La coordination et les phrases juxtaposées en français

Coordination and juxtaposed sentences The object of this study is the examination of the relations between juxtaposed clauses in contemporary French. The matter in question is sentences which are composed of several clauses adjoined without a conjunction or other connector, as in: Je détournai les yeux, mon c ur se mit à battre. The aim of the study is to determine, which quality is the relation in these sentences and, on the other hand, what is the part of the coordination there. Furthermore, what is this relation of coordination, which, according to some grammars, manifests through a conjunction of coordination, but which, according to some others is marked in juxtaposed sentences through different features. The study is based on a corpus of written French from literary and journalistic text sources. Syntactic, semantic and textual properties in the clauses are discussed. The analysis points to differences so, it has been noted, in each case, if one of the clauses is affirmative and the other negative and if in the second clause, the subject has not been repeated. Also, an analysis has been made on the ground of the tense, mode, phrase structure type, and thematic structure, taking into account, in each case, if the clauses are identical or different. Punctuation has been one of the properties considered. The final aim has been to eliminate gradually, based on the partition of properties, subordinate sentences, so that only the hard core of coordinate sentences remains. In this way, the coordination could be defined similarly as the phoneme is defined as a group of distinctive features. The quantitative analyses have led to the conclusion that the sentences which, from a semantic point of view, are interpreted as coordinating, contain the least of these differences, while the sentences which can be considered as subordinating present the most of these differences. The conditions of coordination are, in that sense, hierarchical, so that the syntactic constraints have to make room for semantic, textual and cognitive factors. It is interesting to notice that everyone has the ability to produce correct coordinating structures and recognize incorrect coordinating structures. This can be explained by the human ability to categorize which has been widely researched in the semantic of prototype. The study suggests that coordination and subordination could be considered as prototypical cognitive categories based on different linguistic and pragmatic features.

La música orquestal peruana de 1945 a 2005 : Identidades en la diversidad

Peruvian orchestral music 1945–2005. Identities in diversity Peruvian music for orchestra has not been studied as a whole before, and is hardly known by Peruvian musicians and public. The aim of the thesis is to give a panoramic view of Peruvian orchestral music after 1945, study the particular historical context in which these works were created and how they reflect the search for a musical identity of its own, be it individual, local, national or Latin American. Identity is a construction that changes permanently, and individuals can share many identities at the same time. This is a central issue in multicultural societies as the Peruvian, and music is an important mean for constructing cultural identity. The hypothesis of this research is that orchestral work is a medium for Peruvian composers to express their relationship with traditional and popular musics of the country in different ways, from quotation of melodies to a more abstract appropiation of concepts or suggestive title references. Representative works by selected composers, of different techniques, styles or special reception are chosen and analyzed. Research methodology includes analysis of works with various methods according to their stylistic and technical features, in order to find the particular ways in which composers have approached or expressed diverse identities. The investigation shows that Peruvian orchestral music includes works in the main stylistic trends and using the main compositional techniques of the modernist and postmodern periods. It also shows that the construction and expression of particular identities through the study and use of other Peruvian musical traditions is a constant interest shared by composers of different age and esthetic. In a multicultural society as the Peruvian, characterized by its diversity, different forms of transcultural composition are an important mean of dealing with identity issues in music. This thesis also includes for the first time a list of all orchestral works composed in the country or by Peruvian composers in the period, their composers and genres. KEYWORDS: Peruvian music, contemporary music for orchestra, identity

Principles of Pitch Organization in Béla Bartók's 'Duke Bluebeard's Castle'

