La dernière décennie a connu une révolution dans le traitement du cancer en s'éloignant des médicaments conventionnels qui ciblent directement la tumeur (comme les chimiothérapies et les thérapies moléculaires ciblées) au profit des immunothérapies, et en particulier les inhibiteurs des "checkpoint" immunitaires. Ces immunothérapies libèrent sélectivement le système immunitaire de l'hôte contre la tumeur et ont démontré une rémission durable sans précédent chez des patients atteints de cancers que l'on croyait incurables, comme le mélanome métastatique, le carcinome rénal métastatique et les stades avancés du cancer du poumon non à petites cellules. Cependant, plus de la moitié des patients ne répondent pas à ces traitements, et sont donc contraints à recevoir d’autres traitements potentiellement toxiques et coûteux. Face aux résultats prometteurs des immunothérapies anti‐PD1/PD‐L1, la recherche de nouvelles cibles/marqueurs moléculaires permettant d'améliorer l'efficacité et de permettre un traitement personnalisé s'est intensifiée. Nos travaux portent sur l’étude de la protéine Sequestosome 1 (SQSTM1/p62) qui est un substrat de l'autophagie sélective et une plateforme de signalisation impliquée dans l’agressivité tumorale. Nous mettons en évidence l’implication de SQSTM1/p62 dans l'inflammation tumorale et dans l’évasion immunitaire et ceci grâce à la stabilisation du messager de PD‐L1. Nous observons que la surexpression tumorale de SQSTM1/p62 caractérise les tumeurs infiltrées et immunosuppressives qui répondent le mieux aux anti‐PD1/PD‐L1. Ainsi, nous proposons SQSTM1/p62 en tant que biomarqueur potentiel et cible thérapeutique pour améliorer la stratification des patients susceptibles de répondre aux immunothérapies. / The past decade has witnessed a new revolution in cancer treatment by shifting away from the conventional drugs that directly target the tumor (such as chemotherapies and molecular targeted therapies) towards immune‐based therapies, and in particular the so‐called immune checkpoint inhibitors. These immunotherapies selectively release the host immune system against the tumor and have shown unprecedented durable remission for patients with cancers that were thought incurable such as metastatic melanoma, metastatic renal cell carcinoma and late stages of non‐small cell lung cancer. However, more than half of the patients fail to respond to these treatments and are therefore forced to receive other potentially toxic and costly treatments. In this era of promising anti‐PD1/PD‐L1 immunotherapies, the quest for reliable molecular markers/therapeutic targets that would enhance the effectiveness and allow a personalized adaptation of the treatments has intensified. In our work we focus on the scaffold protein and autophagy adaptor Sequestosome 1 (SQSTM1/p62), and we show that it is required for tumor inflammation and immune evasion. We find that SQSTM1/p62 tumor overexpression characterizes infiltrated and immunosuppressive tumors and predicts for response to anti‐PD1/PD‐L1 therapies. Thus, we propose SQSTM1/p62 as a potential biomarker and a therapeutic target to improve the stratification of patients to immunotherapies.

