Search

Your search keyword '"Saya H"' showing total 13 results
Start Over Author "Saya H" Database OpenAIRE
13 results on '"Saya H"'

1. An Inquiry About the Roles and Duties of Architects in the Public Sector: Sulaimani Governorate as the Study Field

Author

Saya H. Ahmad, Binay O. Rahim, Lawen A. Karim, and Ashkan Azad

Subjects
Work (electrical), business.industry, media_common.quotation_subject, Field (Bourdieu), Political science, Public sector, Public relations, Iraqi kurdistan, business, Duty, Building construction, media_common
Abstract

Architects throughout the time being experienced many roles in different times, while there have always been unclear what architects underwent and practised was their actual duty. This research tries to find proper answers about architects' duties, roles, and struggles in the Iraqi Kurdistan region. For this reason, questionnaires were applied to ask both the architects and administrative managers in Sulaimani governorate/department of building construction. We find out that the main role of an architect in the Sulaimani governorate is mainly designing projects. However, they are involved in managerial roles as project supervisors destined by the governorate and also another role of the architect is checking the drawings of the projects designed outside of this administration office. Another finding was that the architects in the Sulaimani governorate or Iraqi Kurdistan region generally face the problem that their works are done by other specialists, which sometimes cause some domain faults in the works and do not have enough or proper area to work in.