The topic of my doctoral thesis is to demonstrate the usefulness of incorporating tonal and modal elements into a pitch-web square analysis of Béla Bartók's (1881-1945) opera, 'A kékszakállú herceg vára' ('Duke Bluebeard's Castle'). My specific goal is to demonstrate that different musical materials, which exist as foreground melodies or long-term key progressions, are unified by the unordered pitch set {0,1,4}, which becomes prominent in different sections of Bartók's opera. In Bluebeard's Castle, the set {0,1,4} is also found as a subset of several tetrachords: {0,1,4,7}, {0,1,4,8}, and {0,3,4,7}. My claim is that {0,1,4} serves to link music materials between themes, between sections, and also between scenes. This study develops an analytical method, drawn from various theoretical perspectives, for conceiving superposed diatonic spaces within a hybrid pitch-space comprised of diatonic and chromatic features. The integrity of diatonic melodic lines is retained, which allows for a non-reductive understanding of diatonic superposition, without appealing to pitch centers or specifying complete diatonic collections. Through combining various theoretical insights of the Hungarian scholar Ernő Lendvai, and the American theorists Elliott Antokoletz, Paul Wilson and Allen Forte, as well as the composer himself, this study gives a detailed analysis of the opera's pitch material in a way that combines, complements, and expands upon the studies of those scholars. The analyzed pitch sets are represented on Aarre Joutsenvirta's note-web square, which adds a new aspect to the field of Bartók analysis. Keywords: Bartók, Duke Bluebeard's Castle (Op. 11), Ernő Lendvai, axis system, Elliott Antokoletz, intervallic cycles, intervallic cells, Allen Forte, set theory, interval classes, interval vectors, Aarre Joutsenvirta, pitch-web square, pitch-web analysis.

Signifying Angels : Analyses and Interpretations of Rautavaara s Instrumental Compositions

The subject of doctoral thesis is the analysis and interpretation of instrumental pieces composed by Einojuhani Rautavaara (b. 1928) that have been given angelic titles: Archangel Michael Fighting the Antichrist from the suite Icons (1955)/Before the Icons (2006), Angels and Visitations (1978), the Double Bass Concerto Angel of Dusk (1980), Playgrounds for Angels (1981)and the Seventh Symphony Angel of Light (1994). The aim of the work is to find those musical elements common to these pieces that distinguish them from Rautavaara s other works and to determine if they could be thought of as a series. I prove that behind the common elements and titles stands the same extramusical idea the figure of an angel that the composer has described in his commentaries. The thesis is divided into three parts. Since all of the compositions possess titles that refer to the spiritual symbol of an angel, the first part offers a theoretical background to demonstrate the significant role played by angels in various religions and beliefs, and the means by which music has attempted to represent this symbol throughout history. This background traces also Rautavaara s aesthetic attitude as a spiritual composer whose output can be studied with reference to his extramusical interests including literature, psychology, painting, philosophy and myths. The second part focuses on the analysis of the instrumental compositions with angelic titles, without giving consideration to their commentaries and titles. The analyses concentrate in particular on those musical features that distinguish these pieces from Rautavaara s other compositions. In the third part these musical features are interpreted as symbols of the angel through comparison with vocal and instrumental pieces which contain references to the character of an angel, structures of mythical narration, special musical expressions, use of instruments and aspects of brightness. Finally I explore the composer s interpretative codes, drawing on Rilke s cycle of poems Ten Duino Elegies and Jung s theory of archetypes, and analyze the instrumental pieces with angelic titles in the light of the theory of musical ekphrasis.

