Le contexte général dans lequel s'inscrivent les travaux développés dans ce mémoire est le contrôle des processus industriels complexes. Ces travaux proposent des nouvelles techniques d'amélioration du contrôle statistique des processus non gaussiens : la carte de contrôle avec des paramètres variables et la carte de contrôle théorique pour la loi de distribution de Rayleigh. Un modèle d'intégration des outils des domaines de l'APC (Automatic Process Control) et de la MSP est proposée et ensuite analysé par le biais des deux modèles de processus réel.

Transforming growth factor (TGF) β is a tumor suppressor during early tumor development, by inhibiting proliferation and inducing apoptosis. At later stages of cancer, it becomes a tumor promoter, and promotes tumor cell migration and invasion. TGFβ signals via its type II and type I receptors to several downstream signaling pathways. In the present work we have focused on the TRAF6 (tumor necrosis factor receptor-associated factor 6)/ TAK1 (TGFβ activated kinase 1) signaling pathway and the Smad7-dependent activation of p38 in prostate carcinoma cells (PC3U). We found that TGFβ-induced activation of the ubiquitin ligase TRAF6 was needed for cell invasion, by a mechanism that involves activation of the metalloproteinase TNFα converting enzyme (TACE), via protein kinase Cζ (PKCζ). TACE cleaves the TβRI, whereafter the intracellular domain (ICD) translocates to the nucleus, where it binds to the transcriptional co-activator p300 and regulates gene expression, promoting invasion. Interestingly, the translocation of the TβRI ICD was observed in several cancer cell lines and in sections of primary tumors, but not in primary prostate epithelial cells. We also found that Smad7 and adenomatous polyposis coli (APC) are important for TGFβ- and epidermal growth factor (EGF)-induced cell migration in PC3U cells. TGFβ induces the formation of a complex consisting of Smad7, p38, glycogene synthase kinase 3β (GSK-3β), APC and β-catenin, which localizes to the membrane ruffles in the leading edge of migrating cells. The complex links the TβRI to the microtubule system and promotes membrane ruffling and microtubule polarization, which are known to be important for cell migration. In the EGF signaling pathway, Smad7 was found to be important for phosphorylation of the EGF receptor at Tyr1068, for the activation of p38 and JNK, and for induction of membrane ruffles. Smad7 is required for TGFβ-induced activation of p38 and apoptosis. We found that Smad7 forms a complex with p38 and ataxia telangiectasia mutated (ATM), which is important for activation of p53 mediated apoptosis. Many tumor cells including the PC3U cells lack a functional p53, which is one of the reasons to why cancer cells can avoid the tumor suppressor effects of TGFβ.

Le cancer colorectal (CCR) est le troisième cancer dans le monde et devenu un véritable enjeu de santé publique. Environ 5% sont associés à une forme familiale : la polypose adénomateuse familiale, le Syndrome de Lynch et la MAP (MUTYH-Associated Polyposis). Implication du syndrome MAP dans les polyposes: Parmi 31 patients avec une polypose sans mutation sur APC, 6 (20%) présentaient une mutation biallélique sur MUTYH. Fréquence de la mutation c.1185_1186dup dans les MAP: Au sein d'un groupe de 36 familles mutées sur MUTYH, 11 avaient une mutation biallélique homozygote c.1185_1186dup. Cette mutation était significativement plus fréquemment observée chez les patients d'Afrique du Nord (79% vs. 5%, p<0,0001). La recherche d'un haplotype commun en utilisant 10 microsatellites a identifié un segment de 1,3 cM présent chez tous les patients avec la mutation c.1185_1186dup. Variants rares (VR) de la cycline D1 : La comparaison des fréquences alléliques des VR de la cycline D1 fut réalisée entre les cas (112 patients avec une polypose indéterminée et 44 avec un CCR précoce) et 866 témoins. Les VR étaient plus fréquemment observés dans le groupe de malades. En combinant les VR, une augmentation du risque était retrouvée pour le groupe de patients avec une polypose indéterminée: (OR=2,2); 95%IC, 1,1-4,4; P=0,03). Rôle des variants rares : 70 variants provenant de 17 gènes ont été examinés au sein de la même population. 21 était des VR (fréquence<1%) et 4 étaient plus fréquemment observés chez les cas (EXO1-12, MLH1-1, CTNNB1-1 et BRCA2-37, p<0,05). En combinant tous les VR avec une fréquence allélique <0,5%, un sur risque de 3,2 était observé (95%CI=1,1-9,5; p=0,04)

