A Leucemia Mielóide Crônica (LMC) é uma neoplasia mieloproliferativa resultante da expansão clonal de células mielóides positivas para o cromossomo Philadelphia. A patogênese da LMC está associada à expressão do oncogene BCR-ABL1, que codifica a proteína Bcr-Abl com constitutiva atividade da tirosina quinase, promovendo a mieloproliferação exacerbada e a resistência à apoptose das células leucêmicas. Os pacientes com LMC são tratados principalmente com inibidores de tirosina quinase (TKI), mas a resistência aos inibidores e a refratariedade tem sido relatada em alguns pacientes na fase crônica e na maioria dos pacientes em fases avançadas da doença. Assim sendo, continua a ser de suma importância a elucidação da patogênese da LMC e a busca de novos alvos terapêuticos, como os membros da via de sinalização Hippo e reguladores do ciclo celular, da família Aurora quinase. O presente estudo quantificou o nível de expressão de genes que codificam componentes da via de sinalização Hippo (MST1, MOB1B, MOBKL1B, LATS1, LATS2, YAP e TAZ) e Aurora quinases A e B em: 1) pacientes com LMC em diferentes fases da doença, resistentes ou sensíveis à terapia com mesilato de imatinibe (MI), em indivíduos saudáveis e 2) linhagens celulares HL-60, HL-60.Bcr- Abl tratadas com TKI (imatinibe, dasatinibe e nilotinibe), KCL22 e LAMA84 resistentes e sensíveis ao MI. Os níveis de expressão dos genes alvo foram correlacionados com o índice de prognóstico de Sokal. Os principais resultados revelaram que há alteração nos genes MST1, MOB1B, MOBKL1B, LATS1, LATS2, TAZ, AURKA e AURKB em pacientes com LMC em relação aos controles. Não houve correlação entre o índice de Sokal e a expressão gênica dos genes da via Hippo, MST1, MOB1B, MOBKL1B, LATS1, LATS2 e TAZ, assim como os genes Aurora quinases A e B. Pacientes com LMC em fases avançadas apresentaram maiores valores de expressão dos genes TAZ e AURKB, comparado aos pacientes na fase crônica. Os pacientes resistentes ao TKI apresentaram as expressões dos genes MST1, TAZ e AURKB, significativamente mais elevadas, comparado aos pacientes sensíveis ao MI. Os resultados dos estudos em linhagens celulares indicaram principalmente que a expressão do gene LATS1 pode ser modulada pela atividade de tirosina quinase Bcr-abl e que o oncogene BCR-ABL1 induz a expressão de AURKA, AURKB, LATS1 e TAZ. Em conjunto os dados obtidos revelam que a alteração da expressão dos genes da família Aurora quinase, A e B, e dos genes que codificam proteínas da via Hippo contribui para a patogênese e progressão da LMC. O desenvolvimento de fármacos e/ou a identificação de marcadores tumorais para a via de sinalização Hippo e família Aurora quinase, podem otimizar o tratamento da LMC, aumentando a susceptibilidade das células leucêmicas a apoptose e levando a um melhor prognóstico da doença / Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm resulting from clonal expansion of myeloid cells positive for the Philadelphia chromosome. The CML pathogenesis is associated with BCR-ABL1 oncogene expression, which encodes the Bcr-Abl protein with a constitutive tyrosine kinase activity, leading to leukemic cell high proliferation and resistance to apoptosis. CML patients are mainly treated with tyrosine kinase inhibitors (TKI), but some of CML patients in chronic phase are resistant and in advanced phases are refractory to TKI. Thus, it is still relevant to elucidate the CML pathogenesis and seek to new therapeutic targets, including the Hippo signaling pathway members and cell cycle regulatory genes such as those encoding the Aurora kinase family. The present study quantified the RNA expression level of genes encoding components from the Hippo cell signaling pathway (MST1, MOB1B, MOBKL1B, LATS1, LATS2, YAP, and TAZ) and Aurora kinase A and B in: 1) CML patients at different stages of the disease, in CML patients resistant or sensitive to imatinib mesylate therapy, healthy individuals and 2) in cell lines HL-60, HL-60.Bcr-Abl treated with TKI (imatinib mesylate, dasatinib and nilotinib), KCL22 and LAMA84 resistant and sensitive to IM. The RNA expression levels of the target genes were also correlated to the CML Sokal\'s prognostic score values. The main results revealed that there are alterations in the genes MST1, MOB1B, MOBKL1B, LATS1, LATS2, TAZ, AURKA and AURKB in patients with CML in relation to the controls. There was no correlation between the Sokal index and the gene expression of the Hippo, MST1, MOB1B, MOBKL1B, LATS1, LATS2 and TAZ genes, as well as the Aurora kinase genes A and B. Patients with advanced phase CML had higher values of expression of the TAZ and AURKB genes, compared to the patients in the chronic phase. Patients resistant to TKI had significantly higher MST1, TAZ and AURKB gene expression compared to MI-sensitive patients. The results of the studies in cell lines indicated primarily that the expression of the LATS1 gene can be modulated by the Bcr-abl tyrosine kinase activity and the BCR-ABL1 oncogene induces the expression of AURKA, AURKB, LATS1 and TAZ. Together, the data show that altered expression of Aurora kinase family genes, A and B, and genes coding for Hippo pathway proteins contribute to the pathogenesis and progression of CML. The development of drugs and/or identification of tumor markers for the Hippo signaling pathway and the Aurora kinase family can optimize CML treatment by enhancing the susceptibility of leukemic cells to apoptosis and leading to a better disease prognosis

No description available.