Published
2021

2. Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

Author

Grapotte M., Saraswat M., Bessiere C., Menichelli C., Ramilowski J. A., Severin J., Hayashizaki Y., Itoh M., Tagami M., Murata M., Kojima-Ishiyama M., Noma S., Noguchi S., Kasukawa T., Hasegawa A., Suzuki H., Nishiyori-Sueki H., Frith M. C., Abugessaisa I., Aitken S., Aken B. L., Alam I., Alam T., Alasiri R., Alhendi A. M. N., Alinejad-Rokny H., Alvarez M. J., Andersson R., Arakawa T., Araki M., Arbel T., Archer J., Archibald A. L., Arner E., Arner P., Asai K., Ashoor H., Astrom G., Babina M., Baillie J. K., Bajic V. B., Bajpai A., Baker S., Baldarelli R. M., Balic A., Bansal M., Batagov A. O., Batzoglou S., Beckhouse A. G., Beltrami A. P., Beltrami C. A., Bertin N., Bhattacharya S., Bickel P. J., Blake J. A., Blanchette M., Bodega B., Bonetti A., Bono H., Bornholdt J., Bttcher M., Bougouffa S., Boyd M., Breda J., Brombacher F., Brown J. B., Bult C. J., Burroughs A. M., Burt D. W., Busch A., Caglio G., Califano A., Cameron C. J., Cannistraci C. V., Carbone A., Carlisle A. J., Carninci P., Carter K. W., Cesselli D., Chang J. -C., Chen J. C., Chen Y., Chierici M., Christodoulou J., Ciani Y., Clark E. L., Coskun M., Dalby M., Dalla E., Daub C. O., Davis C. A., de Hoon M. J. L., de Rie D., Denisenko E., Deplancke B., Detmar M., Deviatiiarov R., Di Bernardo D., Diehl A. D., Dieterich L. C., Dimont E., Djebali S., Dohi T., Dostie J., Drablos F., Edge A. S. B., Edinger M., Ehrlund A., Ekwall K., Elofsson A., Endoh M., Enomoto H., Enomoto S., Faghihi M., Fagiolini M., Farach-Carson M. C., Faulkner G. J., Favorov A., Fernandes A. M., Ferrai C., Forrest A. R. R., Forrester L. M., Forsberg M., Fort A., Francescatto M., Freeman T. C., Frith M., Fukuda S., Funayama M., Furlanello C., Furuno M., Furusawa C., Gao H., Gazova I., Gebhard C., Geier F., Geijtenbeek T. B. H., Ghosh S., Ghosheh Y., Gingeras T. R., Gojobori T., Goldberg T., Goldowitz D., Gough J., Greco D., Gruber A. J., Guhl S., Guigo R., Guler R., Gusev O., Gustincich S., Ha T. J., Haberle V., Hale P., Hallstrom B. M., Hamada M., Handoko L., Hara M., Harbers M., Harrow J., Harshbarger J., Hase T., Hashimoto K., Hatano T., Hattori N., Hayashi R., Herlyn M., Hettne K., Heutink P., Hide W., Hitchens K. J., Sui S. H., 't Hoen P. A. C., Hon C. C., Hori F., Horie M., Horimoto K., Horton P., Hou R., Huang E., Huang Y., Hugues R., Hume D., Ienasescu H., Iida K., Ikawa T., Ikemura T., Ikeo K., Inoue N., Ishizu Y., Ito Y., Ivshina A. V., Jankovic B. R., Jenjaroenpun P., Johnson R., Jorgensen M., Jorjani H., Joshi A., Jurman G., Kaczkowski B., Kai C., Kaida K., Kajiyama K., Kaliyaperumal R., Kaminuma E., Kanaya T., Kaneda H., Kapranov P., Kasianov A. S., Katayama T., Kato S., Kawaguchi S., Kawai J., Kawaji H., Kawamoto H., Kawamura Y. I., Kawasaki S., Kawashima T., Kempfle J. S., Kenna T. J., Kere J., Khachigian L., Kiryu H., Kishima M., Kitajima H., Kitamura T., Kitano H., Klaric E., Klepper K., Klinken S. P., Kloppmann E., Knox A. J., Kodama Y., Kogo Y., Kojima M., Kojima S., Komatsu N., Komiyama H., Kono T., Koseki H., Koyasu S., Kratz A., Kukalev A., Kulakovskiy I., Kundaje A., Kunikata H., Kuo R., Kuo T., Kuraku S., Kuznetsov V. A., Kwon T. J., Larouche M., Lassmann T., Law A., Le-Cao K. -A., Lecellier C. -H., Lee W., Lenhard B., Lennartsson A., Li K., Li R., Lilje B., Lipovich L., Lizio M., Lopez G., Magi S., Mak G. K., Makeev V., Manabe R., Mandai M., Mar J., Maruyama K., Maruyama T., Mason E., Mathelier A., Matsuda H., Medvedeva Y. A., Meehan T. F., Mejhert N., Meynert A., Mikami N., Minoda A., Miura H., Miyagi Y., Miyawaki A., Mizuno Y., Morikawa H., Morimoto M., Morioka M., Morishita S., Moro K., Motakis E., Motohashi H., Mukarram A. K., Mummery C. L., Mungall C. J., Murakawa Y., Muramatsu M., Nagasaka K., Nagase T., Nakachi Y., Nakahara F., Nakai K., Nakamura K., Nakamura Y., Nakazawa T., Nason G. P., Nepal C., Nguyen Q. H., Nielsen L. K., Nishida K., Nishiguchi K. M., Nishiyori H., Nitta K., Notredame C., Ogishima S., Ohkura N., Ohno H., Ohshima M., Ohtsu T., Okada Y., Okada-Hatakeyama M., Okazaki Y., Oksvold P., Orlando V., Ow G. S., Ozturk M., Pachkov M., Paparountas T., Parihar S. P., Park S. -J., Pascarella G., Passier R., Persson H., Philippens I. H., Piazza S., Plessy C., Pombo A., Ponten F., Poulain S., Poulsen T. M., Pradhan S., Prezioso C., Pridans C., Qin X. -Y., Quackenbush J., Rackham O., Ramilowski J., Ravasi T., Rehli M., Rennie S., Rito T., Rizzu P., Robert C., Roos M., Rost B., Roudnicky F., Roy R., Rye M. B., Sachenkova O., Saetrom P., Sai H., Saiki S., Saito M., Saito A., Sakaguchi S., Sakai M., Sakaue S., Sakaue-Sawano A., Sandelin A., Sano H., Sasamoto Y., Sato H., Saxena A., Saya H., Schafferhans A., Schmeier S., Schmidl C., Schmocker D., Schneider C., Schueler M., Schultes E. A., Schulze-Tanzil G., Semple C. A., Seno S., Seo W., Sese J., Sheng G., Shi J., Shimoni Y., Shin J. W., SimonSanchez J., Sivertsson A., Sjostedt E., Soderhall C., Laurent G. S., Stoiber M. H., Sugiyama D., Summers K. M., Suzuki A. M., Suzuki K., Suzuki M., Suzuki N., Suzuki T., Swanson D. J., Swoboda R. K., Taguchi A., Takahashi H., Takahashi M., Takamochi K., Takeda S., Takenaka Y., Tam K. T., Tanaka H., Tanaka R., Tanaka Y., Tang D., Taniuchi I., Tanzer A., Tarui H., Taylor M. S., Terada A., Terao Y., Testa A. C., Thomas M., Thongjuea S., Tomii K., Triglia E. T., Toyoda H., Tsang H. G., Tsujikawa M., Uhlen M., Valen E., van de Wetering M., van Nimwegen E., Velmeshev D., Verardo R., Vitezic M., Vitting-Seerup K., von Feilitzen K., Voolstra C. R., Vorontsov I. E., Wahlestedt C., Wasserman W. W., Watanabe K., Watanabe S., Wells C. A., Winteringham L. N., Wolvetang E., Yabukami H., Yagi K., Yamada T., Yamaguchi Y., Yamamoto M., Yamamoto Y., Yamanaka Y., Yano K., Yasuzawa K., Yatsuka Y., Yo M., Yokokura S., Yoneda M., Yoshida E., Yoshida Y., Yoshihara M., Young R., Young R. S., Yu N. Y., Yumoto N., Zabierowski S. E., Zhang P. G., Zucchelli S., Zwahlen M., Chatelain C., Brehelin