The One and The Many : In the works of Heraclitus, Parmenides and Lao Zi

This paper concentrates on Heraclitus, Parmenides and Lao Zi. The focus is on their ideas on change and whether the world is essentially One or if it is composed of many entities. In the first chapter I go over some general tendences in Greek and Chinese philosophy. The differences in the cultural background have an influence in the ways philosophy is made, but the paper aims to show that two questions can be brought up when comparing the philosophies of Heraclitus, Parmenides and Lao Zi. The questions are; is the world essentially One or Many? Is change real and if it is, what is the nature of it and how does it take place? For Heraclitus change is real, and as will be shown later in the chapter, quite essential for the sustainability of the world-order (kosmos). The key-concept in the case of Heraclitus is Logos. Heraclitus uses Logos in several senses, most well known relating to his element-theory. But another important feature of the Logos, the content of real wisdom, is to be able to regard everything as one. This does not mean that world is essentially one for Heraclitus in the ontological sense, but that we should see the underlying unity of multiple phenomena. Heraclitus regards this as hen panta: All from One, One from All. I characterize Heraclitus as epistemic monist and an ontological pluralist. It is plausible that the views of Heraclitus on change were the focus of Parmenides’ severe criticism. Parmenides held the view that the world is essentially one and that to see it as consisting of many entities was the error of mortals, i.e. the common man and his philosophical predecessors. For Parmenides what-is, can be approached by two routes; The Way of Truth (Aletheia) and The Way of Seeming (Doxa). Aletheia essentially sees the world as one, where even time is an illusion. In Doxa Parmenides is giving an explanation of the world seen as consisting of many entities and this is his contribution to the line of thought of his predecessors. It should be noted that a strong emphasis is given to the Aletheia, whereas the world-view given is in Doxa is only probable. I go on to describe Parmenides as ontological monist, who gives some plausibility to pluralistic views. In the work of Lao Zi world can be seen as One or as consisting of Many entities. In my interpretation, Lao Zi uses Dao in two different senses; Dao is the totality of things or the order in change. The wu-aspect (seeing-without-form) attends the world as one, whereas the you-aspect attends the world of many entities. In wu-aspect, Dao refers to the totality of things, when in you-aspect Dao is the order or law in change. There are two insights in Lao Zi regarding the relationship between wu- and- you-apects; in ch.1 it is stated that they are two separate aspects in seeing the world, the other chapters regarding that you comes from wu. This naturally brings in the question whether the One is the peak of seeing the world as many. In other words, is there a way from pluralism to monism. All these considerations make it probable that the work attributed to Lao Zi has been added new material or is a compilation of oral sayings. In the end of the paper I will go on to give some insights on how Logos and Dao can be compared in a relevant manner. I also compare Parmenides holistic monism to Lao Zi’s Dao as nameless totality (i.e. in its wu-aspect). I briefly touch the issues of Heidegger and the future of comparative philosophy.

Vapaata mielenjuoksua : Suomenkielisen freestyle-rapin ilmenemismuodot, estetiikka ja kompositio

The thesis is about Finnish freestyle-rap, a modern form of oral poetry producing improvised rap lyrics at the moment of performance. The research material consists of interviews with seven freestyle experts and a DVD from Finnish Rap Championships 2005 containing freestyle-rap. The thesis has three goals: describing the different variations or subgenres of freestyle, outlining the esthetics and register of freestyle, and examining the composition of freestyle. The research material acts a central role in the thesis but the theoretical framework is also wide: cornerstones are John Miles Foley's register analysis, oral formulaic theory and William Levelt's psycholinguistic theory on planning of speech. Freestyle is divided into three partially overlapping genres with slight variation in conventions. The genres are freestyle battle, cypher, and live freestyle. Freestyle's esthetics are composed of certain qualities and preferences: the rhyme is a syllabically repeating vocal rhyme. The rapping must be synchronised with the background rhythm and the rhyme comes in the end of the line. The lyrics must be somehow anchored to the surroundings and the moment of performance. The style of rapping, ie. flow, has to be personal one way or the other. Individual formulas are used to some extent in freestyle compostition. When planning the lines, all other content is subordinate to the rhyme, whose phonetic processing is the primary act in the planning of freestyle. This discovery sets Levelt's theory open to doubt.

Arkeologia, historialliset kartat ja paikkatieto

This licentiate thesis is composed of three parts, of which the parts 2 and 3 have been published elsewhere. Part 1 deals with the research history of large-scaled historical maps in Finland. The research done in four disciplines – archaeology, history, art history and geography – is summarized. Compared to the other disciplines, archaeology is characterized by its deep engagement with the location. Because archaeology studies different aspects of the past through material culture, it is the only discipline in which the concrete remains portrayed on the maps are “dug up”. For the archaeologist, historical maps are not merely historical documents with written information and drawings in scale, but actual maps which can be connected with the physical features they were made to illustrate in the first place. This aspect of historical maps is discussed in the work by looking at the early (17th and 18th century) urban cartographic material of two Finnish towns, Savonlinna and Vehkalahti-Hamina. In both cases, the GIS-based relocating of the historical maps highlights new aspects in the early development of the towns. Part 1 ends with a section in which the contents of the entire licentiate thesis are summarized. Part 2 is a peer reviewed article published in English. This article deals with the role of historical maps converted into GIS in archaeological surveys made in Finnish post-medieval towns (16th and 17th centuries). It is based on the surveys made by the author between 2000 and 2003 and introduces a new method for the archaeological surveying of post-medieval towns with wooden houses. The role of archaeology in the sphere of urban research is discussed. The article emphasizes that the methods used in studying the development of southern European towns with stone houses cannot be adequately applied to the wooden towns of the north. Part 3 is a monograph written in Finnish. It discusses large-scaled historical maps and the methods for producing digital spatial information based on historical maps. Since the late 1990’s, archaeological research in Finland has been increasingly directed towards the historical period. As a result, historical cartography has emerged as one of the central sources of information for the archaeologist, too. The main theme of this work is the need for using historical maps as real maps which, surprisingly, has been uncommon in the historical sciences. Projecting historical maps to the very place they were made to illustrate is essential to understanding the maps. This is self-evident for the archaeologist, who is accustomed to studying the material past, but less so to researchers in other historical disciplines that concentrate on written and visual sources of information. With the help of GIS, the historical maps can be concretely linked to the places they were originally made to illustrate. In doing so, and equipped with a cartographic comprehension, new observations can be made and questions asked, which supplement and occasionally challenge the prevailing views.