Οι υπερίτες του αζώτου (nitrogen mustards) συνιστούν μία αποτελεσματική ομάδα φαρμάκων που χρησιμοποιούνται στη χημειοθεραπεία του καρκίνου. Πρόσφατα ευρήματα της ερευνητικής μας ομάδας έδειξαν ότι οι υπερίτες του αζώτου μελφαλάνη (MEL), χλωραμπουκίλη (CAB) και ο δραστικός της μεταβολίτης, το PHE, επιδεικνύουν ισχυρή θραυσματογόνο δράση, αλλά επιπρόσθετα, εμφανίζουν ανευπλοειδογόνο δράση, διαταράσσοντας το χρωμοσωματικό αποχωρισμό μέσω τροποποιήσεων της δομής και λειτουργίας της μιτωτικής συσκευής. Στην παρούσα διατριβή, διερευνήθηκε περαιτέρω ο μηχανισμός της ανευπλοειδογόνου δράσης των παραπάνω δραστικών ενώσεων και πραγματοποιήθηκε σύγκριση της γενετικής δράσης δύο νέων στεροειδών αναλόγων του PHE, τα ανάλογα ΕΑ-92 και ΕΑ-97 με αυτήν των MEL, CAB και PHE. Τα στεροειδή ανάλογα σχεδιάστηκαν με στόχο την αύξηση της εκλεκτικότητας της αντινεοπλασματικής δράσης. Η ικανότητα των MEL, CAB και PHE να προκαλούν φαινόμενα χρωμοσωματικής καθυστέρησης μελετήθηκε σε σύγκριση με τα στεροειδή ανάλογα ΕΑ-92 και ΕΑ-97. Η μελέτη πραγματοποιήθηκε σε ανθρώπινα λεμφοκύτταρα in vitro με τη μέθοδο αναστολής της κυτταροκίνησης (CBMN) σε συνδυασμό με τη μέθοδο FISH και τη χρήση πανκεντρομερικού ανιχνευτή. Επιβεβαιώθηκε η θραυσματογόνος και ανευπλοειδογόνος δράση των ενώσεων MEL, CAB και PHE, ενώ φάνηκε ότι τα στεροειδή ανάλογα ΕΑ-92 και ΕΑ-97 προκαλούν αποκλειστικά χρωμοσωματική θραύση. Το φαινόμενο της χρωμοσωματικής καθυστέρησης μελετήθηκε επίσης με τη μέθοδο CREST στην κυτταρική σειρά ποντικού C2C12. Με τη μέθοδο αυτή, επιβεβαιώθηκε η διπλή γενετική δράση των ενώσεων MEL, CAB και PHE. Τα στεροειδή ανάλογα ΕΑ-92 και ΕΑ-97 εμφανίστηκαν ως οι ηπιότεροι επαγωγείς ΜΝ και προκαλούν κυρίως χρωμοσωματική θραύση, ενώ ήπια ανευπλοειδογόνο δράση παρουσίασε μόνο το ανάλογο ΕΑ-92. Ακολούθως, εξετάσθηκε η ικανότητα των υπό εξέταση χημικών ενώσεων ΕΑ-92 και ΕΑ-97, να επηρεάζουν τη δομή και λειτουργία της μιτωτικής συσκευής σε σχέση με αυτήν των ενώσεων MEL, CAB, PHE, με διπλό ανοσοφθορισμό για τη β- και γ-τουμπουλίνη. Παρατηρήθηκε ότι όλες οι ενώσεις, εκτός από το στεροειδές ΕΑ-97 προκαλούν τη δημιουργία πολυπολικών μεταφάσεων, ενώ όλες οι ενώσεις επάγουν το σχηματισμό μεσοφασικών κυττάρων με ανώμαλο αριθμό κεντροσωμάτων. Όλες οι υπό εξέταση χημικές ενώσεις εμφανίζουν κυτταροτοξικότητα και καθυστέρηση του κυτταρικού κύκλου σε καλλιέργειες ανθρώπινων λεμφοκυττάρων και στα κύτταρα ποντικού C2C12. Στη συνέχεια διερευνήθηκε η ικανότητα των υπό εξέταση ενώσεων να επάγουν την απόπτωση και μελετήθηκε ο ρόλος της απόπτωσης στην εκδήλωση της γενετικής δράσης των ενώσεων MEL, CAB και PHE. Η μελέτη αυτή πραγματοποιήθηκε στα κύτταρα C2C12 με τη μέθοδο της διπλής χρώσης Αννεξίνης V/Ιωδιούχου προπιδίου και το διπλό ανοσοφθορισμό β- και γ-τουμπουλίνης, ανεξάρτητα, σε κύτταρα