The thesis aims to investigate the mechanical behavior and properties of a centrally notched hybrid Magnesium/Carbon-Fiber/PEEK laminate at elevated temperature. The high performance hybrid composite laminates of 0.5mm Magnesium sheets sandwiched by Carbon-Fiber/PEEK (APC-2) guasi-isotropic and cross-ply laminates were fabricated. The Magnesium sheets were polished and cleaned by acetone, then underwent the surface treatment by CrO3-base solvent etchants, cured by the improved diaphragm curing process. The finished laminates were cut into the specimen than drilled a 4mm diameter hole in the center of specimen. At first, the ultimate strength, stiffness and stress-strain diagram were obtained due to static tension tests at elevated temperature, such as 25¢XC(RT), 75¢XC, 100¢XC, 125¢XC, and 150¢XC. Compare of them, the notched quasi-isotropic ones drop almost 50% in strength, and the notched cross-ply ones are half of unnotched ones. The two lay-up notched specimens are slightly below the unnotched ones in stiffness. The strength of the specimens are decrease as temperature rise. As the temperature rise the stiffness of quasi-isotropic ones drop, but it just change little in cross-ply ones. Then the notched specimen fatigue life and load-cycle (P-N) curves were obtained by tension-tension fatigue test. The P-N curves were adopt to prevent the stress concretion of the notched specimen. Consider the same loading, notched specimens has worse fatigue behavior, but in the same load ratio, the normalized P-N curves of the unnotched ones were below the notched ones means notched ones has better fatigue behavior. Recording the specimen image by video camera during the testing process, the cracks at the edge of hole were found. However delamination was not found. Necking was observed in quasi-isotropic specimens, but not in cross-ply. Observed by optical microscopy, the improved surface treatment will decrease the probability of delamination from 20% to less than 10% after hot press.

ABSTRACT This thesis is aimed to investigate the fatigue life, strength, damage and fracture process in AS-4/PEEK APC-2 composite laminates subjected to both elevated temperature and loading sequences. Our main work is experiment. All specimens are 16-ply thick with lay-up of quasi-isotropic laminates. We accomplish static tensile test, fatigue test of constant stress amplitude, and two-step loading at elevated temperatures, i. e., 75¢Jand 125¢J. The residual strength and stiffiness are obtained. We also use Miner¡¦s rule to analyze the data acquired from experiment and to discuss the fatigue properties and fracture mechanism subjected to both elevated temperatures and loading sequences of combination. Finally, we perform ultrasonic C-Scan non-destructive test to examine laminates. In comparsion with experimental data, we can further understand the damage process and fracture mechanism in laminates. The experimental results can be concluded as follows. The damage of specimens at 125¢J is more serious than that at 75¢J.Furthermore, if the loading sequence is low-high, the cumulative damage value will be smaller than 1,whilst it will be larger than 1 due to reverse loading sequence. The sequence of decreasing residual strength and residual stiffiness of specimen associated with the temperature and stress level in combination is high temperature¡Ðlow stress, low temperature¡Ðlow stress, high temperature¡Ðhigh stress and low temperature¡Ðhigh stress.

