Le stockage de l’énergie reste une problématique majeure pour le développement d’objets embarqués (Internet of Things) à faible facteur de forme. En effet, pour le stockage et la restitution d’énergie électrique, les dispositifs les plus couramment utilisés sont les batteries, les supercondensateurs et les condensateurs électrochimiques ou céramiques. Toutefois, le contexte de la miniaturisation nécessite de fabriquer des systèmes de stockage à forte densité d’intégration, compatibles avec des techniques d’intégration de type SIP (System in Package) et ultimement SoC (System on Chip). Or, les technologies connues dans l’art antérieur produisent des composants à forte épaisseur, via des filières technologiques exotiques, incompatibles avec une co-intégration directe sur des composants silicium. Pour répondre à ces exigences, nous proposons une nouvelle approche pour l’intégration de condensateurs de très faible épaisseur sur silicium. Ces condensateurs présentent une meilleure fiabilité et de meilleures performances en linéarité que les condensateurs céramiques et peuvent stocker une densité énergétique proche de celle d’un condensateur électrochimique.Cette thèse est axée sur la conception, le développement, la réalisation, la caractérisation électrique et fiabilité de capacités MIM (Métal/Isolant/Métal) à forte densité d’intégration et présentant une forte densité énergétique. Ces condensateurs sont modelés dans une nanostructure poreuse ordonnée et développée par un procédé électrochimique. Cette nanostructure 3D permet de décupler la surface spécifique développée, par rapport à une structure planaire simple ou une microstructure 3D telle qu’actuellement exploitée par la société IPDIA. Ce nanocomposant MIM comportant un isolant à base d’alumine, déposé par ALD (Atomic Layer Deposition) d’une épaisseur variant entre 15nm et 21nm. Pour cette gamme d’épaisseur, une densité de capacité de l’ordre de 200nF/mm² à 300nF/mm² est obtenue sur une simple structure MIM, avec un champ de claquage de l’ordre de 7MV/cm et une densité d’énergie volumique maximale de 1.3mWh/cm3. Cette dernière valeur est supérieure d’une décade aux technologies actuellement exploitées par la société IPDIA. Une attention particulière a été apportée à la réduction des parasites de la structure, et lui permettant ainsi de répondre à des transitions rapide en courant. Pour cela, la résistance série de ces structures a été optimisée par l’amélioration du contact entre les nanostructures MIM et les électrodes externes. La stabilité de la capacité MIM en température et en tension est comparable aux performances des technologies de référence IPDIA (respectivement avec un coefficient thermique de 193ppm/°C et un coefficient de tension de 489 ppm/V2), lesquelles sont basées sur une structure composite de type ONO (multicouche oxyde-nitrure). Elle est par ailleurs meilleure que celle observée pour les condensateurs céramiques multicouches disponibles sur le marché. Notre capacité présente également, une excellente robustesse en température et a été utilisée jusqu’à 375°C. Les performances démontrées sur les prototypes réalisés au cours de ce travail, permettent d’envisager un vaste domaine d’applications, incluant des applications de stockage, de filtrage de rails d’alimentation, de mise en forme de signaux analogiques et de puissance. Le niveau de maturité atteint sur les premiers démonstrateurs permet d’envisager un transfert industriel dans les mois à venir. / The energy storage components remain one of the limiting features for scaling of the Internet of Things objects. Indeed, the storage devices nowadays available as batteries, supercapacitors and electrochemical or ceramic capacitors are still quite bulky and remain incompatible with reduced aspect ratio, while roadmap toward miniaturization requires concept with high integration density compatible with integration techniques like SiP ((System in Package) and on longer term SoC (System on Chip). However, technologies known from the prior art, produce components with too large thickness, inflexible shape (mostly circular or rectangular), through exotic technologies that are incompatible with direct co-integration on silicon components. To overcome those limitations, we have proposed a novel approach for the integration of very low thickness capacitors. Those capacitors have better reliability and stability performances than ceramic capacitors and are able to store energy density approaching electrochemical capacitor.This thesis is focused on the development of the capacitive structure, the processing steps, its electrical and reliability characterization and finally the electrical optimization of MIM (Metal/Isolator/Metal) capacitors. Those capacitive structures are based on a porous and self-arranged nano-template obtained by an electrochemical process. Those nanostructures allow to increase the specific surface density with respect to conventional planar or microstructures that are currently exploited by IPDIA. The MIM structure consists of alumina dielectric, deposited