ποντικού C2C12, παρουσία του γενικού αναστολέα της δράσης των κασπασών, Z-VAD-FMK, αλλά και αναστολέων της δράσης συγκεκριμένων κασπασών. Όλες οι υπό εξέταση ενώσεις επάγουν χαμηλά ποσοστά απόπτωσης. Οι κασπάσες-3, -6 και -8 συμμετέχουν στην επαγόμενη από τη MEL απόπτωση αλλά δεν συμμετέχουν στην απομάκρυνση των κυττάρων με μικροπυρήνες που επάγονται από τη δράση της ίδιας ένωσης. Η απόπτωση αποτελεί μηχανισμό απομάκρυνσης των κυττάρων με μικροπυρήνες και κανονικό κεντροσωματικό αριθμό που επάγονται από τις ενώσεις MEL, CAB και PHE. Αντίθετα, τα κύτταρα με υπεράριθμα κεντροσώματα, που προκύπτουν από τη δράση των παραπάνω ενώσεων δεν απομακρύνονται μέσω απόπτωσης. Για την περαιτέρω διερεύνηση του μηχανισμού με τον οποίο οι δραστικές ενώσεις MEL και CAB εκφράζουν τις ανευπλοειδογόνες ιδιότητες τους, μελετήθηκε η επίδραση τους στην έκφραση των πρωτεϊνών Aurora-B, survivin, Aurora-A και γ-τουμπουλίνη σε κύτταρα ποντικού C2C12, με τη μέθοδο της ανοσοαποτύπωσης των πρωτεϊνών. Παράλληλα μελετήθηκε η ένωση ΕΑ-97, η οποία σύμφωνα με τα ευρήματα μας, εμφάνισε αποκλειστικά θραυσματογόνο δράση. Οι ενώσεις MEL και CAB, εκδηλώνουν τις ανευπλοειδογόνες ιδιότητες τους προκαλώντας μείωση της έκφρασης των πρωτεϊνών Aurora-B και survivin και επάγοντας την αύξηση της έκφρασης της πρωτεΐνης Aurora-A. Επιπρόσθετα, η ένωση MEL, προκαλεί αύξηση της έκφρασης της γ-τουμπουλίνης. Τα ευρήματα αυτά υποδεικνύουν τη συμμετοχή των παραπάνω πρωτεϊνών στην εκδήλωση της ανευπλοειδογόνου δράσης των ενώσεων που μελετήθηκαν. Αντίθετα το στεροειδές ανάλογο ΕΑ-97 που εμφανίζει αποκλειστικά θραυσματογόνο δράση, δεν μεταβάλλει την έκφραση των παραπάνω πρωτεϊνών. / Nitrogen mustards represent an effective class of drugs that are used in chemotherapy. Recent findings of our group have shown that nitrogen mustard analogues, melphalan (MEL), chlorambucil (CAB) and PHE, in addition to their clastogenic activity, they exert their aneugenic potential by affecting chromosome segregation due to modifications of mitotic apparatus. In the present study, we investigated the mechanism by which the above compounds display their aneugenicity in comparison with two new steroidal analogues of PHE, EA-92 and EA-97, which were designed aiming at most effective antineoplasmatic activity. The ability of MEL, CAB and PHE to induce chromosome delay events was studied in comparison with the steroidal analogues EA-92 and EA-97. The mechanism of micronucleation was determined by Cytokinesis Block Micronucleus assay (CBMN assay) in combination with Fluorescence In Situ Hybridization (FISH) using pancentromeric DNA probe. It was confirmed that MEL, CAB and PHE generated MNi by two mechanisms, chromosome breakage and chromosome delay, while EA-92 and EA-97 induced the formation of MN originated exclusively