Visual completion in an illusory figure

The visual systems of humans and animals represent physical reality in a modified way, depending on the specific demands that the species in question has for survival. The ability to perceive visual illusions is found in independently evolved visual systems, from honeybees to humans. In humans, the ability emerges early, at the age of four months. Thus the perception of illusion is likely to reflect visual processes of fundamental importance for object perception in natural vision. The experiments reported in this thesis employed various modifications of the Kanizsa triangle, a drawn configuration composed of three black disks with missing sectors on a white background. The sectors appear to form the tips of a triangle. The visual system completes the physically empty area between the disks, generally called inducers, with giving the perception of an illusory triangle. The illusory triangle consists of an illusory surface bounded by illusory contours; the triangle appears brighter than and to lie above the background. If the sectors are coloured, the colour fills the illusory area, a phenomenon known as neon colour spreading . We investigated spatial limitations on the perception of Kanizsa-type illusions and how other stimuli and viewing parameters affected these limitations. We also studied complex configurations thick, bent, mobile and chromatic inducers - to determine whether illusions combining several attributes can be perceived. The results suggest that the visual system is highly effective in completing a percept. The perception of an illusory figure is spatially scale invariant when perceived at threshold. The processing time and the number of fixations modify the percept, making the perception of the illusion more probable in various viewing conditions. Furthermore, the fact that the illusion can be perceived when only one inducer is physically present at any given moment indicates the potential of single inducers. Apparently, modelling illusory figure perception will require a combination of low-level, local processes and higher-level integrative processes. Our studies with stimuli combining several attributes relevant to object perception demonstrate that the perception of an illusory figure is flexible and is maintained also when it contains colour and volume and when shown in movement. All in all, the results confirm the assumed importance of the visual processes related with the perception of illusory figures in everyday viewing. This is indicated by the variety of inducer modifications that can be made without destroying the percept. Furthermore, the illusion can acquire additional attributes from such modifications. Due to individual differences in the perception of illusory figures, universal values for absolute performance are not always meaningful, but stable trends and general relations do exist.

Pelaamiskokemukset ja pelaamisen yksilöllisten merkitysten yhteys flow n kokemiseen