by ALD (Atomic Layer Deposition) with a thickness between 15nm and 21nm. For this thickness, capacitance density is obtained in the range of 200nF/mm² and 300nF/mm² for a simple MIM nanostructure, with a breakdown field about 7 MV/cm and a maximum volumetric energy density of about 1.3mWh/cm3. This last value corresponds to a decade higher with respect to current IPDIA technologies. A specific optimization has been conducted to reduce structure parasitic, and thus enable faster current transition on switching events. For that, a technic to reduce the serial resistance between the MIM nanostructure and the external electrodes has been investigated. The temperature and voltage linearity of this MIM capacitor is on par with actual IPDIA reference technologies (respectively thermal coefficient of 193ppm/°C and quadratic voltage coefficient of 489 ppm/V²), which are based on an ONO composite dielectric (multi-layer nitride oxide). This performance is outperforming the Multi-Layer Ceramic Capacitors that are currently used for equivalent application. Furthermore, demonstration of operation up to 375°C has been demonstrated for this structure. With these capacitors it is envisioned to address a large span of applications, ranging from energy storage, to filtering of power rails, or analogic and power signal conditioning. The maturity obtained on demonstrators allows to envisage an industrial transfer in the coming months.

La densité des circuits intégrés n’a pas cessé d’augmenter depuis la découverte du transistor en 1947, à travers la réduction de la taille de leurs composants. Cependant, cette miniaturisation se heurte aujourd’hui à certaines barrières et la réduction de la longueur de grille des transistors ne permet plus à elle seule l’augmentation des performances globales des circuits intégrés. L’industrie de la microélectronique s’est donc tournée vers de nouvelles solutions d’intégrations hétérogènes visant à développer la diversification des fonctionnalités proposées par les circuits. Parmi ces solutions, l’intégration 3D consistant à empiler plusieurs puces de silicium les unes sur les autres à l’aide de « Through Silicon Vias » (TSV) apparait très prometteuse. Toutefois, de telles structures mettront du temps à atteindre leur maturité puisqu’elles requièrent l’évolution de tout l’écosystème industriel. Une solution intermédiaire en termes de maturité technologique réside dans l’utilisation de l’interposeur : un substrat aminci placé entre les puces haute densité et le « Ball Grid Array » faisant office de plateforme d’intégration permettant le placement côte à côte de puces hétérogènes ainsi que la réalisation d’une forte densité d’interconnexions. Cependant, l’ajout de l’interposeur dans le système a pour effet l’augmentation de l’impédance du réseau de distribution de puissance. L’intégration d’une capacité de découplage au sein de l’interposeur répond à cette problématique en assurant l’intégrité de l’alimentation dans des structures tridimensionnelles.L’objectif de cette thèse de doctorat consiste en l’étude de l’intégration d’un nouveau type de capacité intégrée au sein de l’interposeur silicium. Cette capacité basée sur un empilement Métal-Isolant-Métal (MIM) tridimensionnelle a pour particularité de traverser l’intégralité de l’épaisseur de l’interposeur et d’être co-intégrée avec les TSV.La première étape de l’étude de ce nouveau composant intégré a été la définition d’une architecture performante, réalisée à travers une étude de modélisation permettant l’évaluation de l’influence des nombreux paramètres géométriques et matériaux entrant en jeu. Cette étude a permis de mettre en avant les faibles valeurs d’ESR et d’ESL atteignable par la structure (de l’ordre du m et fH respectivement). Ensuite, la réalisation de la capacité a nécessité le développement de procédés de fabrication innovants permettant le dépôt d’un empilement MIM dans des matrices de vias profonds ainsi que sa co-intégration avec les TSV. Enfin, les performances du composant ont été évaluées à travers la réalisation et la caractérisation d’un démonstrateur de test ainsi qu’une campagne de simulations électromagnétiques par éléments finis. Une densité de capacité de 20 nF.mm-2 a été atteinte sur ce démonstrateur, offrant un gain d’un facteur supérieur à 6 par rapport à une structure planaire. / Integrated circuits density never stopped rising since the discovery of the transistor in 1947, through components size shrinking. However, this miniaturization now encounters barriers and reduction of transistor’s gate size alone no longer allows integrated circuits overall performances increase. Therefore, microelectronic industry turned to new heterogeneous integration solutions aiming to develop the diversification of functionalities offered by the circuits. Among these solutions, 3D integration involving stacking several silicon dies on top of each other with the help of Through Silicon Vias (TSV) appears to be promising. Nevertheless, such structures will take times to reach maturity since they require the