from chromosome breakage events. The ability of the tested compounds to induce chromosome delay was also investigated in C2C12 mouse cells by CREST analysis. The dual genetic activity of MEL, CAB, and PHE was confirmed in a different biological system. The analogues EA-92 and EA-97 appeared as weaker MN inducers and they induced mainly chromosome breakage, while a weak aneugenic activity was observed for EA-92. The ability of the nitrogen mustard analogues to affect the organization of mitotic apparatus was investigated in comparison with MEL, CAB and PHE by double immunofluorescence of β- and γ-tubulin in C2C12 mouse cells. It was observed that all compounds, except EA-97, induced mutlipolar metaphases, and also generated interphase cells with abnormal centrosome number. All compounds displayed increased cytotoxicity and they caused cell cycle delay in human lymphocyte cultures and in C2C12 mouse cells. The ability of the tested compounds to induce apoptosis was studied by Annexin V/PI assay. It was revealed that all compounds induced apoptosis. The effect of apoptosis on the genetic activity of MEL, CAB and PHE was investigated by inhibition of apoptosis in the presence of the inhibitor Z-VAD-FMK and the use of specific inhibitors for caspase -3, -6, -8 and -1. For this reason Annexin V/PI assay and double immunofluorescence of β- and γ-tubulin were performed, independently in C2C12 mouse cells. Caspases -3, -6 and -8 are involved in melphalan-induced apoptosis, but they are not involved in the elimination of cells in the presence of melphalan. Apoptosis is the responsible mechanism for the exclusion of cells with MNi and normal centrosome number that are induced by MEL, CAB and PHE. On the contrary, cells exerting supernumerary centrosomes are not eliminated by apoptosis in the presence of the above compounds. To further elucidate the mechanisms by which MEL and CAB exert their aneugenic potential, we examined the ability of the compounds to alter the expression of proteins having important role in chromosome segregation, such as the proteins Aurora-B, survivin, Aurora-A and γ-tubulin. The analysis was performed by Western blot method in C2C12 mouse cells. We also studied the steroid analogue EA-97, which according to our findings acts as a pure clastogen and do not exert aneugenic potential as opposed to MEL and CAB. MEL and CAB exert their aneugenic potential by the reduction of Aurora-B and survivin expression and by enhancing the expression of Aurora-A. γ-tubulin was upregulated in the presence of MEL. These findings show the implication of these proteins in chromosome delay events induced by MEL and CAB. On the other hand, the analogue EA-97 did not affect the expression of the above proteins.

No description available.

