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

Author

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

Subjects
architect, role of architect, public sector, sulaymaniyah governorate, Science, Engineering (General). Civil engineering (General), TA1-2040
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
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2. Micro-Computed Tomographic Evaluation of Sealing Ability of Different Bioceramic Endodontic Sealers: An in vitro Study

Author

Saya H. Raouf and Dara H. Saeed

Subjects
ah plus, bioroot rcs, endosequence, micro-computed tomography, sealing ability, Science
Abstract

The aim of the present study was to compare sealing ability of three bioceramic sealers, including Endosequence BC and BioRoot RCS, with bioceramic-coated gutta-percha cone (BCGP) or GP in comparison to a clinical reference standard AH Plus sealer using high-resolution micro-computed tomography (micro-CT) analysis. Fifty freshly extracted single canal premolars were included in the study. All the samples were prepared using 2 Shape rotary system TS1 (25/0.04), TS2 (25/0.06), and F35 (35/0.06) file. After completion of the instrumentation, the samples were randomly divided based on the sealer material used and GP into four experimental groups and one control group with Endosequence, BioRoot, and AH Plus sealers with BCGP and conventional GP. All groups were obturated with (35/0.06) single cone obturation and high resolution of micro-CT was used to determine percentage of voids within the canals. BCGP showed better result than GP at all groups. In BCGP group, there were no significant differences in the percentage of the voids except internal voids. However, in all conventional GP groups, there were significant differences. Within the limitations of this study, it could be concluded that none of the groups were free of voids, BCGP with bioceramic sealer significantly better than GP.

Published
2020
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7. Convergent loss of PTEN leads to clinical resistance to a PI(3)K[alpha] inhibitor

Author

Juric, Dejan, Castel, Pau, Griffith, Malachi, Griffith, Obi L., Won, Helen H., Ellis, Haley, Ebbesen, Saya H., Ainscough, Benjamin J., Ramu, Avinash, Iyer, Gopa, Shah, Ronak H., Huynh, Tiffany, Mino-Kenudson, Mari, Sgroi, Dennis, Isakoff, Steven, Thabet, Ashraf, and Elamine, Leila

Subjects
Oncology, Experimental, Metastasis -- Genetic aspects -- Care and treatment, Phosphatases -- Physiological aspects, Drug resistance -- Research, Breast cancer -- Genetic aspects -- Care and treatment, Cancer -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

A study of genome evolution in a metastatic breast cancer bearing an activating PIK3CA mutation, following treatment with the PI(3)K[alpha] inhibitor BYL719, shows that all metastatic lesions, when compared to the pre-treatment tumour, had lost a copy of PTEN; parallel genetic evolution of separate sites with different PTEN genomic alterations had led to a convergent PTEN-null phenotype resistant to PI(3)K[alpha] inhibition. Anticancer resistance due to PTEN loss The emergence and expansion of resistant clonal subpopulations is a major challenge facing the field of targeted therapeutics. Here, the authors study genome evolution in a metastatic breast cancer bearing an activating PIK3CA mutation, following treatment with the phosphatidylinositol-4,5-bisphosphate 3-kinase alpha subunit (PI(3)K[alpha]) selective-inhibitor BYL719. Fourteen metastatic sites were sequenced to reveal that all metastatic lesions, when compared to the pre-treatment tumour, had lost a copy of the gene for the tumour suppressor phosphatase PTEN. Resistance to BYL719 was associated with additional and different PTEN genetic alterations, resulting in loss of PTEN expression. Based on these observations and additional functional characterization, the authors conclude that parallel genetic evolution of separate sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)K[alpha] inhibition. Broad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones.sup.1,2. There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion to that occurring in infectious diseases. Here we studied tumour genomic evolution in a patient (index patient) with metastatic breast cancer bearing an activating PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PI(3)K[alpha]) mutation. The patient was treated with the PI(3)K[alpha] inhibitor BYL719, which achieved a lasting clinical response, but the patient eventually became resistant to this drug (emergence of lung metastases) and died shortly thereafter. A rapid autopsy was performed and material from a total of 14 metastatic sites was collected and sequenced. All metastatic lesions, when compared to the pre-treatment tumour, had a copy loss of PTEN (phosphatase and tensin homolog) and those lesions that became refractory to BYL719 had additional and different PTEN genetic alterations, resulting in the loss of PTEN expression. To put these results in context, we examined six other patients also treated with BYL719. Acquired bi-allelic loss of PTEN was found in one of these patients, whereas in two others PIK3CA mutations present in the primary tumour were no longer detected at the time of progression. To characterize our findings functionally, we examined the effects of PTEN knockdown in several preclinical models (both in cell lines intrinsically sensitive to BYL719 and in PTEN-null xenografts derived from our index patient), which we found resulted in resistance to BYL719, whereas simultaneous PI(3)K p110[beta] blockade reverted this resistance phenotype. We conclude that parallel genetic evolution of separate metastatic sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)K[alpha] inhibition., Author(s): Dejan Juric [sup.1] , Pau Castel [sup.2] , Malachi Griffith [sup.3] [sup.4] [sup.5] , Obi L. Griffith [sup.4] [sup.5] [sup.6] , Helen H. Won [sup.2] [sup.7] , Haley Ellis [...]