evolution of the whole industrial ecosystem. A transitional solution in term of technological maturity lies in the use of the interposer: a thinned substrate placed between the high density silicon dies and the Ball Grid Array acting as an integration platform allowing side by side placement of heterogeneous dies as well as high density interconnections. However, the addition of the interposer in the system leads to the increase of the Power Delivery Network impedance. The integration of a decoupling capacitor on the interposer resolves this issue by ensuring power integrity within 3D structures.The objective of this PhD thesis consists in the study of different aspects of a new kind of integrated capacitor within the silicon interposer. This 3D Metal-Insulator-Metal (MIM) capacitor has the particularity to cross over the whole silicon interposer’s thickness and to be co-integrated with TSV.The first step of this new integrated component study has been the definition of an efficient architecture, achieved through a modeling study allowing the influence evaluation of the numerous geometrical and material parameters coming into play. This modeling study pointed out the low ESR and ESL values achievable by the structure (in the m and fH range respectively). Then, the fabrication of the capacitor required the development of innovative process steps allowing the deposition of a MIM stack in deep vias matrices as well as co-integration with TSV. Finally, component performances have been evaluated through the fabrication of a test demonstrator as well as a finites elements electromagnetic simulation campaign. A capacitance density of 20 nF.mm-2 has been reached on this demonstrator, showing an increase up to a factor 6 compared to a planar structure.

Ce document de thèse est divisé en deux parties indépendantes, la première partie décrit la synthèse et l'évaluation biologique de nouveaux analogues du composé anti-vasculaire, l'isocombretastatine A-4. Ce travail se situe à l'interface entre la chimie et la biologie.Des réactions séquentielles monotopes mettant en œuvre des réactions de couplage pallado-catalysées entre des N-tosylhydrazones et divers bromure de nitro-aryles et bromure de nitro-biaryles suivies d'une cyclisation réductrice ont conduit à la synthèse d’une chimiothèque d'indoles C2-, C3-, N-aryles et des carbazoles de vinyle avec une variété de substrats. De plus, cette méthodologie a permis d'explorer un nouveau mécanisme de synthèse inattendue d’indoles.L'étude biologique de ces nouvelles séries a montré que huit molécules sont dotées d’activités antiprolifératives intéressantes de l'ordre du nanomolaire contre les cellules humaines de cancer du côlon. Deux molécules ont présenté des activités très prometteuses, ayant des IC50 similaires à celle de l'isoCA-4.Par conséquent, cette partie a contribué à développer de nouvelles approches permettant l’accès rapide et simple à des molécules hautement fonctionnalisées, dont certaines possèdent une activité biologique prometteuse.Par ailleurs, la deuxième partie est liée à la synthèse de nouveaux analogues de thiazole et de benzothiazole de MIM-1 (molécule d'inhibition de Mcl-1) grâce à une série de réactions connues. Plusieurs analogues de benzothiazole ont été obtenus en une seule ou deux étapes, et les composés thiazole ont été obtenus en cinq étapes. La modification des structures des deux séries d'analogues est en cours, afin d’évaluer leur activité antitumorale, but principal de cette partie. / This thesis document is divided into two unrelated parts, the first part reported the synthesis and the biological evaluation of new analogs of the anti-vascular compound, isocombretastatin A-4. This work lies at the chemistry-biology interface.One-pot sequential reactions implementing palladium-catalyzed cross-coupling between N-tosylhydrazones and various nitro-aryl bromides and nitro-biaryl bromides followed by reductive cyclization led to the synthesis of a broad library of C2-, C3-, N-aryl indoles and vinyl carbazoles with vast substrate scope. Moreover, this methodology allowed to explore a new mechanism for the synthesis of indoles through unexpected pathways.Interestingly, the biological evaluation of these new series had identified eight molecules with antiproliferative activities in the nanomolar range against human colon carcinoma, with two molecules showing very promising results by having IC50 similar to that of isoCA-4.Hence, this part contributed to develop new processes for an easy access of highly substituted compounds which could possess promising biological activity.On the other hand, the second part is related to the synthesis of original thiazole and benzothiazole analogs of MIM-1 (Mcl-1 inhibition molecule) through a series of known reactions. Several benzothiazole analogs were obtained in one or two steps, and the thiazole compounds were obtained in five steps. More structural modifications of the two series of analogs is ongoing to achieve the innate goal of this part, which is to evaluate their antitumor activity.