L., Grapotte, M., Saraswat, M., Bessiere, C., Menichelli, C., Ramilowski, J. A., Severin, J., Hayashizaki, Y., Itoh, M., Tagami, M., Murata, M., Kojima-Ishiyama, M., Noma, S., Noguchi, S., Kasukawa, T., Hasegawa, A., Suzuki, H., Nishiyori-Sueki, H., Frith, M. C., Abugessaisa, I., Aitken, S., Aken, B. L., Alam, I., Alam, T., Alasiri, R., Alhendi, A. M. N., Alinejad-Rokny, H., Alvarez, M. J., Andersson, R., Arakawa, T., Araki, M., Arbel, T., Archer, J., Archibald, A. L., Arner, E., Arner, P., Asai, K., Ashoor, H., Astrom, G., Babina, M., Baillie, J. K., Bajic, V. B., Bajpai, A., Baker, S., Baldarelli, R. M., Balic, A., Bansal, M., Batagov, A. O., Batzoglou, S., Beckhouse, A. G., Beltrami, A. P., Beltrami, C. A., Bertin, N., Bhattacharya, S., Bickel, P. J., Blake, J. A., Blanchette, M., Bodega, B., Bonetti, A., Bono, H., Bornholdt, J., Bttcher, M., Bougouffa, S., Boyd, M., Breda, J., Brombacher, F., Brown, J. B., Bult, C. J., Burroughs, A. M., Burt, D. W., Busch, A., Caglio, G., Califano, A., Cameron, C. J., Cannistraci, C. V., Carbone, A., Carlisle, A. J., Carninci, P., Carter, K. W., Cesselli, D., Chang, J. -C., Chen, J. C., Chen, Y., Chierici, M., Christodoulou, J., Ciani, Y., Clark, E. L., Coskun, M., Dalby, M., Dalla, E., Daub, C. O., Davis, C. A., de Hoon, M. J. L., de Rie, D., Denisenko, E., Deplancke, B., Detmar, M., Deviatiiarov, R., Di Bernardo, D., Diehl, A. D., Dieterich, L. C., Dimont, E., Djebali, S., Dohi, T., Dostie, J., Drablos, F., Edge, A. S. B., Edinger, M., Ehrlund, A., Ekwall, K., Elofsson, A., Endoh, M., Enomoto, H., Enomoto, S., Faghihi, M., Fagiolini, M., Farach-Carson, M. C., Faulkner, G. J., Favorov, A., Fernandes, A. M., Ferrai, C., Forrest, A. R. R., Forrester, L. M., Forsberg, M., Fort, A., Francescatto, M., Freeman, T. C., Frith, M., Fukuda, S., Funayama, M., Furlanello, C., Furuno, M., Furusawa, C., Gao, H., Gazova, I., Gebhard, C., Geier, F., Geijtenbeek, T. B. H., Ghosh, S., Ghosheh, Y., Gingeras, T. R., Gojobori, T., Goldberg, T., Goldowitz, D., Gough, J., Greco, D., Gruber, A. J., Guhl, S., Guigo, R., Guler, R., Gusev, O., Gustincich, S., Ha, T. J., Haberle, V., Hale, P., Hallstrom, B. M., Hamada, M., Handoko, L., Hara, M., Harbers, M., Harrow, J., Harshbarger, J., Hase, T., Hashimoto, K., Hatano, T., Hattori, N., Hayashi, R., Herlyn, M., Hettne, K., Heutink, P., Hide, W., Hitchens, K. J., Sui, S. H., 't Hoen, P. A. C., Hon, C. C., Hori, F., Horie, M., Horimoto, K., Horton, P., Hou, R., Huang, E., Huang, Y., Hugues, R., Hume, D., Ienasescu, H., Iida, K., Ikawa, T., Ikemura, T., Ikeo, K., Inoue, N., Ishizu, Y., Ito, Y., Ivshina, A. V., Jankovic, B. R., Jenjaroenpun, P., Johnson, R., Jorgensen, M., Jorjani, H., Joshi, A., Jurman, G., Kaczkowski, B., Kai, C., Kaida, K., Kajiyama, K., Kaliyaperumal, R., Kaminuma, E., Kanaya, T., Kaneda, H., Kapranov, P., Kasianov, A. S., Katayama, T., Kato, S., Kawaguchi, S., Kawai, J., Kawaji, H., Kawamoto, H., Kawamura, Y. I., Kawasaki, S., Kawashima, T., Kempfle, J. S., Kenna, T. J., Kere, J., Khachigian, L., Kiryu, H., Kishima, M., Kitajima, H., Kitamura, T., Kitano, H., Klaric, E., Klepper, K., Klinken, S. P., Kloppmann, E., Knox, A. J., Kodama, Y., Kogo, Y., Kojima, M., Kojima, S., Komatsu, N., Komiyama, H., Kono, T., Koseki, H., Koyasu, S., Kratz, A., Kukalev, A., Kulakovskiy, I., Kundaje, A., Kunikata, H., Kuo, R., Kuo, T., Kuraku, S., Kuznetsov, V. A., Kwon, T. J., Larouche, M., Lassmann, T., Law, A., Le-Cao, K. -A., Lecellier, C. -H., Lee, W., Lenhard, B., Lennartsson, A., Li, K., Li, R., Lilje, B., Lipovich, L., Lizio, M., Lopez, G., Magi, S., Mak, G. K., Makeev, V., Manabe, R., Mandai, M., Mar, J., Maruyama, K., Maruyama, T., Mason, E., Mathelier, A., Matsuda, H., Medvedeva, Y. A., Meehan, T. F., Mejhert, N., Meynert, A., Mikami, N., Minoda, A., Miura, H., Miyagi, Y., Miyawaki, A., Mizuno, Y., Morikawa, H., Morimoto, M., Morioka, M., Morishita, S., Moro, K., Motakis, E., Motohashi, H., Mukarram, A. K., Mummery, C. L., Mungall, C. J., Murakawa, Y., Muramatsu, M., Nagasaka, K., Nagase, T., Nakachi, Y., Nakahara, F., Nakai, K., Nakamura, K., Nakamura, Y., Nakazawa, T., Nason, G. P., Nepal, C., Nguyen, Q. H., Nielsen, L. K., Nishida, K., Nishiguchi, K. M., Nishiyori, H., Nitta, K., Notredame, C., Ogishima, S., Ohkura, N., Ohno, H., Ohshima, M., Ohtsu, T., Okada, Y., Okada-Hatakeyama, M., Okazaki, Y., Oksvold, P., Orlando, V., Ow, G. S., Ozturk, M., Pachkov, M., Paparountas, T., Parihar, S. P., Park, S. -J., Pascarella, G., Passier, R., Persson, H., Philippens, I. H., Piazza, S., Plessy, C., Pombo, A., Ponten, F., Poulain, S., Poulsen, T. M., Pradhan, S., Prezioso, C., Pridans, C., Qin, X. -Y., Quackenbush, J., Rackham, O., Ramilowski, J., Ravasi, T., Rehli, M., Rennie, S., Rito, T., Rizzu, P., Robert, C., Roos, M., Rost, B., Roudnicky, F., Roy, R., Rye, M. B., Sachenkova, O., Saetrom, P., Sai, H., Saiki, S., Saito, M., Saito, A., Sakaguchi, S., Sakai, M., Sakaue, S., Sakaue-Sawano, A., Sandelin, A., Sano, H., Sasamoto, Y., Sato, H., Saxena, A., Saya, H., Schafferhans, A., Schmeier, S., Schmidl, C., Schmocker, D., Schneider, C., Schueler, M., Schultes, E. A., Schulze-Tanzil, G., Semple, C. A., Seno, S., Seo, W., Sese, J., Sheng, G., Shi, J., Shimoni, Y., Shin, J. W., Simonsanchez, J., Sivertsson, A., Sjostedt, E., Soderhall, C., Laurent, G. S., Stoiber, M. H., Sugiyama, D., Summers, K. M., Suzuki, A. M., Suzuki, K., Suzuki, M., Suzuki, N., Suzuki, T., Swanson, D. J., Swoboda, R. K., Taguchi, A., Takahashi, H., Takahashi, M., Takamochi, K., Takeda, S., Takenaka, Y., Tam, K. T., Tanaka, H., Tanaka, R., Tanaka, Y., Tang, D., Taniuchi, I., Tanzer, A., Tarui, H., Taylor, M. S., Terada, A., Terao, Y., Testa, A. C., Thomas, M., Thongjuea, S., Tomii, K., Triglia, E. T., Toyoda, H., Tsang, H. G., Tsujikawa, M., Uhlen, M., Valen, E., van de Wetering, M., van Nimwegen, E., Velmeshev, D., Verardo, R., Vitezic, M., Vitting-Seerup, K., von Feilitzen, K., Voolstra, C. R., Vorontsov, I. E., Wahlestedt, C., Wasserman, W. W., Watanabe, K., Watanabe, S., Wells, C. A., Winteringham, L. N., Wolvetang, E., Yabukami, H., Yagi, K., Yamada, T., Yamaguchi, Y., Yamamoto, M., Yamamoto, Y., Yamanaka, Y., Yano, K., Yasuzawa, K., Yatsuka, Y., Yo, M., Yokokura, S., Yoneda, M., Yoshida, E., Yoshida, Y., Yoshihara, M., Young, R., Young, R. S., Yu, N. Y., Yumoto, N., Zabierowski, S. E., Zhang, P. G., Zucchelli, S., Zwahlen, M., Chatelain, C., Brehelin, L., Institute of Biotechnology, Biosciences, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Computationnelle (IBC), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Méthodes et Algorithmes pour la Bioinformatique (MAB), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), National Institute of Advanced Industrial Science and Technology (AIST), SANOFI Recherche, University of British Columbia (UBC), Experimental Immunology, Infectious diseases, AII - Infectious diseases, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)

