model encompassing signalling pathways known to be dysregulated in multiple cancers. By adjusting the model to increase its predictive capacity for pairwise combinations, we next used it for prediction of synergistic third and fourth-order combinations. The model identified three synergistic third-order combinations, out of which all were confirmed in a subsequent screen. Altogether the results point towards the benefits of using computational tools when designing large-scale experiments.
To summarise, this thesis presents a thorough study of models and strategies available for preclinical testing of drugs and drug combinations. As investigated models span over a wide range of application areas, the study is expected to cover many of the aspects of preclinical drug testing; from early computational simulations of drug response to in vitro screening of clinically approved agents in patient-derived tumour cultures
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Studies of cell release and biomass activity of alginate immobilized lactic acid bacteria
No full textThe scope of the work presented in this thesis has been the study of growth, cell release and metabolite production of gel-entrapped viable lactic acid bacteria. As these fermenation systems are mainly aimed at food applications, immobilization methods based on alginate and chitosan were chosen due to the biocompatibility of these materials. In these studies, ways to measure, characterize and influence the activity and release of the immobilized lactic acid bacteria were investigated.
The use of sequential coatings with chitosan (C) and alginate (A) on alginate beads immobilizing Lactococcus lactis ssp. lactis NCMIB 6681 was investigated. The effects of these coatings on biomass activity and cell release were evaluated in batch and continuous systems. In this work, and argument is made for the use of and experimental system based on continuous fermentation at a controlled pH and a high dilution rate for these types of studies. When examined in this system, chitosan coating alone seemed to reduce the ratio of cell release to lactate production in the early stages of fermentation, while sequential coatings with chitosan and alginate (CAC) showed significant reductions in this ratio throughout the whole 48 hour test period.
Under normal growth conditions, diffusional limitations direct most of the biomass growth in beads immobiizing lactic acid bacteria to the ooutermost parts of the beads. Therefore, a study was conducted in order to investigate if biomass distributions, and thereby cell release, could be affected through changes of the growth conditions. A change in operating pH from 6.5 to 9.25 initially reduced the ratios of rates of cell release to lactate production by almost a factor of 105. Compared to fermentations at pH 6.5, growth at pH 9.25 also increased the final internal bead biomass concentration by a factor of 5 and increased the final rate of lactate production by 25%. After 48 hours, the ratio of the rates of cell release to lactate production was still 10 times lower than in fermentaions at pH of 6.5. These data illustrate that diffusionsal limitations and corresponding pH-gradients can be exploited in affecting the distribution of immobilized growing cells and their concomitant release.
The use of sequential coatings with chitosan and alginate was investigated as a way to a reduced cell release during immobilized bacteriocin production. Production of the bacteriocins enterocins A and B by immobilized E.faecium CTC492 in uncoated and CAC-coated alginate beads was evaluated in batch and continuous ferminations. In batch fermenations with E. faecium CTC492 immobilized in CAC.coated beads substantial amount of the maximal bacteriocin activity in traditional free-cell fermentaion was obtained, combined with a more than 3 log unit reduction of the amount of free biomass in the product. Longer-term studies of bead performance were performed using continuous fermentaions at high dilution rates. These experiments showed the the use of CAC-coatings reduced the ratio of rates of bacteriocin production to cell release significantly the first 20 hours of fermentaion. In these studies, the presence of large pH gradients within beads containing immobilized E. facium CTC492 during continuos fermentation were demonstrated using a microelectrode. As expected, the bacteriocin production and fermination characteristics of immobilized E. faecium CTC492 seemed to be significantly influenced by the presence of these local pH-gradients.dr.ing.dr.ing
Studies of cell release and biomass activity of alginate immobilized lactic acid bacteria
No full textThe scope of the work presented in this thesis has been the study of growth, cell release and metabolite production of gel-entrapped viable lactic acid bacteria. As these fermenation systems are mainly aimed at food applications, immobilization methods based on alginate and chitosan were chosen due to the biocompatibility of these materials. In these studies, ways to measure, characterize and influence the activity and release of the immobilized lactic acid bacteria were investigated. The use of sequential coatings with chitosan (C) and alginate (A) on alginate beads immobilizing Lactococcus lactis ssp. lactis NCMIB 6681 was investigated. The effects of these coatings on biomass activity and cell release were evaluated in batch and continuous systems. In this work, and argument is made for the use of and experimental system based on continuous fermentation at a controlled pH and a high dilution rate for these types of studies. When examined in this system, chitosan coating alone seemed to reduce the ratio of cell release to lactate production in the early stages of fermentation, while sequential coatings with chitosan and alginate (CAC) showed significant reductions in this ratio throughout the whole 48 hour test period. Under normal growth conditions, diffusional limitations direct most of the biomass growth in beads immobiizing lactic acid bacteria to the ooutermost parts of the beads. Therefore, a study was conducted in order to investigate if biomass distributions, and thereby cell release, could be affected through changes of the growth conditions. A change in operating pH from 6.5 to 9.25 initially reduced the ratios of rates of cell release to lactate production by almost a factor of 105. Compared to fermentations at pH 6.5, growth at pH 9.25 also increased the final internal bead biomass concentration by a factor of 5 and increased the final rate of lactate production by 25%. After 48 hours, the ratio of the rates of cell release to lactate production was still 10 times lower than in fermentaions at pH of 6.5. These data illustrate that diffusionsal limitations and corresponding pH-gradients can be exploited in affecting the distribution of immobilized growing cells and their concomitant release. The use of sequential coatings with chitosan and alginate was investigated as a way to a reduced cell release during immobilized bacteriocin production. Production of the bacteriocins enterocins A and B by immobilized E.faecium CTC492 in uncoated and CAC-coated alginate beads was evaluated in batch and continuous ferminations. In batch fermenations with E. faecium CTC492 immobilized in CAC.coated beads substantial amount of the maximal bacteriocin activity in traditional free-cell fermentaion was obtained, combined with a more than 3 log unit reduction of the amount of free biomass in the product. Longer-term studies of bead performance were performed using continuous fermentaions at high dilution rates. These experiments showed the the use of CAC-coatings reduced the ratio of rates of bacteriocin production to cell release significantly the first 20 hours of fermentaion. In these studies, the presence of large pH gradients within beads containing immobilized E. facium CTC492 during continuos fermentation were demonstrated using a microelectrode. As expected, the bacteriocin production and fermination characteristics of immobilized E. faecium CTC492 seemed to be significantly influenced by the presence of these local pH-gradients
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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