This Diploma thesis thematizes the problem of students' time perspective and its diagnostics. The whole text is divided into two parts - theoretical and practical with emphasis on the theoretical part. The theoretical part will look upon the conceptions of time perspective. Ideas of time perception, the influence of time on human behavior and a connection of time pespective with an achievement motivation are presented. The personality-motivational concept of time perspective by European expert of motivational psychology Jopeph Nuttin are analyzed. From the domestic authors I describe the concept of perpsective orientation by Isabella Pavelkova. These theories are completed with information gained by Rayner, Gjesme and Fraisse. The important section is a chapter where diagnostics and specifics methods are presented. The empirical section contains the results of research provided by 5 classes of high school students with an eight year (or four year) study plan in April 2012 in Caslav. Using two questionaries (Motivational Induction Method and Perspective Orientation Questionary). Motivational Induction Method investigates objects of students' time perspective and summarized these themes into exact time frames. The Perspective Orientation Questionnaire helps investigate external validity. Key words:...

The I-BAR proteins are a family of actin regulators which include IRSp53 and Missing-In-Metastasis (MIM). These proteins possess an N-terminal I-BAR domain which associates with both the actin cytoskeleton and membrane phospholipids and is able to induce membrane curvature. Previous cell culture and in vitro studies have implicated I-BAR proteins in the regulation of actin protrusion formation, however their roles within the organism are poorly understood. We have used Drosophila melanogaster as a model system in which to study I-BAR protein function at the cellular and organismal level. Drosophila possess two I-BAR proteins, one homologous to IRSp53 and one homologous to MIM. Using full- length and truncated splice variants generated for both dMIM and dIRSp53, we have performed structure/function analysis to determine the role of specific domains in the localisation and actin modifying abilities of the proteins in both cell culture and in vivo. We found that dMIM overexpression typically promotes a lamellipodial morphology, with dMIM localising to the edges of extending lamellipodia. dIRSp53 expression induced a more filopodial phenotype in cell culture, which was not as notable in vivo, however expression of a dIRSp53 splice variant with a WH2 domain resulted instead in a predominantly lamellipodial morphology. Similar to dMIM, dIRSp53 localises to the tip of extending protrusions, albeit more transiently. We found that multiple domains contribute to the localisation and activity of dIRSp53 and dMIM. Following overexpression analysis, complementary loss-of-function analysis was performed in vivo using Drosophila mutants lacking dMIM, dIRSp53 or both genes together. Surprisingly these mutants were viable and morphologically normal. Absence of these genes individually or together did not greatly affect cell migration or actin dynamics in haemocytes or epithelial cells undergoing dorsal closure. However, a role for I- BAR proteins in axonal filopodia formation within primary neuronal cultures was apparent, as was a notable role in neuromuscular junction morphology. We have also identified potential redundancy between Drosophila MIM and the Drosophila F-BAR protein Cip4 in actin bundle regulation within embryonic haemocytes, with an additional novel role for Cip4 alone in haemocyte lamellipodial maintenance. Our results suggest that the Drosophila I-BAR proteins contribute to actin cytoskeleton regulation in vitro and in vivo, particularly within the CNS, and with novel shared functions with other BAR domain family proteins contributing to their regulation of actin cytoskeletal organisation and function.