Abstract The development of colorectal cancer ( CRC ) is believed to follow series progress of pathological changes and with correspondent genetic changes of many genes. This includes intestinal epithelial crypts, aberrant focus, adenoma and carcinoma, each of that commonly involved genetic and proteomic alterations. And in genetic level, it usually includes mutations of APC, p53, K-ras and microsatellite instability. The somatic mutations of APC gene mostly occur in MCR ( Mutation Cluster Region ) in codon 1286-1513. The p53 mutations is dispersed in whole gene with 3 hot spots: codon 175, 248 273. K-ras codon 12 and 13 mutations is preferentially involved in polyps growth of CRC. And microsatellite instability is found in 15-25% CRC patients. We collect polyps and various stages CRC samples in Taiwan, and design 6 primer pairs of APC and p53 which is widely used in western countries to analyze mutations of the local CRC genetic changes. We also use two-dimensional electrophoresis and mass spectrometry to identify protein expression changes in CRC. We have found 30 proteins that exhibited either a significant decrease or increase between normal colon tissue and carcinoma, and 3 out of ( TSD1, TSD2, and TSD3 ) these were significantly associated with tumor progression. TSD3 is annotated by mass spectrometry and is identified to be a c1q-related protein. Though there are no report on the function of c1q-related protein, a NCBI virtual northern analysis shows its expression is varied in various cancer. On the other hand, there are only about 56 % genetic changes of APC and p53 during carcinogensis, which is much less than the 70-85 % mutational rate in western CRC patients. It indicates different genetic mutational pattern of CRC in Taiwan.

The aim of this thesis is to manufacture Ti/APC-2 hybrid composite laminates and obtain its mechanical properties and fatigue characteristics at elevated temperatures. Ti/APC-2 laminates were composed of two layers of APC-2 and three layers of titanium sheets. For superior bonding ability between titanium and APC-2, chromic anodic method was adopted to treat titanium sheets in manufacturing process and APC-2 was stacked according to cross-ply [0/90]s and quasi-isotropic [0/45/90/-45] sequences. Then, the modified curing process was adopted to fabricate Ti/APC-2 hybrid composite laminates. Tension and fatigue tests carried out with MTS 810 and MTS 651 environmental control chamber to lift and maintain experimental temperatures, such as 25¢XC, 75¢XC, 100¢XC, 125¢XC and 150¢XC. From static tensile tests, the mechanical properties of cross-ply and quasi-isotropic composite laminates, such as ultimate strength, longitudinal stiffness were gained and the stress-strain diagrams of laminates were also plotted from testing data at elevated temperature. From fatigue tests we obtained laminate¡¦s fatigue resistance properties and the experimental data of applied stress vs. cycles were plotted as S-N diagrams at elevated temperature. From the tensile and fatigue tests, the important remarks were summarized as follows. First, no matter what the APC-2 stacking sequence was, the ultimate strength and longitudinal stiffness decreased while temperature rising, especially at 150¢XC; second, a turning point appeared at each stress-strain diagram that kink angle caused the decrease of stiffness while temperature rising; third, combining fatigue data and stress-strain diagrams we analogized a presumption that the region before turning point was in elastic behavior and after turning point in plastic deformation; fourth, quasi-isotropic laminates had better fatigue resistance than that of cross-ply laminates; sixth, the longitudinal stiffness before turning point was in good agreement with the prediction by using the modified ROM, however, after turning point the errors became large.

Both Notch and the Wnt pathways are key regulators in maintaining the homeostasis in the intestine. Defects on the key tumor suppressor adenomatous polyposis coli, APC a gene in the Wnt pathway is most frequently mutated in colorectal cancer. Previous studies have indicated that there is a crosstalk between these two pathways. We investigate if there is correlation by first using bioinformatics to find Lef1/Tcf sites in several of the Notch pathway gene promoters. Bioinformatically we found that a lot of the genes contained theses sites controlled by the APC's destruction target β-catenin. By using semi quantitative PCR and western blot we found that Hes 1, Hes 7, JAG 2, MAML 1, Notch 2, NUMB, NUMBL, RFNG and LFNG was downregulated in HT29 colon cancer cells carrying a vector containing wild type APC. All but JAG 2 contains at least one Lef1/Tcf site in their promoter region. The results were verified in HT29 cells transfected with siRNA against β-catenin. We also investigated what would happen to the Lef1/Tcf target gene program of the Wnt pathway, if the Notch pathway was inhibited with the gamma-secretase inhibitor DAPT. Results showed no downregulution of β-catenin or its target gene Cyclin D1.Taken together, these results demonstrate that the Wnt pathway can be placed upstream of the Notch pathway and regulates the latter through β-catenin and the Lef1/Tcf target gene program. However, preliminary results indicate that there is no regulation of APC/β-catenin by the Notch pathway.