Les thérapies anticancéreuses nécessitent aujourd’hui une approche plus ciblée. L’approche immunologique est devenue dans cette optique un enjeu d’importance notamment grâce à sa capacité d’atteindre de manière plus spécifique des cibles tumorales. Récemment, mon équipe a identifié des peptides antigéniques issus de la préprocalcitonine (ppCT), qui étaient capables d’induire une réponse T cytotoxique spontanée chez un patient atteint de cancer bronchique non à petites cellules bénéficiant d’une longue survie et correspondent donc à des candidats potentiels dans des approches vaccinales. Dans ma thèse, je fournis une preuve de concept préclinique pour un vaccin fondé sur la ppCT à usage thérapeutique contre le cancer du poumon. Cette approche est optimisée en la combinant avec un anticorps monoclonal anti-PD- 1. En plus, j'ai identifiée de nouveaux épitopes issus de cet antigène et j'ai construit un lentivirus codant la ppCT pour des perspectives thérapeutiques. / Cancer therapies today require a more targeted approach to optimize the anti-tumor response. In this context, the immunological approach has become an important issue, mostly through the identification of specific tumor-associated antigens (TAA). Recently, my team identified new tumor antigens derived from the preprocalcitonin (ppCT) which were able to induce a spontaneous cytotoxic T-cell response with long term survival in patients with non-small cell lung cancer and therefore correspond to be potential candidates for vaccine approaches. In my thesis, I provide a preclinical proof of concept for the ppCT peptide vaccine for the therapeutic use against lung cancer which is optimized by combining the treatment with the monoclonal antibody anti-PD-1, nivolumab. In addition, I identified new epitopes from this Ag and constructed a lentivirus encoding ppCT for further therapeutic perspectives.

Bibliographische Beschreibung Pharmakokinetisch/pharmakodynamische Untersuchung zur in vitro Aktivtität von Levofloxacin und Moxifloxacin gegenüber B. fragilis und E. coli in Mono- und Mischkultur Universität Leipzig, Dissertation 92 S., 190 Lit., 25 Abb., 20 Tab., 3 Anlagen Referat: Bei intraabdominellen Infektionen findet sich häufig ein polymikrobielles Erregerspektrum aus fakultativ und obligat anaeroben Bakterien. Natürliches Habitat der dabei am häufigsten isolierten Erreger E. coli und B. fragilis ist der gastrointestinale Trakt. Durch Störungen der Darmwandintegrität und nachfolgendem Eindringen der Bakterien in eine sterile Umgebung, wie beispielsweise der Peritonealhöhle, kann es zur Infektion kommen. Die häufigste Form der intraabdominellen Infektionen ist die sekundäre Peritonitis. Die Therapie erfolgt chirurgisch, begleitet von einer antibiotischen Therapie. Dabei sind Kenntnisse über Wirksamkeit und Empfindlichkeit der Erreger gegenüber den verwendeten Antibiotika von entscheidender Bedeutung. In dieser Arbeit wurden die MHK-Werte von vier B. fragilis und vier E. coli Stämmen für Levofloxacin und Moxifloxacin bestimmt, wobei ein B. fragilis und drei E. coli Stämme resistent gegenüber Levofloxacin und Moxifloxacin waren. Anschließend wurden mit einem in vitro PK/PD-Modell die pharmakodynamischen Effekte von Levofloxacin und Moxifloxacin in Mono- und Mischkulturen von B. fragilis und E. coli untersucht. Die Monokulturversuche mit E. coli Stämmen wurden sowohl unter aeroben als auch anaeroben Bedingungen durchgeführt. Durch die Untersuchung von Aktivität und Wirksamkeit von Levofloxacin und Moxifloxacin in vitro können Aussagen über eine mögliche Verwendung bei intraabdominellen Infektionen getroffen werden. Levofloxacin wirkte auf den sensiblen E. coli Stamm nur unter aeroben Bedingungen bakterizid, nicht jedoch unter anaeroben Bedingungen. Hingegen wirkte Moxifloxacin in aerober und anaerober Umgebung bakterizid auf diesen E. coli Stamm. In den Mischkulturen zeigte Moxifloxacin eine bessere in vitro Aktivität als Levofloxacin, wobei Moxifloxacin allerdings auch nur eine moderate Aktivität hatte. Aufgrund der Ergebnisse könnte Moxifloxacin dennoch eine theraupeutische Option bei der Behandlung intraabdomineller Infektionen bieten. Der Einsatz dieser Substanzen sollte jedoch nicht unkritisch erfolgen.

