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Department: search.filters.department.Department of Industrial EngineeringSubject: search.filters.subject.Science and technology

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    PublicationOpen Access
    Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
    (Nature Publishing Group (NPG), 2019) Menden, Michael P.; Wang, Dennis; Mason, Mike J.; Szalai, Bence; Bulusu, Krishna C.; Guan, Yuanfang; Yu, Thomas; Kang, Jaewoo; Jeon, Minji; Wolfinger, Russ; Nguyen, Tin; Zaslavskiy, Mikhail; Jang, In Sock; Ghazoui, Zara; Ahsen, Mehmet Eren; Vogel, Robert; Neto, Elias Chaibub; Norman, Thea; Tang, Eric K. Y.; Garnett, Mathew J.; Di Veroli, Giovanni Y.; Fawell, Stephen; Stolovitzky, Gustavo; Guinney, Justin; Dry, Jonathan R.; Saez-Rodriguez, Julio; Abante, Jordi; Abecassis, Barbara Schmitz; Aben, Nanne; Aghamirzaie, Delasa; Aittokallio, Tero; Akhtari, Farida S.; Al-lazikani, Bissan; Alam, Tanvir; Allam, Amin; Allen, Chad; de Almeida, Mariana Pelicano; Altarawy, Doaa; Alves, Vinicius; Amadoz, Alicia; Anchang, Benedict; Antolin, Albert A.; Ash, Jeremy R.; Romeo Aznar, Victoria; Ba-alawi, Wail; Bagheri, Moeen; Bajic, Vladimir; Ball, Gordon; Ballester, Pedro J.; Baptista, Delora; Bare, Christopher; Bateson, Mathilde; Bender, Andreas; Bertrand, Denis; Wijayawardena, Bhagya; Boroevich, Keith A.; Bosdriesz, Evert; Bougouffa, Salim; Bounova, Gergana; Brouwer, Thomas; Bryant, Barbara; Calaza, Manuel; Calderone, Alberto; Calza, Stefano; Capuzzi, Stephen; Carbonell-Caballero, Jose; Carlin, Daniel; Carter, Hannah; Castagnoli, Luisa; Celebi, Remzi; Cesareni, Gianni; Chang, Hyeokyoon; Chen, Guocai; Chen, Haoran; Chen, Huiyuan; Cheng, Lijun; Chernomoretz, Ariel; Chicco, Davide; Cho, Kwang-Hyun; Cho, Sunghwan; Choi, Daeseon; Choi, Jaejoon; Choi, Kwanghun; Choi, Minsoo; De Cock, Martine; Coker, Elizabeth; Cortes-Ciriano, Isidro; Cserzo, Miklos; Cubuk, Cankut; Curtis, Christina; Van Daele, Dries; Dang, Cuong C.; Dijkstra, Tjeerd; Dopazo, Joaquin; Draghici, Sorin; Drosou, Anastasios; Dumontier, Michel; Ehrhart, Friederike; Eid, Fatma-Elzahraa; ElHefnawi, Mahmoud; Elmarakeby, Haitham; van Engelen, Bo; Engin, Hatice Billur; de Esch, Iwan; Evelo, Chris; Falcao, Andre O.; Farag, Sherif; Fernandez-Lozano, Carlos; Fisch, Kathleen; Flobak, Asmund; Fornari, Chiara; Foroushani, Amir B. K.; Fotso, Donatien Chedom; Fourches, Denis; Friend, Stephen; Frigessi, Arnoldo; Gao, Feng; Gao, Xiaoting; Gerold, Jeffrey M.; Gestraud, Pierre; Ghosh, Samik; Gillberg, Jussi; Godoy-Lorite, Antonia; Godynyuk, Lizzy; Godzik, Adam; Goldenberg, Anna; Gomez-Cabrero, David; de Graaf, Chris; Gray, Harry; Grechkin, Maxim; Guimera, Roger; Guney, Emre; Haibe-Kains, Benjamin; Han, Younghyun; Hase, Takeshi; He, Di; He, Liye; Heath, Lenwood S.; Hellton, Kristoffer H.; Helmer-Citterich, Manuela; Hidalgo, Marta R.; Hidru, Daniel; Hill, Steven