Subjects
0301 basic medicine, General Physics and Astronomy, Genome, Mice, 0302 clinical medicine, Transcription (biology), Promoter Regions, Genetic, Transcription Initiation, Genetic, 0303 health sciences, Multidisciplinary, 1184 Genetics, developmental biology, physiology, High-Throughput Nucleotide Sequencing, Neurodegenerative Diseases, 222 Other engineering and technologies, Genomics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], humanities, Enhancer Elements, Genetic, Microsatellite Repeat, Transcription Initiation Site, Sequence motif, Transcription Initiation, Human, Enhancer Elements, Neural Networks, Science, 610 Medicine & health, Computational biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Promoter Regions, 03 medical and health sciences, Computer, Deep Learning, Tandem repeat, Genetic, Clinical Research, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Machine learning, Genetics, Animals, Humans, Polymorphism, Enhancer, Transcriptomics, Gene, A549 Cell, 030304 developmental biology, Polymorphism, Genetic, Neurodegenerative Disease, Base Sequence, Animal, Genome, Human, Human Genome, Computational Biology, Promoter, General Chemistry, 113 Computer and information sciences, Cap analysis gene expression, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cardiovascular and Metabolic Diseases, A549 Cells, Minion, Generic health relevance, 3111 Biomedicine, Neural Networks, Computer, 610 Medizin und Gesundheit, 030217 neurology & neurosurgery, FANTOM consortium, Microsatellite Repeats
Abstract