School reform efforts ultimately affect the students, but what is seldom looked at is how they affect teachers. This phenomenological study examined the experiences of teachers with regards to web-based professional development during a systemic change. The purpose of this qualitative study was to generate an in-depth understanding of the lived experiences of 6 teachers in a Southeastern state who had participated in the initial process of implementing organizational changes and the diffusion of the new state educational standards. Rogers's diffusion of innovation theory served as the study's conceptual framework. Research questions focused on the perspectives of teachers regarding the impact of web-based professional development on implementing the new state standards, and the perceived barriers and challenges faced in their attempts to make the implementation of the new state standards successful. Interview data were analyzed using first- and second-level coding to identify external and internal factors related to the research questions and themes that emerged across all interview transcripts. Key findings indicted that teachers perceived that they did not receive adequate professional development or planning time to implement the new standards. This study has implications for social change on an organizational and individual level. On an organizational level, districts can provide K-12 teachers with an implementation process that allows adequate planning time and proper professional development that enhances their pedagogical needs by using a framework more aligned to the diffusion innovation theory. Teachers can then better plan instruction with ample time to acquire, process, and implement new knowledge, allowing them to improve their pedagogical practice.

The immune checkpoint blockade is a novel approach of cancer therapy, which markedly enhanced treatment efficacy of several cancer types. However, the frequency of cancer patients non-responding to this treatment is high. Establishment of predictive markers to distinguish patients suitable for the immune checkpoint blockade would enhance the number of patients receiving benefit from the therapy. This dissertation thesis focuses on the enhancement of efficacy of immune checkpoint inhibitors (ICIs) and predictive markers in experimental models of mouse tumours induced by TC-1 and TC-1/A9 cell lines and its clones with deactivation of interferon (IFN)-γ signalling (TC-1/dIfngr1 and TC-1/A9/dIfngr1), or CD80 molecule (TC-1/dCD80-1). IFN-γ is presumed to be the main inducer of programmed death ligand 1 (PD-L1) and a major histocompatibility complex I (MHC-I). Moreover, PD-L1 expression may predict sensitivity to PD-1/PD-L1 blockade. Non-functional IFN-γ signalling or downregulated MHC-I expression has been associated with resistance to ICIs in some patients. We found that IFNs type I (IFN-α and IFN-β) induced the expression of PD-L1 and MHC-I on TC-1/A9/dIfngr1 tumour cells with reversible downregulation of both molecules. We also showed that deactivation of IFN-γ signalling in TC-1/A9 cells was not a...

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This thesis contextualises the life and work of John Josias Conybeare (1779-1824), one of the first to hold the Rawlinson chair of Anglo-Saxon at the University of Oxford, and considers his contribution to the development of Old English studies as a discipline. I argue that he has been unduly marginalised as a result of posthumous criticism that has failed to acknowledge the extent of his contribution to Old English scholarship. Part I of the thesis considers this issue from the perspective of John Josias himself, setting him in the context of the period in which he lived and the longer continuum of Old English studies as a whole. It also reconstructs what is known of his associates and friends, illustrating that he occupied a central position among the literati of his day alongside figures such as Thomas Gaisford (1779-1855), Joseph Hunter (1783-1861), Robert Southey (1774-1843), and Sharon Turner (1768-1847). Part II focuses on Illustrations of Anglo-Saxon Poetry (1826), the scholar’s most well-known and significant contribution to Old English studies, which was published posthumously by John Josias’ brother, William Daniel (1787-1857), and widow, Mary (1790-1848). This section traces the composition of the book from its first conception through to its final publication and critical reception, using previously unpublished correspondence to disambiguate the contribution of the author from that of his editors. This is followed by an examination of John Josias’ ability as an early editor of Old English, which critically evaluates some of his transcriptions, translations, and interpretations as they appeared in Illustrations of Anglo-Saxon Poetry, with particular attention to his work on Widsith and the Exeter Book. Part III contains transcripts of unpublished correspondence and other documents that provide details about John Josias’ life and, in particular, about the preparation and posthumous publication of his Illustrations of Anglo-Saxon Poetry. This thesis, which brings together genealogical, scholarly, and archival materials, constitutes the first comprehensive study of his life and work. My reassessment of his scholarship concludes that John Josias in fact made a substantial and influential contribution to the discipline, deserving of greater recognition today.