M.; Hochreiter, Sepp; Hong, Seungpyo; Hovig, Eivind; Hsueh, Ya-Chih; Hu, Zhiyuan; Huang, Justin K.; Huang, R. Stephanie; Hunyady, Laszlo; Hwang, Jinseub; Hwang, Tae Hyun; Hwang, Woochang; Hwang, Yongdeuk; Isayev, Olexandr; Walk, Oliver Bear Don't; Jack, John; Jahandideh, Samad; Ji, Jiadong; Jo, Yousang; Kamola, Piotr J.; Kanev, Georgi K.; Karacosta, Loukia; Karimi, Mostafa; Kaski, Samuel; Kazanov, Marat; Khamis, Abdullah M.; Khan, Suleiman Ali; Kiani, Narsis A.; Kim, Allen; Kim, Jinhan; Kim, Juntae; Kim, Kiseong; Kim, Kyung; Kim, Sunkyu; Kim, Yongsoo; Kim, Yunseong; Kirk, Paul D. W.; Kitano, Hiroaki; Klambauer, Gunter; Knowles, David; Ko, Melissa; Kohn-Luque, Alvaro; Kooistra, Albert J.; Kuenemann, Melaine A.; Kuiper, Martin; Kurz, Christoph; Kwon, Mijin; van Laarhoven, Twan; Laegreid, Astrid; Lederer, Simone; Lee, Heewon; Lee, Jeon; Lee, Yun Woo; Leppaho, Eemeli; Lewis, Richard; Li, Jing; Li, Lang; Liley, James; Lim, Weng Khong; Lin, Chieh; Liu, Yiyi; Lopez, Yosvany; Low, Joshua; Lysenko, Artem; Machado, Daniel; Madhukar, Neel; De Maeyer, Dries; Malpartida, Ana Belen; Mamitsuka, Hiroshi; Marabita, Francesco; Marchal, Kathleen; Marttinen, Pekka; Mason, Daniel; Mazaheri, Alireza; Mehmood, Arfa; Mehreen, Ali; Michaut, Magali; Miller, Ryan A.; Mitsopoulos, Costas; Modos, Dezso; Van Moerbeke, Marijke; Moo, Keagan; Motsinger-Reif, Alison; Movva, Rajiv; Muraru, Sebastian; Muratov, Eugene; Mushthofa, Mushthofa; Nagarajan, Niranjan; Nakken, Sigve; Nath, Aritro; Neuvial, Pierre; Newton, Richard; Ning, Zheng; De Niz, Carlos; Oliva, Baldo; Olsen, Catharina; Palmeri, Antonio; Panesar, Bhawan; Papadopoulos, Stavros; Park, Jaesub; Park, Seonyeong; Park, Sungjoon; Pawitan, Yudi; Peluso, Daniele; Pendyala, Sriram; Peng, Jian; Perfetto, Livia; Pirro, Stefano; Plevritis, Sylvia; Politi, Regina; Poon, Hoifung; Porta, Eduard; Prellner, Isak; Preuer, Kristina; Angel Pujana, Miguel; Ramnarine, Ricardo; Reid, John E.; Reyal, Fabien; Richardson, Sylvia; Ricketts, Camir; Rieswijk, Linda; Rocha, Miguel; Rodriguez-Gonzalvez, Carmen; Roell, Kyle; Rotroff, Daniel; de Ruiter, Julian R.; Rukawa, Ploy; Sadacca, Benjamin; Safikhani, Zhaleh; Safitri, Fita; Sales-Pardo, Marta; Sauer, Sebastian; Schlichting, Moritz; Seoane, Jose A.; Serra, Jordi; Shang, Ming-Mei; Sharma, Alok; Sharma, Hari; Shen, Yang; Shiga, Motoki; Shin, Moonshik; Shkedy, Ziv; Shopsowitz, Kevin; Sinai, Sam; Skola, Dylan; Smirnov, Petr; Soerensen, Izel Fourie; Soerensen, Peter; Song, Je-Hoon; Song, Sang Ok; Soufan, Othman; Spitzmueller, Andreas; Steipe, Boris; Suphavilai, Chayaporn; Tamayo, Sergio Pulido; Tamborero, David; Tang, Jing; Tanoli, Zia-ur-Rehman; Tarres-Deulofeu, Marc; Tegner, Jesper; Thommesen, Liv; Tonekaboni, Seyed Ali Madani; Tran, Hong; De Troyer, Ewoud; Truong, Amy; Tsunoda, Tatsuhiko; Turu, Gabor; Tzeng, Guang-Yo; Verbeke, Lieven; Videla, Santiago; Vis, Daniel; Voronkov, Andrey; Votis, Konstantinos; Wang, Ashley; Wang, Hong-Qiang