Published
2015
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10. 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
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11. Conditional reverse tet-transactivator mouse strains for the efficient induction of TRE-regulated transgenes in mice.

Author

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

Subjects
Medicine, Science
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
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24. Abstracts for the Tenth International Conference on Brain Tumour Research and Therapy: Stalheim Hotel, Voss, Norway, September 6–9, 1993

Author

Abrahamsen, Tore G., Wesenberg, Finn, Mørk, Sverre, Allen, Jeffrey, Hayes, Roberta, DaRosso, Robert, Nirenberg, Anita, Ali-Osman, Francis, Akande, Nike, Amberger, V., Seulberger, H., Paganetti, P. A., Schwab, M. E., Schwab, M. E., Arita N., Ohnishi T., Hiraga S., Yamamoto H., Taki T., Izumoto S., Higuchi M., Hayakawa T., Kusakabe M., Sakakura T., Baldwin, N. G., Rice, C. D., Merchant, R. E., Ashmore, Sally M., Darling, J. L., Bailey, C. C., Balmaceda C., Diez B., Villablanca J., Walker R., Finlay J., Bergenheim, A. Tommy, Hartman, Magdalena, Bergh, Jonas, Ridderheim, PerÅke, Henriksson, Roger, Berens, Michael E., Rief, Monique D., Giese, Alf, Zackrisson, Björn, Elfversson, Jörgen, Bernstein, Mark, Cabantog, Alberto, Glen, Jennifer, Mikulis, David, Bjerkvig, Rolf, Pedersen, Paal-Henning, Mathisen, Berit, Mahesparan, Rupavathana, Haugland, Hans Kristian, Bernstein, Mark, Laperriere, Normand, Thomason, Cindy, Leung, Phil, Bobola M. S., Berger M. S., Silber J. R., Bongcam-Rudloff, Erik, Wang, Jia-Lun, Nistér, Monica, Westermark, Bengt, Brem, Steven, Breslow, Gary, Ho, Jason, Gately, Stephen, Takano, Shingo, Ward, William, Brada, M., Laing, R., Warrington, J., Brem, Steven, Engelhard, Herbert, Takano, Shingo, Gately, Stephen, Brem, Steven, Landau, Barry, Kwaan, Hau, Verrusio, Elaine, Buckner, J. C., Cascino, T. L., Schomberg, P. S., O'Fallon, J. R., Dinapoli, R. P., Burch, P. A., Shaw, E. G., Broaddus, William C., Hager-Loudon, Kathryn, Merchant, Randall E., Loudon, William, Couldwell, William T., Jiang, Jack B., Burns, David, Couldwell, William T., Weiss, Martin H., Apuzzo, Michael L. J., Desbaillets I., Tada M., de Tribolet N., Van Meir, E., Davis, R. L., Onda, K., Prados, M. D., Dolan, M. Eileen, Fleig, Matthew J., Friedman, Henry S., Ekstrand, A. Jonas, Longo, Nicola, James, C. David, Chou, D., Wijnhoven, B., Bellinzona, M., Nakagawa, M., Feuerstein B. G., Basu H. S., Dolan