Previously, research on multinational teamwork with various nationalities and cultures involved, which looked at the aspect of communication, was largely based on the examination of specific facilitators and barriers to its communication (i.e. Watson, et al., 1993; Hofner Saphiere, 1996). There it was found that multinational teams might have specific communication facilitators dependent upon the cultures involved. This is reflected in the theoretical development in the field of intercultural management, which gives guidance for culturally complex team settings (i.e. Trompenaars, 1993). The complexity managers’ face is increasing further through China’s involvement in the implementation of globalization strategies (Podsiadlowski, 2002). Recently, the relevance of China’s involvement has been increasing for Germany, in particular given Chinese companies’ investments in Germany. Therefore, the study of various nationalities in one research project has been reconsidered and currently there is new demand for studies, which seek to understand the complexity of Sino-German teamwork (Podsiadlowski, 2002). However, besides non-research based literature, research focusing solely on Sino-German teamwork occupies a marginal place (i.e. Podsiadlowski, 2002). Additionally, much of the multinational team research (for example, Watson, et al., 1993) looked at outcomes and disregarded the team members’ experience itself by using quantitative methods. It provided an understanding influenced by positivistic perspectives, saying that certain factors are pre-conditions for successful team communication. This study recognized these positions, but questioned the positivist bias demonstrated there. Throughout this research, associated factors were understood as being non-linear and interrelated, representing the complexity managers are experiencing. As a result this study argued that Chinese and Germans working in teams were marginalised in the intercultural management research field until today and their needs were not addressed by much of the existing research. These led to my conclusion that there is a need to conduct research that for the first time is informed by a postmodern theoretical framework that seeks to privilege multiplicity and diversity and that also attends to the silences surrounding this group. Therefore, a postmodern framework provided the theoretical lens through which this research, and its authorial, methodological, and interpretive characteristics were construed and represented. This perspective emphasised local stories about experiences, attended to ‘difference’, was concerned with the multiple nature of ‘reality’, and recognised the importance of language as a medium for the social construction of what may be considered ‘truth’ (Cheek, 2000). Narrative inquiry represented in this thesis the postmodern epistemological framework to understand subjective experiences by exploring the stories of twelve Chinese and German participants and the meanings derived from these. These stories were themselves experiences structured and recalled inside wider cultural and social contexts (Kirkman, 2002; Webster & Mertova, 2007). The socio-cultural contexts were woven into the language used by the participants to explain their experiences and signified the meanings of these experiences. However, Chinese and Germans not only differed with regards to language and language variety, but also with respect to their patterns of usage and how meaning was generated in interactive situations on the basis of socio-cultural knowledge. Therefore, my narrative inquiry took into account both linguistic and sociocultural aspects and addressed the relations between interactive communication strategies and larger social and cultural phenomena. Within the context presented above, the focus and contribution of this study were the descriptions of the intercultural communication experiences of members of Sino- German teams and the analysis of factors relating to interferences in communication to provide a thicker explanation of communication interferences in intercultural communication, where theoretical attempts so far remained rather fragmented, and to contribute findings from different perspectives on what has traditionally been viewed from a positivistic standpoint. Through sharing the participants’ lived experiences of working and communicating with Chinese and Germans and vice versa, a number of linguistic and socio-cultural factors influencing communication behaviour and causing interferences were uncovered. The factors identified from the study resonate with a number of factors previously established in existing multinational