Horace; Wang, Po-Wei; Wang, Sheng; Wang, Wei; Wang, Xiaochen; Wang, Xin; Wennerberg, Krister; Wernisch, Lorenz; Wessels, Lodewyk; van Westen, Gerard J. P.; Westerman, Bart A.; White, Simon Richard; Willighagen, Egon; Wurdinger, Tom; Xie, Lei; Xie, Shuilian; Xu, Hua; Yadav, Bhagwan; Yau, Christopher; Yeerna, Huwate; Yin, Jia Wei; Yu, Michael; Yu, MinHwan; Yun, So Jeong; Zakharov, Alexey; Zamichos, Alexandros; Zanin, Massimiliano; Zeng, Li; Zenil, Hector; Zhang, Frederick; Zhang, Pengyue; Zhang, Wei; Zhao, Hongyu; Zhao, Lan; Zheng, Wenjin; Zoufir, Azedine; Zucknick, Manuela; Department of Industrial Engineering; Department of Industrial Engineering; Gönen, Mehmet; Faculty Member; College of Engineering; 237468
    The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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    PublicationOpen Access
    Structure based discovery of small molecules to regulate the activity of human insulin degrading enzyme
    (Public Library of Science, 2012) Department of Chemical and Biological Engineering; Department of Industrial Engineering; Department of Chemical and Biological Engineering; Department of Industrial Engineering; Çakır, Bilal; Dağlıyan, Onur; Dağyıldız, Ezgi; Barış, İbrahim; Kavaklı, İbrahim Halil; Kızılel, Seda; Türkay, Metin; PhD Student; Master Student; PhD Student; Teaching Faculty; Faculty Member; Faculty Member; College of Engineering; N/A; N/A; N/A; 111629; 40319; 28376; 24956
    Background: Insulin-degrading enzyme (IDE) is an allosteric Zn+2 metalloprotease involved in the degradation of many peptides including amyloid-beta, and insulin that play key roles in Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM), respectively. Therefore, the use of therapeutic agents that regulate the activity of IDE would be a viable approach towards generating pharmaceutical treatments for these diseases. Crystal structure of IDE revealed that N-terminal has an exosite which is similar to 30 angstrom away from the catalytic region and serves as a regulation site by orientation of the substrates of IDE to the catalytic site. It is possible to find small molecules that bind to the exosite of IDE and enhance its proteolytic activity towards different substrates.Methodology/Principal Findings: In this study, we applied structure based drug design method combined with experimental methods to discover four novel molecules that enhance the activity of human IDE. The novel compounds, designated as D3, D4, D6, and D10 enhanced IDE mediated proteolysis of substrate V, insulin and amyloid-b, while enhanced degradation profiles were obtained towards substrate V and insulin in the presence of D10 only. Conclusion/Significance: This paper describes the first examples of a computer-aided discovery of IDE regulators, showing that in vitro and in vivo activation of this important enzyme with small molecules is possible.