An importance of spa services is especially in the medical treatment, but their economic significance is also very substantial. It significantly affects investment activities and an employment and it contributes to a regional development. Aurora Spa in Třeboň specializes in treating of musculoskeletal disorders, rheumatic diseases, post-traumatic and post-operative conditions and overall recondition of the body. Spa services in Třeboň have been, since a long time ago, associated with a natural healing source, which is abundant in this locality ? a boggy soil. Aurora Spa is not determined only for ill clients, but it is frequently visited by healthy people who undergo reconditioning and relaxation stays. The current trend heads toward to the fact that in the future the spa care covered from the public health insurance, will be in some way limited and clients will have to pay either a part or the entire treatment from their own financial funds. For this reason it is necessary to concentrate with spa service operators on a great clients´ satisfaction with their spa stay, so that they would return to the spa facility. Since I have worked for five years in the area of providing of the treatment services, I followed my bachelor thesis ?Clients´ satisfaction with spa services? by this diploma thesis, in order to re-map the clients´ satisfaction with services provided in above mentioned spa. I wanted to find out whether clients´ attitudes to the provided services had significantly changed from the research in 2009 year in my bachelor thesis. I used for the research the same questionnaire as in the research in 2009 year. 220 respondents were chosen for the research in the period of September 2011; 110 respondents had their stay covered by some of health insurance companies, either in a form of a complex or a contributory spa care and 110 respondents paid their treatment stay from their own funds as private payers. I supposed that men would be more satisfied than women and clients to whom some of the health insurance companies paid the stay, would be more satisfied than clients paying the stay from their own funds. After processing the data, there were not found out any significant differences in the satisfaction between these groups of respondents and in comparison with the research in the bachelor thesis from 2009 year there were not apparent any significant variations in the clients´ satisfaction with the services provided, which confirms, that the spa services in Aurora Spa are still on a very high level. Results of this diploma thesis can be used by employees of Aurora Spa to enhance the quality of provided spa service in all areas and to improve staff access to their clients.

Made available in DSpace on 2014-12-17T14:36:45Z (GMT). No. of bitstreams: 1 MariaFFA.pdf: 2142481 bytes, checksum: 62cdcab237481ec3fcc9eb304996d61a (MD5) Previous issue date: 2007-04-26 / La recherche intitul?e l Histoire des femmes ag?es du group Aurore de La Vie: Campina Grande-PB (1940-1950) a surgit comme consequence de mon observation sur les inter?ts de femmes en retrouner ? l ?cole apr?s qu elles ?taient arriv?es aux soixante ans, um moment de la vie que malgr? son importance est encore consider?e par trop de gens comme des moments d ?tre seul jusqu ? la fin de la vie. Alors, nous avons formul? la question la plus importante de ce travail: Quel est l histoire de l ?ducation des femmes ag?es du group Aurore de La Vie, dans le p?riode de son education d enfant? Un group de 25 femmes qui ont ?tudi? le projet Digna, on a fait une seletion de treize ag?es, entre 65 et 80 ans, qui s appellent: Perp?tua, Florinda, Benta, Ambr?sia, Celestine, Cord?lia, Circe, Filomena, Desd?mona, Dorot?ia, Ofelia, Mart?tius e Nausica. Beaucoup d intelectuels nous ont aid? avec la base the?rico-methodologique et nous ont present? l histoire des exclud?es comment une histoire en construction. Parmis ces intelectuelles on rencontre Chartier, Halbwachs, Elias, Perrot, Bosi, Bezerra, Morais et Machado. Pendant notre recherche nous avons employ?s des narrations, des entrevues, des questions ouvertes ou les femmes puissent parler sur l histoire de leur vie. Nous avons regard? aussi le fiche des ag?es, le arquive de La Secretarie Municipale de Assistence Social (SEMAS) du H?tel de Ville de Campina Grande-PB. Nous avons aussi ?tudi? sur la legislation reli? ? la tematique de la Constituition Br?silienne dans l estatute et dans la Politique Nacional de l age. Notre ?tude nous a donn? des analises sur les themas: pauvresse, travail, sourvenirs, jeux e aussi punitions scolaires. Nous sommes arriv?s ? la conclusion qu ? l ?poque de son enfance, l ?ducation formale ?tait d?j? determin?e pour le mariage, la pr?