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism., Nature Communications, 12 (1), ISSN:2041-1723

Published
2020

3. The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein

Author

Lorna Wills, Saya H. Ebbesen, Wu Zheng, Navneet Narula, Scott Powers, Kendra S. Plafker, Lloyd C. Trotman, Tali Herzka, Brian D. Robinson, Kaitlin Watrud, Vivek Mittal, Brendon M. Stiles, Nasser K. Altorki, Carlos Stahlhut, Dawid G. Nowak, John E. Wilkinson, Abu Nasar, Raffaella Sordella, Matthias Minderer, Carlos Cordon-Cardo, Mireia Castillo-Martin, Martha E. Zeeman, Alexandra Ambrico, Muhan Chen, Victoria M.-Y. Wang, and Scott M. Plafker

Subjects
0301 basic medicine, Cytoplasm, Lung Neoplasms, Phosphatase, Receptors, Cytoplasmic and Nuclear, Importin, Biology, Article, Cell Line, law.invention, Metastasis, Mice, 03 medical and health sciences, law, Cell Line, Tumor, medicine, Animals, Humans, Tensin, PTEN, Receptor, Research Articles, Cell Nucleus, Tumor Suppressor Proteins, PTEN Phosphohydrolase, Cell Biology, beta Karyopherins, medicine.disease, 3. Good health, 030104 developmental biology, Ubiquitin-Conjugating Enzymes, Cancer research, biology.protein, Suppressor, Adenocarcinoma, HeLa Cells
Abstract

Reduced PTEN protein is linked to tumorigenesis. Here, Chen et al. show that the nuclear transport receptor Importin-11 separates PTEN from degradation machinery. IPO11 mutant mice exhibit PTEN degradation, lung adenocarcinoma, and prostate neoplasia. In human prostatectomy patients, IPO11 status predicts disease recurrence and metastasis., Phosphatase and tensin homologue (PTEN) protein levels are critical for tumor suppression. However, the search for a recurrent cancer-associated gene alteration that causes PTEN degradation has remained futile. In this study, we show that Importin-11 (Ipo11) is a transport receptor for PTEN that is required to physically separate PTEN from elements of the PTEN degradation machinery. Mechanistically, we find that the E2 ubiquitin-conjugating enzyme and IPO11 cargo, UBE2E1, is a limiting factor for PTEN degradation. Using in vitro and in vivo gene-targeting methods, we show that Ipo11 loss results in degradation of Pten, lung adenocarcinoma, and neoplasia in mouse prostate with aberrantly high levels of Ube2e1 in the cytoplasm. These findings explain the correlation between loss of IPO11 and PTEN protein in human lung tumors. Furthermore, we find that IPO11 status predicts disease recurrence and progression to metastasis in patients choosing radical prostatectomy. Thus, our data introduce the IPO11 gene as a tumor-suppressor locus, which is of special importance in cancers that still retain at least one intact PTEN allele.

Published
2017

5. Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

Author

Lukas E. Dow, Maurizio Scaltriti, Natasha Morse, Hannah Y. Wen, José Baselga, Edward R. Kastenhuber, Scott W. Lowe, Carl Uli Bialucha, and Saya H. Ebbesen

Subjects
0301 basic medicine, MAPK/ERK pathway, Tumor suppressor gene, MAP Kinase Signaling System, Receptor, ErbB-2, MAP Kinase Kinase 1, Mice, Nude, Mice, Transgenic, medicine.disease_cause, HER2/neu, 03 medical and health sciences, Mice, Phosphatidylinositol 3-Kinases, Breast cancer, medicine, PTEN, Animals, Humans, Neoplasm Metastasis, Phosphorylation, RNA, Small Interfering, Protein kinase A, skin and connective tissue diseases, Extracellular Signal-Regulated MAP Kinases, PI3K/AKT/mTOR pathway, Multidisciplinary, biology, PTEN Phosphohydrolase, Mammary Neoplasms, Experimental, Biological Sciences, Genes, erbB-2, medicine.disease, Neoplasm Proteins, 030104 developmental biology, Mammary Tumor Virus, Mouse, Cancer research, biology.protein, Female, RNA Interference, Carcinogenesis, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