The main goal of this study was to explore experiences induced by playing digital games (i.e. meaning of playing). In addition, the study aimed at structuring the larger entities of gaming experience. This was done by using theory-driven and data grounded approaches. Previously gaming experiences have not been explored as a whole. The consideration of gaming experiences on the basis of psychological theories and studies has also been rare. The secondary goal of this study was to clarify, whether the individual meanings of playing are connected with flow experience in an occasional gaming situation. Flow is an enjoyable experience and usually activities that induce flow are gladly repeated. Previously, flow has been proved to be an essential concept in the context of playing, but the relations between meanings of playing and flow have not been studied. The relations between gender and gaming experiences were examined throughout the study, as well as the relationship between gaming frequency and experiences. The study was divided into two sections, of which the first was composed according to the main goals. Its data was gathered by using an Internet questionnaire. The other section covered the themes that were formulated on the basis of the secondary aims. In that section, the participants played a driving game for 40 minutes and then filled in a questionnaire, which measured flow related experiences. In both sections, the participants were mainly young Finnish adults. All the participants in the second section (n = 60) had already participated in the first section (n = 267). Both qualitative and quantitative research techniques were used in the study. In the first section, freely described gaming experiences were classified according to the grounded theory. After that, the most common categories were further classified into the basic structures of gaming experience, some according to the existing theories of experience structure and some according to the data (i.e. grounded theory). In the other section flow constructs were measured and used as grouping variables in a cluster analysis. Three meaningful groups were compared regarding the meanings of gaming that were explored in the first section. The descriptions of gaming experiences were classified into four main categories, which were conceptions of the gaming process, emotions, motivations and focused attention. All the theory-driven categories were found in the data. This frame of reference can be utilized in future when reliability and validity of already existing methods for measuring gaming experiences are considered or new methods will be developed. The connection between the individual relevance of gaming and flow was minor. However, as the scope was specified to relations between primary meanings of playing and flow, it was noticed that attributing enjoyment to gaming did not lead to the strongest flow-experiences. This implies that the issue should be studied more in future. As a whole this study proves that gamer-related research from numerous vantage points can benefit from concentrating on gaming experiences.

Koulukasvatusta teknologisoituvaan yhteiskuntaan : Kansakoulun opetussuunnitelman rakentuminen, 1945-1952

Education for a Technological Society. Public School Curriculum Construction, 1945-1952. The subject of my research is the significance of technology in the construction process of the public school curriculum during the years 1945-1952. During the period the war reparation and rebuilding placed demands and actions to rationalise and dramatise industry and agriculture. Thereby the ambitions of building a technological country and the reformation of curriculum took place simultaneously. Fordistian terms of reference, of which the principles were mass production, rationalisation and standardisation, a hierarchical division of labour and partition of assignments, provided a model for the developing curriculum. In the research the curriculum is examined as an artefact, which shapes socio-technically under the influence of social and technical factors. In the perspective of socio-technical construction the artefact is represented by the viewpoints of members of relevant social groups. The groups give meaning to the curriculum artefact, which determines the components of the curriculum. The weakness of the curriculum was its ineffectiveness, which was due to three critical problems. Firstly, the curriculum was to be based on scientific work, which meant the development of schools through experiments and scientific research. Secondly, the civilised conseption in the curriculum was to be composed of theoretical knowledge, as well as practical skills. Practical education was useful for both the individual and society. Thirdly, the curriculum was to be reformed in a way that the individuality of the pupil would be taken into account. It was useful for the society that talents and natural abilities of every pupil were observed and used to direct the pupil to the proper place in the social division of labour, according to the "right man in a right place" principle. The solutions to critical problems formed the instructions of the public school curriculum, which described the nature and content of education. Technology and its development were on essential part of the whole school curriculum process. The quality words connected to the development of technology - progress, rationality and effectiveness - were also suitable qualifiers and reasons for the reform of the curriculum. On the other hand, technology set a point of comparison and demand for the development of all phases of education. The view of technology was not clearly deterministic - it was also possible to shape technological society with the help of education. The public school curriculum process indicates how originally the principles of technological systems were shaped to the language of education and accepted in educational content.

Becoming a teacher: emerging teacher identity in mathematics teacher education

This research examines three aspects of becoming a teacher, teacher identity formation in mathematics teacher education: the cognitive and affective aspect, the image of an ideal teacher directing the developmental process, and as an on-going process. The formation of emerging teacher identity was approached in a social psychological framework, in which individual development takes place in social interaction with the context through various experiences. Formation of teacher identity is seen as a dynamic, on-going developmental process, in which an individual intentionally aspires after the ideal image of being a teacher by developing his/her own competence as a teacher. The starting-point was that it is possible to examine formation of teacher identity through conceptualisation of observations that the individual and others have about teacher identity in different situations. The research uses the qualitative case study approach to formation of emerging teacher identity, the individual developmental process and the socially constructed image of an ideal mathematics teacher. Two student cases, John and Mary, and the collective case of teacher educators representing socially shared views of becoming and being a mathematics teacher are presented. The development of each student was examined based on three semi-structured interviews supplemented with written products. The data-gathering took place during the 2005 2006 academic year. The collective case about the ideal image provided during the programme was composed of separate case displays of each teacher educator, which were mainly based on semi-structured interviews in spring term 2006. The intentions and aims set for students were of special interest in the interviews with teacher educators. The interview data was analysed following the modified idea of analytic induction. The formation of teacher identity is elaborated through three themes emerging from theoretical considerations and the cases. First, the profile of one s present state as a teacher may be scrutinised through separate affective and cognitive aspects associated with the teaching profession. The differences between individuals arise through dif-ferent emphasis on these aspects. Similarly, the socially constructed image of an ideal teacher may be profiled through a combination of aspects associated with the teaching profession. Second, the ideal image directing the individual developmental process is the level at which individual and social processes meet. Third, formation of teacher identity is about becoming a teacher both in the eyes of the individual self as well as of others in the context. It is a challenge in academic mathematics teacher education to support the various cognitive and affective aspects associated with being a teacher in a way that being a professional and further development could have a coherent starting-point that an individual can internalise.