M. E., Bergeron C., Pellarm M., Deen D. F., Marton L. J., Finlay, Jonathan, Fulton D. S., Urtasun R. C., Giese, Alf, Scheck, Adrienne C., Geddes, J., Vowles, G. M., Ashmore, S. M., Gillespie, G. Y., Goldman, C. K., Tucker, M. T., Lyon, E., Tsai, J. -C., Gobbel, G. T., Chan, P. H., Greenberg, Hairy S., Chandler, W. F., Ensminger, W. D., Junck, L., Sandler, H., Bromberg, J., McKeever, P., Gonzalez G. G., Sarkar A., Basu H., Feuerstein B. G., Deen D. F., Haugland, Kr., Tysnes, Ole-Bjørn, Hiraga, Shoju, Arita, Norio, Ohnishi, Takanori, Taki, Takuyu, Yamamoto, Hiroshi, Higuchi, Masahide, Hayakawa, Toru, Isern, Erik, Unsgaard, Geirmund, Marthinsen, Anne Beate Langeland, Strickert, Trond, Helseth, Eirik, Hochberg F., Cosgrove R., Valenzuela R., Pardo F., Zervas N., Jenkins, Robert B., Ritland, Steven R., Hailing, Kevin C., Thibodeau, Stephen N., Juillerat L., Darekar P., Janzer R. C., Hamou M. F., Kato, Tsutomu, Sawamura, Yutaka, Tada, Mitsuhiro, Sakuma, Shirou, Sudo, Masako, Abe, Hiroshi, Kallio M., Leppää J., Nikula T., Nikkinen P., Gylling H., Färkkilä M., Hiltunen J., Jääskeläinen J., Liewendahl K., Keles, G. Evren, Berger, Mitchel S., Deliganis, Anna, Kellie S. J., De Graaf S. S. N., Bloemhof H., Johnston I., Uges D. D. R., Besser M., Chaseling R. W., Ouvrier R. A., Kitchen, N. D., Hughes, S., Beaney, R., Thomas, D. G. T., Kim D. H., Maeda T., Mohapatra G., Park S., Waldman F. W., Gray J. W., Koala, D., Silber, J., Berger, M., Krauseneck P., Müller B., Strik H., Warmuth-Metz M., Kuratsu, Jun-ichi, Takeshima, Hideo, Ushio, Yukitaka, Kretschmar, C., Grodman, H., Linggood, R., Kyritsis, A. P., Bondy, M., Cunningham, J., Xiao, M., Levin, V., Leeds, N., Bruner, J., Yung, W. K. A., Saya, H., Lampson, L. A., Nichols, M. R., Lampson, M. A., Dunne, A. D., Li, Hong, Hamou, Marie-France, Jaufeerally, Rehana, Diserens, Annie-Claire, Van Meir, Erwin, de Tribolet, Nicolas, Levin, V. A., Maor, M., Sawaya, R., Leavens, M., Woo, S., Thall, P., Gleason, M. J., Liang, Bertrand C., Ross, D. A., Meltzer, P. S., Trent, J. M., Greenberg, H. S., Lillehei K. O., Kong Q., DeMasters B. K., Withrow S. J., Macdonald D. R., Cairncross J. G., Ludwin S., Lee D., Cascino T., Buckner J., Dropcho E., Fulton D., Stewart D., Schold C., Wainman N., Eisenhauer E., Kirby S., Fisher B. J., Magrassi, L., Butti, G., Pezzotta, S., Milanesi∘, G., Matsutani, Masao, Marienhagen, Kirsten, Laerum, Ole Didrik, Baldwin, N. G., Merzak, Abderrahim, Koocheckpour, Shahriar, Roxanis, Yannis, Pilktngton, Geoffrey