teamwork research and whilst others contributed new information that adds to the understandings of the meanings that may be made from such experience of communication interferences. Comparing the experiences related by Chinese participants with those related by German participants showed a substantial consensus with regards to the communication interferences experienced in Sino-German teams and the factors relating to these interferences, as well as observable differences in communication behaviours. The lack of foreign language proficiency on the side of both Chinese and German individuals was stated as being a major factor for communication interferences that was further enhanced through the strong linguistic barrier between these two languages. Good language proficiency minimises the occurrence of misunderstandings and miscommunications. It allows better personal contact between the team members since it better enables people to establish personal contacts and relationships, as well as to use an interlinked communication structure that allows informal communication and therefore compliance with the Chinese cultural ‘rules of the game’. However, foreign language proficiency alone is not a guarantee for successful intercultural communication in Sino-German teams. This study also analysed, in addition to the practical and theoretical significance of language and language skills, the cultural influences on the communication between Chinese and German team members. Many participants were either unaware (especially on the German side) or only partially aware of the fact that differences in communication behaviour are based on different culture-specific communication conventions and strategies. It was found that intercultural awareness on the part of individuals in a team, meaning the knowledge and awareness of culture-specific conventions and norms, had a positive influence on communication within the team. Knowledge of the meaning of the two key terms mianzi and guanxi plays an important role in Sino-German teams. On the other hand, an ethnocentric perspective on either one or both sides inevitably results in mutual negative attributions. This findings added to the understanding how this communication could be improved and, most importantly, as a prerequisite for actions of any kind to achieve improvements, to draw the attention of German team members to the relevance of communication when working with their Chinese colleagues and vice versa. Furthermore, the study functioned as an act of empowerment, a way to give voice to managers and team members who were methodologically not heard.

Zusammenfassung Neueste Daten deuten daraufhin, dass maligne Tumoren der immunologischen Überwachung über eine Herunterregulierung der T-Zell-Aktivierung mittels eines PD-1 (programmed death 1)/ PDL-1/PDL-2 Signals ausweichen. Dies führt offensichtlich zu einer herabgesetzten Immunantwort und kann somit das Tumorwachstum fördern. Das Oberflächenmolekül PD-1, welches auf T- und B-Zellen, myeloischen Zellen und auf vielen menschlichen Karzinomen exprimiert wird, gehört zu der CD28 Familie, und PDL-1 (B7H1) und PDL-2 (B7DC) wurden als Liganden zu PD-1 beschrieben. Der CD28/B7 Signalweg gehört zu der Gruppe kostimulatorischer Signale, die beim zustande kommen einer T-Zell-gerichteten Immunantwort als zweites kostimulatorisches Signal notwendig sind. In dieser Arbeit wurde die molekulare Expression von PD-1, PDL-1 und PDL-2, von Zytokinen und T-Zell-Subpopulationen im Tumorgewebe von 81 Patienten analysiert, die sich einer kurativen oder palliativen Operation (gemäß UICC- Stadien I-IV) eines primären kolorektalen Karzinoms unterzogen hatten. Es zeigte sich auf Protein- als auch auf molekularer Ebene erstmals, dass PDL-1 und PDL-2 im Tumorgewebe fortgeschrittener Tumorstadien (UICC III/IV) signifikant überexprimiert wurden, PD-1 dagegen erniedrigt exprimiert war. PD-1 wurde dagegen deutlich auf infiltrierenden CD4+ Zellen bei Patienten fortgeschrittener Tumorstadien (UICC III/IV) detektiert, wohingegen PDL-1 auf CD4+ Zellen in frühen Stadien gefunden wurde. Im Vergleich zu den frühen Stadien (UICC I/II) wurde eine grössere Anzahl an T-Zellen mit regulatorischem Charakter in den Tumorstadien III/IV beobachtet. Letzteres würde dem Tumor im Bezug auf sein fortschreitendes Wachstum von Vorteil sein, da regulatorische T-Zellen T-Effektorzellen inhibieren können. Im Tumorgewebe fand sich zudem eine verminderte Expression an IFN-gamma, welches unter anderem T-Effektorzellen aktiviert und damit eine Immunantwort verstärkt. Das Zytokin IL-10, welches mit regulatorischen T-Zellen, aber auch mit T-Helfer (Th)2-Zellen und