The main objective of the thesis “Conceptual Product Development in Small Corporations” is by the use of a case study test the MFD™-method (Erixon G. , 1998) combined with PMM in a product development project. (Henceforth called MFD™/PMM-method). The MFD™/PMM-method used for documenting and controlling a product development project has since it was introduced been used in several industries and projects. The method has been proved to be a good way of working with the early stages of product development, however, there are almost only projects carried out on large industries which means that there are very few references to how the MFD™/PMM-method works in a small corporation. Therefore, was the case study in the thesis “Conceptual Product Development in Small Corporations” carried out in a small corporation to find out whether the MFD™/PMM-method also can be applied and used in such a corporation.The PMM was proposed in a paper presented at Delft University of Technology in Holland 1998 by the author and Gunnar Erixon. (See appended paper C: The chart of modular function deployment.) The title “The chart of modular function deployment” was later renamed as PMM, Product Management Map. (Sweden PreCAD AB, 2000). The PMM consists of a QFD-matrix linked to MIM (Module Indication Matrix) via a coupling matrix which makes it possible to make an unbroken chain from the customer domain to the designed product/modules. The PMM makes it easy to correct omissions made in creating new products and modules.In the thesis “Conceptual Product Development in Small Corporations” the universal MFD™/PMM-method has been adapted by the author to three models of product development; original-, evolutionary- and incremental development.The evolutionary adapted MFD™/PMM-method was tested as a case study at Atlings AB in the community Ockelbo. Atlings AB is a small corporation with a total number of 50 employees and an annual turnover of 9 million €. The product studied at the corporation was a steady rest for supporting long shafts in turning. The project team consisted of management director, a sales promoter, a production engineer, a design engineer and a workshop technician, the author as team leader and a colleague from Dalarna University as discussion partner. The project team has had six meetings.The project team managed to use MFD™ and to make a complete PMM of the studied product. There were no real problems occurring in the project work, on the contrary the team members worked very well in the group, having ideas how to improve the product. Instead, the challenge for a small company is how to work with the MFD™/PMM-method in the long run! If the MFD™/PMM-method is to be a useful tool for the company it needs to be used continuously and that requires financial and personnel resources. One way for the company to overcome the probable lack of recourses regarding capital and personnel is to establish a good cooperation with a regional university or a development centre.

Surface-enhanced Raman scattering (SERS) effect on Ag films with different morphology is studied. We varied the deposition rates and also proposed a new method to control the nano-gaps on the silver island film. By bending the glass substrates during film deposition, we can control the gap width on the fractal Ag film. The measured SERS intensity is related to the metal film morphology and we found that the gap width is the dominant factor to analyze the SERS signal. The 3-layer metal-insulator-metal structure is simulated and the E-field intensity with different gaps fits to our measurement results.

Metal/organic/indium tin oxide (ITO) structures, including OLEDs, are demonstrated to contain multiple nonvolatile conductance states that can be programmed by the application of an external bias above a certain threshold voltage (Vth). These conductance states are stable and in turn can be probed by the use of a bias lower in value than Vth. The unbiased retention time of states is greater than several weeks, and more than 48,000 write-read-rewrite-read cycles have been performed with minimal degradation. It is found that the programming of a continuum of conductance states is possible, and techniques to do so are outlined. The electrical conductivity of the highest and lowest states can differ by six orders of magnitude. Switching speeds below 50 ns are shown, resulting in an energy requirement of about 100 pJ to switch from one conductance state to another. The memory phenomenon is shown to be influenced by the active layer thickness and anode/surface roughness while temperature dependence is limited. The electrical characteristics of these devices are consistent with metal diffusion or filament phenomena found in metal-insulator-metal structures, suggesting a possible mechanism by which the states are stored.Electroluminescent devices employing several new organic-inorganic lumophore-functionalized macromolecules are presented. In this study, macromolecules incorporating several lumophores covalently bonded to the vertices of a cubical core structure based on Polyhedral Oligomeric Silsesquioxane (POSS) in multiple configurations are implemented as light-emitting centers. The hole-transporting polymer poly(N-vinylcarbazole) (PVK) and electron-transporting additive 2-(4-biphenylyl)-5-(4-tert-butylphenyl)1,3,4-oxadiazole (PBD) are used as a two-part host to enhance the carrier transport in these simple solution-processed single-layer devices. A study of energy transfer in several systems is carried out to understand the requirements needed to create white-light emission from a single macromolecule. A single macromolecule incorporating twenty-one blue and one yellow lumophore is shown to exhibit field-independent stable white-light electroluminescence with Commission Internationale de l'Eclairage (CIE) coordinates of (0.31, 0.37). An external quantum efficiency of 0.55 percent and a maximum brightness of 1600 cd/m2 are attained with simple solution-processed single-layer devices. High solubility and ease of purification give these macromolecule white-light emitters advantages over their small molecule and polymeric type counterparts.