J., Nagai, Masakatsu, Watanabe, Kunihiko, Narita, Jun-ichi, Hagiwara, Hideaki, Noble, Mark, Nomura, K., Oyama, H., Motoo, M., Shibui, S., Tokuue, K., Akine, Y., Ohnishi, T., Arita, N., Hiraga, S., Hayakawa, T., Nygaard, Svein J. Tjoflaat, Tysnes, Ole-Bjørn, Pardo, F. S., Hsu, D. W., Hedley-Whyte, E. T., Efird, J., Schmidt, E. V., Marienhagen, Paal-Henning Pedersenl Kirsten, Pilkington, Geoffrey J., Clarke, Tracey M., Yu, Hui Tian, Rogers, Joan P., Stern, Robert, Phuphanich, Surasak, Greenberg, Harvey, Murtagh, R., Viloria, Jesus, Ransohoff, Joseph, Martin, Kimberly, Hatva, V. Erika, Rao, Jasti S., Mohanam, S., Rempel, Sandra A., Schwechheimer, Karl, Davis, Richard L., Cavenee, Webster K., Rosenblum, Mark L., Reifenberger, Guido, Liu, Lu, Ichimura, Koichi, Schmidt, Esther E., Collins, V. Peter, Revesz T., Scaravilli F., Cockburn H., Thomas D. G. T., Rice, C. D., Biron, R. T., Merchant, R. E., McKerrow, James, Sloane, Bonnie, Mikkelsen, Tom, Roosen, Norbert, Coopersmith, Peter, Smith, Robert, Rooprai, Harcharan Kaur, Maidment, Steven, Rucklidge, Garry, Volovsek, Anton, Rutka J. T., Smith S. L., Matsuzawa K., Sankar, A. A., Darling, J. L., Williams, S. R., Fukuyama K., Marton L. J., Ikeda, Jun, Selker, R. G., Vertosick, F. T., Goldenberg, M. T., Bindal, R., Diez B., Taratuto A., Picco P., Monges J., Martinez M., Pacheco G., Gamboni M., Schultz M., Silber J. R., Mueller B. A., Ewers T. G., Berger M. S., Shiraishi, T., Tabuchi, K., Nakagawa, S., Kihara, S., Stewart, D. J., Eapen, L., Agboola, O., Popovic, P., Goel, R., Raaphorst, P., Wong, P. T. T., Shimokawa, S., Oh-uchida, M., Hori, K., Markert C., Pflughaupt K. -W., Tada M., Diserens A. -C., Jauferrally R., Desbaillets I., Hamou M. -F., de Tribolet N., Takeshima H., Mochizuki H., Clifford J. L., Nishi T., Levin V. A., Lotan R., Saya H., Terzis, A. J. A., Arnold, H., Laerum, O. D., Bjerkvig, R., Taratuto A. L., Sevlever G., Diaz D., Di Tella M., Cuccia V., Pomata H., Gallo G., Dietze, A., Knopp, U., Thomas, R., Brada, M., Carnochan, P., Flux, G., Kitchen, N., Thomas, D., Zalutsky, M., Bigner, D., Tofilon, Philip, Borchardt, Paul, Torp, Sverre H., Dalen, Are, Tohyama, Takashi, Kubo, Osami, Takakura, Kintomo, Lee, Virginia M. -Y., Trojanowski, John Q., Nygaard, Svein, Urtasun, R. C., Parliament, M. B., McEwan, A. J., Mannan, R. H., Weibe, L. I., Unsgårp, G., Sonnewald, U., Gribbestad, I., Isern, E., Petersen, S. B., Wang J., Delgado D. A., Warr, Tracy J., Sheer, Denise, Gorman, Pat, Yamaguchi, F., Westphal, M., Anker, L., Hamel, W., Lücke, M., Shepard, M., Kleihues, P., Herrmann, H. D., Yung, W. K. Alfred, Taylor, Scott, and Steck, Peter A.