Do UNESCO Schools in Finland Prepare Their Students for the Future? : A Study of Their School-based Curriculums

The purpose of the research was to study how Finnish lower-stage schools participating in the international network of UNESCO schools, also called the Associated Schools Project (ASP), prepare their students for the future at the level of their school-based curriculums. In the research, the future trends were discussed, and the importance of their consideration in educational practice was explained from a global viewpoint: Based on the examination of today's problematic world state, and development trends characterized by globalization, the challenges and demands set for schooling and education in the future were discussed. Understanding the significance of an individual's action and responsibility was considered to be the central resource for building a more just and sustainable future. The study was grounded on a theoretical model developed by the researcher, which combined the models of Dalin & Rust (1996) and UNESCO (Delors et al. 1996) about future-oriented learning. The model consists of four basic elements of curriculum; "Nature", "Culture", "Myself", and "Others", and four dimension of learning; "Learning to know", "Learning to do", "Learning to live together" and "Learning to be". The model represents the holistic aspect of educational theory, and its aim is to maintain a balance between its different components. The research material composed of ten lower-stage UNESCO schools' school-based curriculums. They were analyzed using the theoretical model by the methology of content analysis. The research results were notably consistent between the different schools. They showed cultural learning and learning concerned with "myself" to be clearly more emphasized than learning referring to nature and other people. In addition, they reflected the central position of subjects, knowledge and skills, thus leaving the development of the pupils' personalities, and particularly learning concerned with living with other people, in a marginal role. The question about whether the schools prepare for the future interms of their curriculums, was discussed in the light of the results. The research offered a way and a model to approach the relationship between education and the future, and to evaluate schools' future-orientation. Based on the results, the schools are suggested to lay more stress on learning concerned with nature and other people, and focus more on developing the mental capasities of their pupils and competencies they need for living with other people. Above all, what the present societies require of schools is education which produces balanced and broadly aware human beings who have the mental strength to face the challenges of the future and abilities to direct it along the lines they desire. Keywords: future, curriculum, content analysis