Significance PTEN mutations are associated with disease progression and therapy resistance in human epidermal growth factor receptor 2 ( HER2/neu )-amplified breast cancer patients but the role of PTEN loss in breast cancer maintenance is unknown. Here, using a regulatable RNAi mouse model of HER2/neu-driven metastatic breast cancer, we show that Pten silencing accelerates disease progression and that restoration of endogenous Pten expression triggers marked disease regression. By comparing and contrasting how pharmacologic perturbations of various signaling pathways compare to genetic reactivation of Pten, we identify a requirement for Mek signaling in Pten-suppressed tumors. Our findings imply that even advanced tumors can remain dependent on Pten loss and provide a rationale for exploring the utility of MEK inhibitors in therapy-resistant breast cancer patients acquiring PTEN mutations.

Published
2016

6. A Novel Anti-cancer Strategy Targeting CD44-positive Cancer Stem Cells

Author

Masashi Tsuruta, Okabayashi K, Ryo Seishima, Nagano O, Saya H, Hasegawa H, and Kitagawa Y

Subjects
biology, Cancer stem cell, business.industry, CD44, Cancer research, biology.protein, medicine, Cancer, Bioinformatics, medicine.disease, Omics, business
Published
2016

7. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver

Author

Caitlin Williams, Kavita Mallya, Saya H. Ebbesen, Gonçalo Rodrigues, Henrik Molina, Irina Matei, Ayuko Hoshino, Annette Becker, William R. Jarnagin, Bruno Costa-Silva, Yujie Huang, Milica Tesic Mark, Inger Marie Bowitz Lothe, Nicole M. Aiello, Michael A. Hollingsworth, Tang-Long Shen, Guillermo García-Santos, Till Martin Theilen, Elin H. Kure, Yonathan Ararso, Haiying Zhang, Robert E. Schwartz, Alexandre Doussot, Allyson J. Ocean, Basant Kumar Thakur, Jonathan M. Hernandez, Knut Jørgen Labori, Paul M. Grandgenett, David Lyden, Ben Z. Stanger, Swarnima Singh, Maneesh Jain, Jenny Xiang, Tuo Zhang, Héctor Peinado, Jacqueline Bromberg, and Surinder K. Batra

Subjects
endocrine system diseases, Liver cytology, Bone Marrow Cells, Biology, Exosomes, Article, Metastasis, Mice, Cell Movement, Transforming Growth Factor beta, Pancreatic cancer, Cell Line, Tumor, medicine, Hepatic Stellate Cells, Animals, Humans, Secretion, RNA, Small Interfering, Macrophage Migration-Inhibitory Factors, Mice, Knockout, Base Sequence, Sequence Analysis, RNA, Macrophages, Liver Neoplasms, Cancer, Cell Biology, medicine.disease, digestive system diseases, Microvesicles, Cell biology, Fibronectins, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Pancreatic Neoplasms, medicine.anatomical_structure, Liver, Hepatic stellate cell, Female, RNA Interference, Pancreas, Precancerous Conditions, Carcinoma, Pancreatic Ductal, Signal Transduction
Abstract

Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.

Published
2014

8. Conditional reverse tet-transactivator mouse strains for the efficient induction of TRE-regulated transgenes in mice

Author

Jerry Pelletier, Saya H. Ebbesen, Lukas E. Dow, Teresa Lee, Nilgun Tasdemir, Zeina Nasr, Michael Saborowski, Scott W. Lowe, and Eusebio Manchado

Subjects
Transgene, Gene Expression, lcsh:Medicine, Mice, Transgenic, Mouse Models, Biology, Response Elements, Research and Analysis Methods, Molecular Genetics, 03 medical and health sciences, Transactivation, Mice, 0302 clinical medicine, RNA interference, Model Organisms, Gene expression, Molecular Cell Biology, medicine, Genetics, Cancer Genetics, Tissue specific, Animals, Gene Regulation, Transgenes, lcsh:Science, 030304 developmental biology, Regulation of gene expression, Cloning, Cell specific, Doxycycline, 0303 health sciences, Multidisciplinary, Models, Genetic, Biology and life sciences, lcsh:R, Cell Biology, Animal Models, Cell biology, Repressor Proteins, Gene Expression Regulation, 030220 oncology & carcinogenesis, Genetics of Disease, Epigenetics, lcsh:Q, Gene Function, Animal Genetics, medicine.drug, Research Article
Abstract

Tetracycline or doxycycline (dox)-regulated control of genetic elements allows inducible, reversible and tissue specific regulation of gene expression in mice. This approach provides a means to investigate protein function in specific cell lineages and at defined periods of development and disease. Efficient and stable regulation of cDNAs or non-coding elements (e.g. shRNAs) downstream of the tetracycline-regulated element (TRE) requires the robust expression of a tet-transactivator protein, commonly the reverse tet-transactivator, rtTA. Most rtTA strains rely on tissue specific promoters that often do not provide sufficient rtTA levels for optimal inducible expression. Here we describe the generation of two mouse strains that enable Cre-dependent, robust expression of rtTA3, providing tissue-restricted and consistent induction of TRE-controlled transgenes. We show that these transgenic strains can be effectively combined with established mouse models of disease, including both Cre/LoxP-based approaches and non Cre-dependent disease models. The integration of these new tools with established mouse models promises the development of more flexible genetic systems to uncover the mechanisms of development and disease pathogenesis.