Published
1993
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26. Clinical utility of SARS-CoV-2 whole genome sequencing in deciphering source of infection

Author

Takenouchi, T., primary, Iwasaki, Y.W., additional, Harada, S., additional, Ishizu, H., additional, Uwamino, Y., additional, Uno, S., additional, Osada, A., additional, Abe, K., additional, Hasegawa, N., additional, Murata, M., additional, Takebayashi, T., additional, Fukunaga, K., additional, Saya, H., additional, Kitagawa, Y., additional, Amagai, M., additional, Siomi, H., additional, and Kosaki, K., additional

Published
2021
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29. 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
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30. Characterization of a novel BBB-permeable mutant IDH1 inhibitor, DS-1001b

Author

Matsunaga, H., primary, Machida, Y., additional, Nakagawa, M., additional, Yamaguchi, M., additional, Ogawara, Y., additional, Shima, Y., additional, Yamagata, K., additional, Katsumoto, T., additional, Hattori, A., additional, Itoh, M., additional, Seki, T., additional, Nishiya, Y., additional, Nakamura, K., additional, Suzuki, K., additional, Imaoka, T., additional, Suzuki, M., additional, Sampetrean, O., additional, Saya, H., additional, Ichimura, K., additional, and Kitabayashi, I., additional

Published
2019
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33. Recurrent Spindle Cell Carcinoma Shows Features of Mesenchymal Stem Cells

Author

Ouchi, T., primary, Morikawa, S., additional, Shibata, S., additional, Takahashi, M., additional, Yoshikawa, M., additional, Soma, T., additional, Miyashita, H., additional, Muraoka, W., additional, Kameyama, K., additional, Kawana, H., additional, Arima, Y., additional, Saya, H., additional, Okano, H., additional, Nakagawa, T., additional, and Asoda, S., additional

Published
2018
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34. 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

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

Author

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

Published
2017
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40. 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

41. 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

43. Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells

Author

Tominaga, K, primary, Shimamura, T, additional, Kimura, N, additional, Murayama, T, additional, Matsubara, D, additional, Kanauchi, H, additional, Niida, A, additional, Shimizu, S, additional, Nishioka, K, additional, Tsuji, E-i, additional, Yano, M, additional, Sugano, S, additional, Shimono, Y, additional, Ishii, H, additional, Saya, H, additional, Mori, M, additional, Akashi, K, additional, Tada, K-i, additional, Ogawa, T, additional, Tojo, A, additional, Miyano, S, additional, and Gotoh, N, additional

Published
2016
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44. Abstract P3-07-58: CD44v as a potential predictive biomarker for pathologic complete response in primary HER2+ breast cancer: Utility of adaptive response biopsy in preoperative therapy

Author

Yamauchi, T, primary, Imamura, CK, additional, Yamauchi, H, additional, Jinno, H, additional, Takahashi, M, additional, Kitagawa, Y, additional, Nakamura, S, additional, Lim, B, additional, Krishnamurthy, S, additional, Reuben, JM, additional, Liu, D, additional, Tripathy, D, additional, Zujewski, JA, additional, Chen, H, additional, Takebe, N, additional, Saya, H, additional, and Ueno, NT, additional

Published
2016
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45. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver

Author

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

Published
2015
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47. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor

Author

Juric, Dejan, primary, Castel, Pau, additional, Griffith, Malachi, additional, Griffith, Obi L., additional, Won, Helen H., additional, Ellis, Haley, additional, Ebbesen, Saya H., additional, Ainscough, Benjamin J., additional, Ramu, Avinash, additional, Iyer, Gopa, additional, Shah, Ronak H., additional, Huynh, Tiffany, additional, Mino-Kenudson, Mari, additional, Sgroi, Dennis, additional, Isakoff, Steven, additional, Thabet, Ashraf, additional, Elamine, Leila, additional, Solit, David B., additional, Lowe, Scott W., additional, Quadt, Cornelia, additional, Peters, Malte, additional, Derti, Adnan, additional, Schegel, Robert, additional, Huang, Alan, additional, Mardis, Elaine R., additional, Berger, Michael F., additional, Baselga, José, additional, and Scaltriti, Maurizio, additional

Published
2014
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48. CB-04 * EPIGENETIC REGULATION OF GLIOBLASTOMA TUMORIGENICITY: A HYBRID MODEL

Author

Chen, C., primary, Kozono, D., additional, Li, J., additional, Nitta, M., additional, Sampetrean, O., additional, Gonda, D., additional, Kushwaha, D., additional, Vandenberg, S., additional, Ramakrishnan, V., additional, Zhu, S., additional, Furnari, F., additional, Matsui, H., additional, Harismendy, O., additional, Cavenee, W., additional, Mao, Y., additional, Becher, O., additional, Kwon, C.-H., additional, Ligon, K., additional, Saya, H., additional, and Carter, B., additional

Published
2014
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