-cr?ation la famille. Enfim toujours d?dans de la maison exclud?es du reste du monde. Nous avons compris que pesquiser cet object d ?tude est un contribut avec l histoire des exclud?es en cassant le silence des femmes lesqueles on ?t? ignor?es par presque toute la prodution historiographique / A pesquisa intitulada Hist?ria das mulheres idosas do Grupo Aurora da Vida Campina Grande-PB (1940 -1950), surgiu a partir da indaga??o sobre o interesse das mulheres em voltar ? escola ap?s 60 anos, numa etapa da vida considerada por muitos como uma fase de reclus?o e finitude. A quest?o norteadora desse trabalho: Qual ? a hist?ria da educa??o das mulheres idosas do Grupo Aurora da Vida, durante o per?odo correspondente ? inf?ncia? Do grupo de 25 mulheres que estavam estudando no Projeto Digna, foram selecionadas 13, com idade entre 65 a 80 anos, aqui cognominadas de: Perp?tua, Florinda, Benta, Ambr?sia, Celestina, Cord?lia, Circe, Filomena, Desd?mona, Dorot?ia, Of?lia, Mart?rius e Nausica. Recorremos para o embasamento te?rico-metodol?gico, autores que valorizam e apresentam a hist?ria dos exclu?dos, como uma hist?ria em constru??o, dentre eles destacamos Chartier, Halbwachs, Elias, Perrot, Bosi, Bezerra, Morais e Machado. Como fonte de pesquisa, fizemos uso das narrativas em entrevistas com roteiro semi-estruturado e perguntas abertas, em que as mulheres pudessem falar das suas hist?rias de vida. Coletamos dados pessoais no arquivo da Secretaria Municipal de Assist?ncia Social (SEMAS), da prefeitura de Campina Grande - PB. Consultamos legisla??o pertinente ? tem?tica na Constitui??o Brasileira, no Estatuto e na Pol?tica Nacional do Idoso. O estudo revelou como categorias de an?lise os temas: pobreza, trabalho, lembran?as, brincadeiras e castigos escolares. Constatamos que, na configura??o da ?poca vivida por estas mulheres, a educa??o formal n?o se constitu?a como prioridade. Significa dizer que o lugar social da mulher j? estava pr?-determinado em fun??o do casamento, da pr?-cria??o, do cuidar da fam?lia e para o mundo interno do lar. Portanto pesquisar este objeto de estudo ? contribuir com o registro da hist?ria dos exclu?dos, com a quebra do sil?ncio e, em particular, o sil?ncio das mulheres ignoradas e alijadas da produ??o historiogr?fica

This thesis deals with the business process based transformation of two businesses - Lázně Aurora s.r.o. and Bertiny lázně s.r.o. The outline of a system development analysis is based on a theoretical framework of the business process reengineering and the production management in a contemporary dynamic and turbulent corporate environment. A conversion into a holding arrangment with parent corporation Slatinné lázně Třeboň a.s. and two subsidiaries Lázně Aurora s.r.o. and Bertiny lázně s.r.o. is proposed in relation with restructuring and redesigning all business processes. The outline of new Slatinné lázně Třeboň group based on business process management precedes a detailed analysis of current state and future lookout of spa industry from the point of view of the new business entity. This analysis implies that current management techniques facing the challenging environment cannot guarantee a substantial economic growth of the businesses. Within a whole host of named reasons there are changes related to the transformation of the national health sector, strengthened by demographic changes. Current management practices and enterprise enablers of process management are evaluated through Process and Enterprise Maturity Model (PEMM). Last part of this thesis presents the outline of the new business system development analysis. The goal is to overcome the dynamic environment issues by engagement of business process management and to prepare a production system for serving different segments of clients that are characterized by considerably different needs and requirements. New model of core business processes is proposed in order to meet this goal. It comprises a description of process relations and positioning within the new enterprise structure, including the main reasons of such an alignment.

La polarité cellulaire est un déterminant essentiel dans le maintien de l’architecture tissulaire et la fonction de l’organe. Ainsi, la division cellulaire, la ciliogenèse, la prolifération, et la migration sont des évènements étroitement associés au processus de la polarisation cellulaire. L’altération de la polarité cellulaire contribue à la perte de l’intégrité des épithéliums et favorise le développement des cancers. La signalisation des lipides, telle que des phosphatidylinositols (PtdIns) joue un rôle vital dans la polarité apico-basale. Dans cette étude, nous avons développé des recherches pour mieux comprendre les mécanismes impliqués dans les effets de la phosphatase SHIP2 sur la polarité cellulaire. Nous avons pu démontrer que SHIP2 est impliquée dans la formation du site d’initiation de la formation de la lumière (AMIS) en régulant d’une part la contractilité acto-myosine induite par RhoA kinase et d’autre part YAP, un composant de la voie de signalisation Hippo. De plus, nous avons montré que l'inhibition de SHIP2 contribue à un défaut dans la formation de fuseau mitotique et dans le clivage de ce fuseau mitotique. La surexpression de SHIP2 induit une lumière large et des cils allongés attribuables à la diminution de l’expression de YAP, Aurora A et HEF1. Par contre, la diminution