Tumorgewebe assoziiert ist und antiinflammatorische Eigenschaften besitzt, wurde in höheren Stadien verstärkt nachgewiesen. Dadurch verschafft es dem Tumor einen Überlebensvorteil. Die Beobachtungen in dieser Arbeit zeigen, dass PDL-1 und PDL-2 eine Schlüsselrolle während der Tumorprogression zukommen. Regulatorische T-Zellen sind offensichtlich in den Prozeß der Immunantwort gegen den Tumor eingebunden. Die deutliche PDL-1- und PDL-2-Expression auf T-Zellen insbesondere in frühen Tumorstadien lässt darauf schließen, dass die PD-1/PDL-1- bzw. PD-1/PDL-2-Interaktion inhibitorische Signale zwischen Tumorzellen und den T-Zellen vermittelt. In fortgeschrittenen Stadien (UICC III/IV) waren diese kostimulatorischen Signale auf den T-Zellen nur vermindert vorzufinden. Dies hat zur Folge, dass der Tumor sein Wachstum ungehindert fortsetzen kann, da die anti-Tumor-T-Zell-Antwort, die den Tumor normalerweise in seiner Expansion beeinträchtigt, gestört ist. Es wird somit festgestellt, dass eine Blockade der untersuchten Oberflächenmoleküle PDL-1 oder PDL-2 auf Tumorzellen eine wertvolle Option in der Immuntherapie des humanen kolorektalen Karzinoms darstellen könnte. Angesichts der diskutierten Tatsachen im Hinblick auf das Verhalten der regulatorischen T-Zellen in höheren Tumorstadien könnte sich eventuell eine Option damit eröffnen, die regulatorischen T-Zellen mittels eines spezifischen Antikörpers gegen PDL-1 und/oder PDL-2 zu beeinflussen, um somit die hemmenden Auswirkungen gegenüber der anti-Tumor-Immunantwort zu verhindern oder zu revidieren. / Summary Recent data have suggested that malignant tumors are able to escape from the immunological surveillance on a downregulation of the T cells via a PD-1 (programmed death 1) / PDL-1/PDL-2 signal. This obviously leads to a reduced immune response and thus may promote tumor growth. The surface molecule PD-1, which is expressed on T and B cells, myeloid cells and on many human carcinoma, belongs to the CD28 family, and PDL-1 (B7H1) and PDL-2 (B7DC) are ligands to PD-1. The CD28/B7 signal belongs to the group of costimulatory pathways, which is needed for a T-cell-directed immune response as a second costimulatory signal. In this work, the molecular expression of PD-1, PDL-1 and PDL-2, cytokines and T-cell-subpopulations was analyzed in tumor tissue of 81 patients, which have undergone a curative or palliative surgery (according UICC- stages I-IV) of a primary colorectal cancer. For the first time it was shown on the protein and molecular level, that PDL-1 and PDL-2 were significantly overexpressed in tumor tissue of advanced tumor stages (UICC III/IV), the expression of PD-1, on the other hand was decreased. PD-1 was much more detected on infiltrating CD4+ cells in patients of advanced tumor stages (UICC III/IV), while PDL-1 was found on CD4+ cells in the early stages. In comparison to the early stages (UICC I/II), a larger number of T cells with regulatory character in the tumor stage III/IV was observed. The latter would be an advantage for the tumor in relation to its progressive growth, because regulatory T cells are able to inhibit T-effector-cells. In tumor tissue the expression of IFN-gamma was also reduced, which among others activate T-effector-cells and thus reinforced an immune response. The cytokine IL-10, which is associated with regulatory T cells, but also with T-helper(Th)2-cells and tumor tissue, has antiinflammatory properties and was demonstrated enhanced at higher stages. Thus it gives the tumor a survival advantage. The observations in this study show that PDL-1 and PDL-2 plays a key role during tumor progression. Regulatory T cells are obviously involved in the process of immune response against the tumor. The significant PDL-1- and PDL-2-Expression on T-cells, particularly in the early stages of tumor suggests that the PD-1/PDL-1- or PD-1/PDL-2-interaction mediated inhibitory signals between tumor cells and the T-cell. In advanced stages (UICC III/IV) the costimulatory signals on T-cells were decreased. This means that the tumor's growth can continue unhindered, because the anti-tumor-T-cell-response which the tumor usually affected is disrupted in its expansion. It is thus found that a blockade of the investigated surface molecules PDL-1 and PDL-2 in tumor cells could be a valuable option in the immunotherapy of human colorectal cancer. Given the facts discussed in relation to the behavior of regulatory T cells in advanced tumor stages could possibly be an option to influence the regulatory T cells with a specific antibody against PDL-1 and / or PDL-2, thus to prevent or revise the inhibitory effects against the anti-tumor-immunresponse.