Published
2014

9. Abstract LB-327: Loss of PTEN leads to clinical resistance to the PI3Kα inhibitor BYL719 and provides evidence of convergent evolution under selective therapeutic pressure

Author

Malachi Griffith, David B. Solit, Helen Won, Michael F. Berger, José Baselga, Haley Ellis, Iyer Gopakumar, Elaine R. Mardis, Cornelia Quadt, Scott W. Lowe, Benjamin J. Ainscough, Pau Castel, Saya H. Ebbesen, Maurizio Scaltriti, Malte Peters, Dennis C. Sgroi, Steven J. Isakoff, Obi L. Griffith, and Dejan Juric

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Splice site mutation, biology, Cancer, P110α, medicine.disease, Primary tumor, Frameshift mutation, Oncology, Genetic model, biology.protein, medicine, Cancer research, PTEN, PI3K/AKT/mTOR pathway
Abstract

Activating mutations of PIK3CA, the gene encoding the p110α subunit of PI3K, are frequent in breast cancer and selective inhibitors of this enzyme have shown promising clinical activity in breast tumors harboring these mutations. We studied the case of a patient with metastatic breast cancer harboring a PIK3CA mutation that was treated in a clinical trial with BYL719, a highly selective PI3Kα inhibitor. The treatment resulted in a robust partial response that lasted 7 months followed by rapid progression and death. A rapid autopsy was performed with collection of tissue samples from 16 different metastatic sites. We compared by whole genome and exome sequencing the original primary tumor, a rapidly progressing lung metastasis and a periaortic lesion that was still responding to BYL719 at time of death. Besides several common alterations, PTEN loss and a missense mutation were detected only in the lung metastasis. Using targeted exome sequencing we analyzed all the other available samples. Strikingly, we observed a consistent loss in PTEN (via different mechanisms such as deletion, splice site mutation and frameshift mutations) in all the lesions refractory to BYL719 but not in the responding ones. In every case, the loss of PTEN was also documented by lack of protein expression by immunohistochemistry (IHC). Finally, we were able to build a dendrogram showing the phylogenetic evolution of the lesions and the evolutionary convergence of the PTEN alterations. To validate PTEN loss as a possible mechanism of acquired resistance to selective PI3Kα inhibition, we generated doxycycline-inducible PTEN shRNA stable clones starting from three different BYL719-sensitive cell lines. In all the studied models, induction of PTEN shRNA resulted in resistance to BYL719. Since PTEN deficient genetic models have been shown to rely on the β subunit of the PI3K holoenzyme, we tested whether the concomitant inhibition of both p110α and p110β was sufficient to revert the resistant phenotype. BKM120 (a pan-PI3K inhibitor) or the addition of AZD6482 (p110β inhibitor) to BYL719 re-sensitized the cells to BYL719. To expand our findings in vivo, we generated a patient-derived xenograft (PDX) model from a PTEN-null non-responding lesion (lung). Consistently, this PDX model was refractory to the antitumor activity of BYL719 but conserved sensitivity to BKM120 or the combination of AZD6482 and BYL719. In both cases, IHC analysis revealed a decrease in PI3K/AKT downstream effectors pPRAS40 (246) and pS6 (240/4) staining with BKM120 or AZD6482+BYL719, but not with BYL719 alone. Preliminary analyses of other samples collected from patients treated with BYL719 suggest that PTEN loss is a relatively frequent event upon therapy progression. Taken together, the different mechanisms that inactivate PTEN in the tumor treated with BYL719 can be explained by convergent phenotypic evolution in a heterogeneous tumor and highlight the importance of PTEN and PI3Kβ in acquired resistance to PI3Kα inhibitors. Citation Format: Pau Castel, Dejan Juric, Helen Won, Benjamin Ainscough, Haley Ellis, Saya Ebbesen, Malachi Griffith, Obi Griffith, Iyer Gopakumar, Dennis Sgroi, Steven Isakoff, Elaine Mardis, David Solit, Scott Lowe, Cornelia Quadt, Malte Peters, Michael Berger, Maurizio Scaltriti, José Baselga. Loss of PTEN leads to clinical resistance to the PI3Kα inhibitor BYL719 and provides evidence of convergent evolution under selective therapeutic pressure. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-327. doi:10.1158/1538-7445.AM2014-LB-327

Published
2014

10. Germline p53 gene mutations in subsets of glioma patients

Author

Kyritsis, A. P., Bondy, M. L., Xiao, M., Berman, E. L., Cunningham, J. E., Lee, P. S., Levin, V. A., and Saya, H.