Together, colorectal (CRC) and bladder cancer (BlCa) are responsible for a large percentage of cancer related morbidity and mortality in Western society. A dramatic reduction in patient survival occurs as these cancers progress towards invasive and metastatic disease, from a five year survival rate of about 90% for localised disease to approximately 5-10% for advanced disease involving distant metastasis. A greater understanding of disease progression will lead to enhanced screening, diagnostic and treatment strategies, in turn providing an improved prognosis for the patient. The purpose of this study was to expand the current molecular knowledge of CRC and BlCa by elucidating the role of Mxi1 mutations and MTSS1 expression in CRC and BlCa respectively, and to examine the diagnostic potential of these genes. The Mxi1 coding region for 41 tumours, collected by the South Western Sydney Colorectal Cancer Tumour Bank from 2000-2001, was screened for mutations using Dideoxy Fingerprinting (ddF) and sequencing. Sequence alterations were detected in 34% of tumours. Three different polymorphisms and three mutations were detected. One mutation could possibly affect the tumour suppressor function of Mxi1. The presence of a gene mutation did not correlate to any clinical characteristics and is therefore not a suitable diagnostic marker. Microsatellite instability (MSI) status however, significantly correlated with tumour grade. Expression levels of MTSS1 and an associated gene, MTSS2, were examined in 16 BlCa cell lines, 9 clonally-derived BlCa sublines, and 30 transitional cell carcinomas (TCCs) collected by the Heinrich-Heine University from 1993-2000. Variable gene expression was observed in BlCa cell lines and tumour samples. No significant correlation of MTSS expression and invasive ability was observed for the cell lines or tumour samples. Further studies eliminated promoter methylation and p53 functional status as mechanisms involved in MTSS1 and MTSS2 down-regulation. Functional studies performed on stable MTSS1-expressing BlCa lines found that although migration was increased, cells displayed reduced anchorage-independent growth. The invasive ability of these cells was unchanged confirming that expression does not correlate with invasive ability. These data support the role of MTSS1 as a tumour suppressor and not as a metastasis suppressor gene. Although MTSS1 may not be useful in predicting more invasive disease, its role as a tumour suppressor in cancer may be useful.

Together, colorectal (CRC) and bladder cancer (BlCa) are responsible for a large percentage of cancer related morbidity and mortality in Western society. A dramatic reduction in patient survival occurs as these cancers progress towards invasive and metastatic disease, from a five year survival rate of about 90% for localised disease to approximately 5-10% for advanced disease involving distant metastasis. A greater understanding of disease progression will lead to enhanced screening, diagnostic and treatment strategies, in turn providing an improved prognosis for the patient. The purpose of this study was to expand the current molecular knowledge of CRC and BlCa by elucidating the role of Mxi1 mutations and MTSS1 expression in CRC and BlCa respectively, and to examine the diagnostic potential of these genes. The Mxi1 coding region for 41 tumours, collected by the South Western Sydney Colorectal Cancer Tumour Bank from 2000-2001, was screened for mutations using Dideoxy Fingerprinting (ddF) and sequencing. Sequence alterations were detected in 34% of tumours. Three different polymorphisms and three mutations were detected. One mutation could possibly affect the tumour suppressor function of Mxi1. The presence of a gene mutation did not correlate to any clinical characteristics and is therefore not a suitable diagnostic marker. Microsatellite instability (MSI) status however, significantly correlated with tumour grade. Expression levels of MTSS1 and an associated gene, MTSS2, were examined in 16 BlCa cell lines, 9 clonally-derived BlCa sublines, and 30 transitional cell carcinomas (TCCs) collected by the Heinrich-Heine University from 1993-2000. Variable gene expression was observed in BlCa cell lines and tumour samples. No significant correlation of MTSS expression and invasive ability was observed for the cell lines or tumour samples. Further studies eliminated promoter methylation and p53 functional status as mechanisms involved in MTSS1 and MTSS2 down-regulation. Functional studies performed on stable MTSS1-expressing BlCa lines found that although migration was increased, cells displayed reduced anchorage-independent growth. The invasive ability of these cells was unchanged confirming that expression does not correlate with invasive ability. These data support the role of MTSS1 as a tumour suppressor and not as a metastasis suppressor gene. Although MTSS1 may not be useful in predicting more invasive disease, its role as a tumour suppressor in cancer may be useful.