The automotive engineering process is characterized by a long and complex design process which starts with the first sketches in the preliminary design phase and proceeds to the final detailed CAD and physical models. In this process, every design phase includes different process steps and tasks which are closely interconnected with each other. Therefore the different design stages demand capable Computer Aided Design (CAD) systems which are able to handle the different kinds of design information created and manipulated in the process. Currently in automotive practice, parametric and associative (PA) CAD systems are widely applied in the product development process. Such systems allow design knowledge to be embedded in CAD models by means of rules and formulae. In addition, CAD parts and assemblies can be generated faster and easier by modification of design parameters and therefore there is a possibility to create different CAD model variants which are based on the same CAD model. The four key element of the following work are (a) to identify the problems during the design process with parametric and associative (PA) methods during a three year of study and also the analysis of the literature survey. Furthermore (b) in this study the author will develop and implement a newly developed PA design approach (PARAMASS) in a ―real‖ industrial context. Beside this the following work will (c) discuss the issues which are important during the implementation of the developed PA approach in an industrial surrounding. The last key element (d) is to develop an evaluation approach for the PARAMASS approach during the application in an industrial context. In this case the author will be able to do action research in the industry and get first hand information during the accomplishment of these key elements. This thesis presents the results of a research programme carried out using the design research methodology of Blessing and Chakrabarti, aimed at understanding the difficulties and challenges faced by designers in using PA CAD systems and then developing and evaluating an integrated approach to the creation of PA CAD models in an automotive power train design context. Firstly, this thesis presents a review of the state of the art in PA design methods and approaches and also reviews previous research on the development of methodologies for the construction of PA CAD models. It then presents results of a descriptive study of the use of PA CAD tools and methods in vehicle power train design in an automotive original equipment manufacturer and in companies in its supply chain using questionnaires, interviews, tests and other field studies with a number of practising engineers. This study identified a number of issues faced by designers in the use of PA CAD tools and allowed the requirements for improved methods for the use of PA CAD tools to be formulated and indicators identified for their evaluation. Based on the results of the descriptive study a new integrated parametric associative (PA) approach for the design process of power train components was created in a prescriptive study stage. The approach, called PARAMASS, allows designers to construct and modify models in a methodical way based on three main phases: a specification phase to prepare the relevant parameters and associative relationships, a structuring phase that allows part and assembly structures to be created and a modification phase in which the created parametric and associative information can be modified and changed. The method makes extensive use of predefined structures matrix approaches adapted from the Design Structure Matrix. The prescriptive study phase of the research was followed by a second descriptive study to evaluate and investigate in both a qualitative and quantitative way the changes achieved by the PARAMASS approach. The qualitative evaluation was based on the Goal Question Metric approach and showed that there are advantages related to the reusability aspects like learning, application and acceptance of the developed integrated approach. The quantitative evaluation was based on the Use Case approach and demonstrated good advantages in applying the developed approach, but dependent on the complexity of the created parts and assemblies.