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    PublicationOpen Access
    Structure-based design and classifications of small molecules regulating the circadian rhythm period
    (Nature Portfolio, 2021) Yılmaz, Fatma; Öztürk, Nuri; Department of Industrial Engineering; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Department of Industrial Engineering; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Türkay, Metin; Rahim, Fatih; Gül, Şeref; Kavaklı, İbrahim Halil; Işın, Şafak; Faculty Member; Researcher; Faculty Member; College of Engineering; Graduate School of Sciences and Engineering; 24956; N/A; N/A; 40319; N/A
    Circadian rhythm is an important mechanism that controls behavior and biochemical events based on 24 h rhythmicity. Ample evidence indicates disturbance of this mechanism is associated with different diseases such as cancer, mood disorders, and familial delayed phase sleep disorder. Therefore, drug discovery studies have been initiated using high throughput screening. Recently the crystal structures of core clock proteins (CLOCK/BMAL1, Cryptochromes (CRY), Periods), responsible for generating circadian rhythm, have been solved. Availability of structures makes amenable core clock proteins to design molecules regulating their activity by using in silico approaches. In addition to that, the implementation of classification features of molecules based on their toxicity and activity will improve the accuracy of the drug discovery process. Here, we identified 171 molecules that target functional domains of a core clock protein, CRY1, using structure-based drug design methods. We experimentally determined that 115 molecules were nontoxic, and 21 molecules significantly lengthened the period of circadian rhythm in U2OS cells. We then performed a machine learning study to classify these molecules for identifying features that make them toxic and lengthen the circadian period. Decision tree classifiers (DTC) identified 13 molecular descriptors, which predict the toxicity of molecules with a mean accuracy of 79.53% using tenfold cross-validation. Gradient boosting classifiers (XGBC) identified 10 molecular descriptors that predict and increase in the circadian period length with a mean accuracy of 86.56% with tenfold cross-validation. Our results suggested that these features can be used in QSAR studies to design novel nontoxic molecules that exhibit period lengthening activity.
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    PublicationOpen Access
    Comparison of the results of blood glucose self-monitoring and continuous glucose monitoring in pregnant women with previous diabetes mellitus
    (Moscow Region Research and Clinical Institute (MONIKI), 2015) Dreval, A. V.; Shestakova, T. P.; Dreval, O. A.; Kulikov, D. A.; Medvedev, O. S.; Department of Industrial Engineering; Department of Industrial Engineering; Türkay, Metin; Faculty Member; College of Engineering; 24956
    Background: Pregnancy is one of the indications for continuous glucose monitoring (CGM). The data on its efficiency in pregnant women are contradictory. Aim: To compare the results of blood glucose self-monitoring (SMBG) and CGM in pregnant women with previous diabetes mellitus. Materials and methods: We performed a cross-sectional comparative study of glycemia in 18 pregnant women with previous type 1 (87.8% of patients) and type 2 diabetes (22.2% of patients) with various degrees of glycemic control. Their age was 27.7 ± 4.9 year. At study entry, the patients were at 17.2 ± 6.1 weeks of gestation. CGM and SMBG were performed in and by all patients for the duration of 5.4 ± 1.5 days. Depending on their hba1c levels, all patients were divided into two groups: group 1 – 12 women with the hba1c above the target (8.5 ± 1%), and group 2 – 6 women with the hba1c levels within the target (5.6 ± 0.3%). Results: According to SMBG results, women from group 2 had above-the-target glycemia levels before breakfast, at 1 hour after breakfast and at bedtime: 6.2 ± 1.6, 8.7 ± 2.1, and 5.7 ± 1.9 mmol/L, respectively. According to CGM, patients from group 1 had higher postprandial glycemia than those from group 2 (8.0 ± 2.1 and 6.9 ± 1.8 mmol/L, respectively, p = 0.03). The analysis of glycemia during the day time revealed significant difference between the groups only at 1 hour after dinner (7.1 ± 1.4 mmol/L in group 1 and 5.8 ± 0.9 mmol/L in group 2, р = 0.041) and the difference was close to significant before lunch (6.0 ± 2.2 mmol/L in group 1 and 4.8 ± 1.0 mmol/L in group 2, р = 0.053). Comparison of SMBG and CGM results demonstrated significant difference only at one timepoint (at 1 hour after lunch) and only in group 1: median glycemia was 7.4 [6.9; 8.1] mmol/L by SMBG and 6 [5.4; 6.6] mmol/L by CGM measurement (р = 0.001). Lower median values by CGM measurement could be explained by averaging of three successive measurements carried out in the period of rapid changes of glycemia. Conclusion: The achievement of control of diabetes by hba1c doesn't necessarily reflect current achievement of the target glycemic levels. As long as there was no significant difference in glycemia measured by SMBG and CGM, we conclude that CGM doesn't have any advantage over routine frequent SMBG in pregnant women.