Oncolytic Adenoviruses for Gynecologic Cancer

Gene therapy is a promising novel approach for treating cancers resistant to or escaping currently available modalities. Treatment approaches are based on taking advantage of molecular differences between normal and tumor cells. Various strategies are currently in clinical development with adenoviruses as the most popular vehicle. Recent developments include improving targeting strategies for gene delivery to tumor cells with tumor specific promoters or infectivity enhancement. A rapidly developing field is as well replication competent agents, which allow improved tumor penetration and local amplification of the anti-tumor effect. Adenoviral cancer gene therapy approaches lack cross-resistance with other treatment options and therefore synergistic effects are possible. This study focused on development of adenoviral vectors suitable for treatment of various gynecologic cancer types, describing the development of the field from non-replicating adenoviral vectors to multiple-modified conditional replicating viruses. Transcriptional targeting of gynecologic cancer cells by the use of the promoter of vascular endothelial growth factor receptor type 1 (flt-1) was evaluated. Flt-1 is not expressed in the liver and thus an ideal promoter for transcriptional targeting of adenoviruses. Our studies implied that the flt-1 promoter is active in teratocarcinomas.and therefore a good candidate for development of oncolytic adenoviruses for treatment of this often problematic disease with then poor outcome. A tropism modified conditionally replicating adenovirus (CRAd), Ad5-Δ24RGD, was studied in gynecologic cancers. Ad5-Δ24RGD is an adenovirus selectively replication competent in cells defective in the p16/Rb pathway, including many or most tumor cells. The fiber of Ad5-Δ24RGD contains an integrin binding arginine-glycine-aspartic acid motif (RGD-4C), allowing coxackie-adenovirus receptor independent infection of cancer cells. This approach is attractive because expression levels of CAR are highly variable and often low on primary gynecological cancer cells. Oncolysis could be shown for a wide variety of ovarian and cervical cancer cell lines as well as primary ovarian cancer cell spheroids, a novel system developed for in vitro analysis of CRAds on primary tumor substrates. Biodistribution was evaluated and preclinical safety data was obtained by demonstrating lack of replication in human peripheral blood mononuclear cells. The efficicacy of Ad5-Δ24RGD was shown in different orthotopic murine models including a highly aggressive intraperitoneal model of disseminated ovarian cancer cells, where Ad5-Δ24RGD resulted in complete eradication of intraperitoneal disease in half of the mice. To further improve the selectivity and specificity of CRAds, triple-targeted oncolytic adenoviruses were cloned, featuring the cyclo-oxygenase-2 (cox-2) promoter, E1A transcomplementation and serotype chimerism. Those viruses were evaluated on ovarian cancer cells for specificity and oncolytic potency with regard to two different cox2 versions and three different variants of E1A (wild type, delta24 and delta2delta24). Ad5/3cox2Ld24 emerged as the best combination due to enhanced selectivity without potency lost in vitro or in an aggressive intraperitoneal orthotopic ovarian tumor model. In summary, the preclinical therapeutic efficacy of the CRAds tested in this study, taken together with promising biodistribution and safety data, suggest that these CRAds are interesting candidates for translation into clinical trials for gynecologic cancer.

Adenoviral gene therapy for non-small cell lung cancer

Adenoviral gene therapy is an experimental approach to cancer refractory to standard cancer therapies. Adenoviruses can be utilized as vectors to deliver therapeutic transgenes into cancer cells, while gene therapy with oncolytic adenoviruses exploits the lytic potential of viruses to kill tumor cells. Although adenoviruses demonstrate several advantages over other vectors - such as the unparalleled transduction efficacy and natural tropism to a wide range of tissues - the gene transfer efficacy to cancer cells has been limited, consequently restricting the therapeutic effect. There are, however, several approaches to circumvent this problem. We utilized different modified adenoviruses to obtain information on adenovirus tropism towards non-small cell lung cancer (NSCLC) cells. To enhance therapeutic outcome, oncolytic adenoviruses were evaluated. Further, to enhance gene delivery to tumors, we used mesenchymal stem cells (MSCs) as carriers. To improve adenovirus specificity, we investigated whether widely used cyclooxygenase 2 (Cox-2) promoter is induced by adenovirus infection in nontarget cells and whether selectivity can be retained by the 3 untranslated region (UTR) AU-rich elements. In addition, we investigated whether switching adenovirus fiber can retain gene delivery in the presence of neutralizing antibodies. Our results show that adenoviruses, whose capsids were modified with arginine-glycine-aspartatic acid (RGD-4C), the serotype 3 knob, or polylysins displayed enhanced gene transfer into NSCLC cell lines and fresh clinical specimens from patients. The therapeutic efficacy was further improved by using respective oncolytic adenoviruses with isogenic 24bp deletion in the E1A gene. Cox-2 promoter was also shown to be induced in normal and tumor cells following adenovirus infection, but utilization of 3 UTR elements can increase the tumor specificity of the promoter. Further, the results suggested that use of MSCs could enhance the bioavailability and delivery of adenoviruses into human tumors, although cells had no tumor tropism per se. Finally, we demonstrated that changing adenovirus fiber can allow virus to escape from existing neutralizing antibodies when delivered systemically. In conclusion, these results reveal that adenovirus gene transfer and specificity can be increased by using modified adenoviruses and MSCs as carriers, and fiber modifications simultaneously decrease the effect of neutralizing antibodies. This promising data suggest that these approaches could translate into clinical testing in patients with NSCLC refractory to current modalities.