de l’expression de SHIP2 inhibe la formation des cils en provoquant la surexpression de YAP, Aurora A et HEF1 et ainsi l’apparition d’un phénotype multilumens. L’ensemble de nos travaux définissent un nouveau rôle de SHIP2 dans le maintien de l’intégrité et de l’homéostasie des cellules épithéliales. Nous avons aussi pu démontrer que l’expression de SHIP2 peut discriminer les différents cancers du foie (HCC, ICC et mixte) et que SHIP2 et Merlin/NF2, une protéine de la voie de signalisation Hippo, ont une forte expression dans le cholangiocarcinome (ICC) qui s’oppose à celle de YAP et de RhoA kinase. / Cell polarity is critical caracteristic for the maintenance of tissue architecture. Cell division, ciliogenesis, cell proliferation and migration are events tightly associated to cell polarization processes. Alteration in cell polarity contributes to loss of epithelium integrity and enhances cancer development. Lipids signaling, such as phosphatidylinositol (PtdIns), play a vital role in apico-basal polarity. In this study, we developed researches to better understand mechanisms implicated the role of the phosphatase SHIP2 in cell polarity. We demonstrated that SHIP2 is implicated in formation of the apical membrane initiation site (AMIS) by regulating YAP, a component of Hippo pathway, and RhoA-dependant acto-myosin contractility. Furthermore, we demonstrated that inhibition of SHIP2 contributes to defect in the formation and cleavage of the mitotic spindle. Overexpression of SHIP2 induced a large lumen with long cilia due to a decrease in YAP, Aurora A and HEF1 luminal localization. On the contrary, down regulation of SHIP2 impaired cilia outgrowth by increasing Aurora A, HEF1 and YAP luminal localization with appearance of a multilumens phenotype. Thus, our results reinforced the role of SHIP2 in maintain of integrity and homeostasis of epithelial cells. In this study, we also demonstrated that expression of SHIP2 distinguished the different types of liver cancer (HCC, ICC and mixte), and that SHIP2 and Merlin/NF2 are overexpressed in ICC which is the opposite of YAP and RhoA expression.

In-memory column-store database systems are state of the art for the efficient processing of analytical workloads. In these systems, data compression as well as vectorization play an important role. Currently, the vectorized processing is done using regular SIMD (Single Instruction Multiple Data) extensions of modern processors. For example, Intel’s latest SIMD extension supports 512-bit vector registers which allows the parallel processing of 8× 64-bit values. From a database system perspective, this vectorization technique is not only very interesting for compression and decompression to reduce the computational overhead, but also for all database operators like joins, scan, as well as groupings. In contrast to these SIMD extensions, NEC Corporation has recently introduced a novel pure vector engine (supercomputer) as a co-processor called SX-Aurora TSUBASA. This vector engine features a vector length of 16.384 bits with the world’s highest bandwidth of up to 1.2 TB/s, which perfectly fits to data-intensive applications like in-memory database systems. Therefore, we describe the unique architecture and properties of this novel vector engine in this paper. Moreover, we present selected in-memory column-store-specific evaluation results to show the benefits of this vector engine compared to regular SIMD extensions. Finally, we conclude the paper with an outlook on our ongoing research activities in this direction.

Aurora Kinase A is a kinase involved in multiple signaling pathways and interactions during mitosis, making it an essential kinase that deregulated causes cancer diseases in affected patients. Structural research shows mainly static snapshots of possible conformations of the partly disordered protein. This is due to challenges in generating a monodisperse pure sample with high stability enough for dynamic biophysical measurements. Optimizing the production of Aurora A and validating constructs with different sequential lengths using light scattering techniques, thermal stability screening, mass characterization, mass spectrometry, and immunoassay techniques is important for future structural insights useful for drug discoveries. In this project, validation of constructs concluded that no significant difference in cleavage of His-tag, purification possibilities, monodispersity nor stability is shown by variate start residue from 118-122 to end residue 403. Expression of an Aurora Kinase A constructs with sequential length 118-403 is preferred to be executed at 18 degrees, otherwise, temperature differences during expression show no impact on produced Aurora A. Magnesium chloride has been shown to have an impact on stability where a higher concentration stabilizes Aurora Kinase A. Moreover, concentration differences of NaCl were shown to not affect the stability of Aurora A. During this project a polydisperse sample was generated and has given insights into Aurora A´s behavior in solution.