Les mutacions germinals d'elevada penetrància del gen APC que originen una proteïna truncada són les responsables de la majoria de casos de poliposi, mentre que les variants missense, que canvien un aminoàcid de la proteïna, es detecten en una minoria dels casos. S'han identificat diverses variants missense en el gen APC, però el seu potencial patogènic és encara motiu de controvèrsia, el què limita la utilitat de la seva detecció en el consell genètic. L'estudi de la presència de les variants en la població control i en les diferents poblacions de càncer colorectal (CCR) esporàdic i hereditari, juntament amb la realització d'anàlisis funcionals, podrien ajudar a conèixer l'impacte de les variants del gen APC en el desenvolupament del CCR. El nostre objectiu és determinar el significat funcional de les variants identificades en el gen APC en pacients afectes de poliposi adenomatosa familiar en relació al risc de desenvolupar CCR tant esporàdic com hereditari.L'anàlisi molecular de la regió codificant del gen APC realitzat en 138 famílies amb poliposi adenomatosa familiar clàssica (n= 98) i poliposi adenomatosa familiar atenuada (n= 40) ha permès la identificació de deu variants missense del gen APC: G101E, K957N, N1026S, L1129S, I1307K, E1317Q, D1822V, A2274V, G2502S i P2681L. En el nostre estudi s'han caracteritzat amb diferent profunditat set d'aquestes deu variants: G101E, N1026S, L1129S, D1822V, A2274V, G2502S i P2681L. La variant APC G101E, identificada en una família de poliposi clàssica, no s'associa a la malaltia ni sembla tenir cap funció modificadora del fenotip de poliposi. L'efecte biològic de les variants APC A2274V i APC P2681L, identificades en dues famílies de poliposi, és encara desconegut. La variant APC G2502S és un polimorfisme que no sembla tenir rellevància clínica. La variant APC L1129S, identificada en dues famílies de poliposi, no altera la interacció de la proteïna APC 4x15 amb la beta-catenina. La variant APC D1822V és un polimorfisme que incrementa el risc de desenvolupar CCR en pacients amb història prèvia d'adenomes i no s'associa amb la història familiar de CCR. La variant APC N1026S, que està present de forma exclusiva en una família de poliposi adenomatosa familiar atenuada, disminueix la unió d'APC amb beta-catenina i activa moderadament la transcripció mitjançada pel complex beta-catenina/Tcf-4. Aquests resultats indiquen que la variant APC N1026S és patogènica i és la mutació responsable del desenvolupament de la poliposi atenuada a la família on es va identificar.La caracterització funcional de les variants del gen APC és de gran importància per conèixer la seva contribució en el desenvolupament de la poliposi i facilitar l'assessorament genètic. / Truncating germline mutations in the APC gene are responsible for the majority of Familial Adenomatous Polyposis (FAP) cases, while in a minority of cases missense mutations, leading to single amino acid changes, are detected. Germline missense variants in the APC gene have been reported although their contribution to FAP is controversial, limiting their use in genetic counseling. The aim of this thesis is to determine the functional relevance of the variants identified in the APC gene in FAP patients in order to establish its pathogenicity.The molecular analysis of the APC gene was performed in 138 classical (n= 98) and attenuated (n= 40) FAP families and allowed the identification of ten missense variants. In this thesis, seven out of these ten APC variants have been characterised: G101E, N1026S, L1129S, D1822V, A2274V, G2502S and P2681L. The APC G101E variant, identified in a classical FAP family, is not associated with the disease. The biological effect of APC A2274V and APC P2681L variants, identified in two FAP families, remains unknown. The APC G2502S variant is a polymorphism without clinical relevance. The APC L1129S variant, identified in two FAP families, does not modify the interaction of the APC 4x15 protein with beta-catenin. The APC D1822V variant is a polymorphism associated with an increased risk of adenoma transformation and does not associate with family history of colorectal cancer. The APC N1026S variant, identified for the first time in an attenuated FAP family, diminishes beta-catenin binding to APC and moderately activates beta-catenin/Tcf-4-mediated transcription. These findings strongly support a pathogenic role of the APC N1026S variant in the AFAP phenotype.In summary, functional characterization of APC variants is crucial to elucidate their contribution to FAP and improve genetic counseling.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.