Subjects
Adult, Male, Base Sequence, Germ-Line Mutation/*genetics, Molecular Sequence Data, Brain Neoplasms/*genetics, Middle Aged, Pedigree, Glioma/*genetics, Genes, p53/*genetics, Humans, Point Mutation, Female, Aged
Abstract

BACKGROUND: Heritable germline mutations of the p53 gene have been described in patients with Li-Fraumeni syndrome, occasionally in nonfamilial malignancies such as multifocal osteosarcoma, in a small subgroup of young patients with two or more primary malignancies, and in patients with sporadic breast carcinoma. We recently reported that multifocal gliomas are frequently associated with other primary malignancies, and we hypothesized that genetic alterations may account for this phenomenon. PURPOSE: We examined the frequency of germline p53 gene mutations in patients with glioma and either multifocality of lesions, history of an additional primary (different) malignancy, or a family history of cancer. METHODS: Lymphocytes from 51 glioma patients were analyzed for germline p53 gene mutations using RNA-polymerase chain reaction analysis, single-strand conformation polymorphism, and gene sequencing techniques. RESULTS: Germline p53 gene mutations were detected in six of 19 patients with multifocal glioma, including two with family history of cancer, one with another primary malignancy, and two with all three risk factors; one of four patients with unifocal glioma, another primary malignancy, and a family history of cancer; and two of 15 patients with unifocal glioma and a family history of cancer but no second malignancies. No mutations were detected in the patient with unifocal glioma and another malignancy or in the 12 control patients with unifocal glioma and no second malignancies or family history of cancer. Patients having mutations were younger than other patients in the same group. CONCLUSIONS: Germline p53 mutations are frequent in patients with multifocal glioma, glioma and another primary malignancy, and glioma associated with a family history of cancer, particularly if these factors are combined. IMPLICATIONS: Relatives at high risk can be identified for genetic counseling, early cancer detection, and possible enrollment in chemoprevention trials. J Natl Cancer Inst

Published
1994

13. Distinct metaplastic and inflammatory phenotypes in autoimmune and adenocarcinoma-associated chronic atrophic gastritis

Author

Rossana Ippolito, Osamu Nagano, Francesco Paolo D'Armiento, Marco Romano, Christine P. Petersen, Joseph T. Roland, Gerardo Nardone, Sang Ho Jeong, Hideyuki Saya, Alessandro Federico, James R. Goldenring, Eun-Young Choi, Jeong, Sangho, Choi, Eunyoung, Petersen, Christine P, Roland, Joseph T, Federico, Alessandro, Ippolito, Rossana, D'Armiento, FRANCESCO PAOLO, Nardone, GERARDO ANTONIO PIO, Nagano, Osamu, Saya, Hideyuki, Romano, Marco, Goldenring, James R., Jeong, S., Choi, E., Petersen, C. P., Roland, J. T., Ippolito, R., D'Armiento, F. P., Nardone, G., Nagano, O., Saya, H., and Goldenring, J. R.

Subjects
Pathology, medicine.medical_specialty, Atrophic gastritis, macrophage, intestinal metaplasia, 03 medical and health sciences, 0302 clinical medicine, Atrophy, CD44 variant 9, medicine, Macrophage, DMBT1, Spasmolytic polypeptide-expressing metaplasia, business.industry, Gastroenterology, Intestinal metaplasia, neutrophil, Original Articles, medicine.disease, gastriti, Phenotype, digestive system diseases, Increased risk, Oncology, 030220 oncology & carcinogenesis, Immunology, Adenocarcinoma, 030211 gastroenterology & hepatology, Gastritis, medicine.symptom, business
Abstract

Background:Autoimmune gastritis (AIG) and adenocarcinoma-associated chronic atrophic gastritis (CAG) are both associated with oxyntic atrophy, but AIG patients demonstrate an increased risk of carcinoid tumors rather than the elevated risk of adenocarcinoma observed with CAG. We therefore sought to compare the characteristics of the metaplastic mucosa in AIG and CAG patients. Methods:We examined markers for metaplasia (spasmolytic polypeptide expressing metaplasia (SPEM) and intestinal metaplasia) as well as proliferation (Ki67) and immune cell populations (neutrophils, macrophages, and eosinophils) in gastric sections from 16 female patients with autoimmune thyroiditis and AIG and 17 patients with CAG associated with gastric adenocarcinoma. Results:Both AIG and CAG patients demonstrated prominent SPEM and intestinal metaplasia. However, AIG patients displayed significantly lower numbers of infiltrating macrophages and significantly reduced mucosal cell proliferation as compared to CAG patients. Conclusions:These findings indicate that, while both AIG and CAG patients display prominent oxyntic atrophy and metaplasia, the AIG patients do not show proliferative metaplastic lineages that would predispose to adenocarcinoma.

Published
2016

Catalog

Books, media, physical & digital resources
See catalog results