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2. Anti-COX-2 autoantibody is a novel biomarker of immune aplastic anemia

Author

Kelkka, Tiina, Tyster, Mikko, Lundgren, Sofie, Feng, Xingmin, Kerr, Cassandra, Hosokawa, Kohei, Huuhtanen, Jani, Keränen, Mikko, Patel, Bhavisha, Kawakami, Toru, Maeda, Yuka, Nieminen, Otso, Kasanen, Tiina, Aronen, Pasi, Yadav, Bhagwan, Rajala, Hanna, Nakazawa, Hideyuki, Jaatinen, Taina, Hellström-Lindberg, Eva, Ogawa, Seishi, Ishida, Fumihiro, Nishikawa, Hiroyoshi, Nakao, Shinji, Maciejewski, Jaroslaw, Young, Neal S., and Mustjoki, Satu

Published
2022
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5. IFN-[alpha] with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia

Author

Huuhtanen, Jani, Ilander, Mette, Yadav, Bhagwan, Dufva, Olli M.J., Lahteenmaki, Hanna, Kasanen, Tiina, Klievink, Jay, Olsson-Stromberg, Ulla, Stentoft, Jesper, Richter, Johan, Koskenvesa, Perttu, Hoglund, Martin, Soderlund, Stina, Dreimane, Arta, Porkka, Kimmo, Gedde-Dahl, Tobias, Gjertsen, Bjorn T., Stenke, Leif, Myhr-Eriksson, Kristina, Markevarn, Berit, Lubking, Anna, Dimitrijevic, Andreja, Udby, Lene, Bjerrum, Ole Weis, Hjorth-Hansen, Henrik, and Mustjoki, Satu

Subjects
Immune system -- Health aspects, Interferon alpha -- Dosage and administration -- Physiological aspects, Dasatinib -- Dosage and administration -- Physiological aspects, Chronic myeloid leukemia -- Drug therapy -- Physiological aspects, Chemotherapy, Combination -- Methods -- Physiological aspects, Health care industry
Abstract

In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-[alpha] is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-[alpha] in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCR[beta] sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and [CD8.sup.+] T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of [CD8.sup.+] recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-[alpha] reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-[alpha] had costimulatory effects on TCR signaling. Our work supports the combination of IFN-[alpha] with TKI therapy, as IFN-[alpha] broadens the immune repertoire and restores immunological function., Introduction Currently, the ultimate therapeutic goal in patients with chronic-phase chronic myeloid leukemia (CP-CML) is to achieve deep molecular remission, which would allow the discontinuation of tyrosine kinase inhibitor (TKI) [...]

Published
2022
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9. JAK1/2 and BCL2 inhibitors synergize to counteract bone marrow stromal cell–induced protection of AML

Author

Karjalainen, Riikka, Pemovska, Tea, Popa, Mihaela, Liu, Minxia, Javarappa, Komal K., Majumder, Muntasir M., Yadav, Bhagwan, Tamborero, David, Tang, Jing, Bychkov, Dmitrii, Kontro, Mika, Parsons, Alun, Suvela, Minna, Mayoral Safont, Mireia, Porkka, Kimmo, Aittokallio, Tero, Kallioniemi, Olli, McCormack, Emmet, Gjertsen, Bjørn T., Wennerberg, Krister, Knowles, Jonathan, and Heckman, Caroline A.

Published
2017
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10. Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells

Author

Haltia, Ulla-Maija, Andersson, Noora, Yadav, Bhagwan, Färkkilä, Anniina, Kulesskiy, Evgeny, Kankainen, Matti, Tang, Jing, Bützow, Ralf, Riska, Annika, Leminen, Arto, Heikinheimo, Markku, Kallioniemi, Olli, Unkila-Kallio, Leila, Wennerberg, Krister, Aittokallio, Tero, and Anttonen, Mikko

Published
2017
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12. Data from Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia

Author

Pemovska, Tea, primary, Kontro, Mika, primary, Yadav, Bhagwan, primary, Edgren, Henrik, primary, Eldfors, Samuli, primary, Szwajda, Agnieszka, primary, Almusa, Henrikki, primary, Bespalov, Maxim M., primary, Ellonen, Pekka, primary, Elonen, Erkki, primary, Gjertsen, Bjørn T., primary, Karjalainen, Riikka, primary, Kulesskiy, Evgeny, primary, Lagström, Sonja, primary, Lehto, Anna, primary, Lepistö, Maija, primary, Lundán, Tuija, primary, Majumder, Muntasir Mamun, primary, Marti, Jesus M. Lopez, primary, Mattila, Pirkko, primary, Murumägi, Astrid, primary, Mustjoki, Satu, primary, Palva, Aino, primary, Parsons, Alun, primary, Pirttinen, Tero, primary, Rämet, Maria E., primary, Suvela, Minna, primary, Turunen, Laura, primary, Västrik, Imre, primary, Wolf, Maija, primary, Knowles, Jonathan, primary, Aittokallio, Tero, primary, Heckman, Caroline A., primary, Porkka, Kimmo, primary, Kallioniemi, Olli, primary, and Wennerberg, Krister, primary

Published
2023
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13. Supplementary Data from Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

Author

Malani, Disha, primary, Kumar, Ashwini, primary, Brück, Oscar, primary, Kontro, Mika, primary, Yadav, Bhagwan, primary, Hellesøy, Monica, primary, Kuusanmäki, Heikki, primary, Dufva, Olli, primary, Kankainen, Matti, primary, Eldfors, Samuli, primary, Potdar, Swapnil, primary, Saarela, Jani, primary, Turunen, Laura, primary, Parsons, Alun, primary, Västrik, Imre, primary, Kivinen, Katja, primary, Saarela, Janna, primary, Räty, Riikka, primary, Lehto, Minna, primary, Wolf, Maija, primary, Gjertsen, Bjorn Tore, primary, Mustjoki, Satu, primary, Aittokallio, Tero, primary, Wennerberg, Krister, primary, Heckman, Caroline A., primary, Kallioniemi, Olli, primary, and Porkka, Kimmo, primary

Published
2023
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14. Supplementary Tables S1-S12 from Drug-Sensitivity Screening and Genomic Characterization of 45 HPV-Negative Head and Neck Carcinoma Cell Lines for Novel Biomarkers of Drug Efficacy

Author

Lepikhova, Tatiana, primary, Karhemo, Piia-Riitta, primary, Louhimo, Riku, primary, Yadav, Bhagwan, primary, Murumägi, Astrid, primary, Kulesskiy, Evgeny, primary, Kivento, Mikko, primary, Sihto, Harri, primary, Grénman, Reidar, primary, Syrjänen, Stina M., primary, Kallioniemi, Olli, primary, Aittokallio, Tero, primary, Wennerberg, Krister, primary, Joensuu, Heikki, primary, and Monni, Outi, primary

Published
2023
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15. Supplementary Tables from Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

Author

Malani, Disha, primary, Kumar, Ashwini, primary, Brück, Oscar, primary, Kontro, Mika, primary, Yadav, Bhagwan, primary, Hellesøy, Monica, primary, Kuusanmäki, Heikki, primary, Dufva, Olli, primary, Kankainen, Matti, primary, Eldfors, Samuli, primary, Potdar, Swapnil, primary, Saarela, Jani, primary, Turunen, Laura, primary, Parsons, Alun, primary, Västrik, Imre, primary, Kivinen, Katja, primary, Saarela, Janna, primary, Räty, Riikka, primary, Lehto, Minna, primary, Wolf, Maija, primary, Gjertsen, Bjorn Tore, primary, Mustjoki, Satu, primary, Aittokallio, Tero, primary, Wennerberg, Krister, primary, Heckman, Caroline A., primary, Kallioniemi, Olli, primary, and Porkka, Kimmo, primary

Published
2023
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16. Data from Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

Author

Malani, Disha, primary, Kumar, Ashwini, primary, Brück, Oscar, primary, Kontro, Mika, primary, Yadav, Bhagwan, primary, Hellesøy, Monica, primary, Kuusanmäki, Heikki, primary, Dufva, Olli, primary, Kankainen, Matti, primary, Eldfors, Samuli, primary, Potdar, Swapnil, primary, Saarela, Jani, primary, Turunen, Laura, primary, Parsons, Alun, primary, Västrik, Imre, primary, Kivinen, Katja, primary, Saarela, Janna, primary, Räty, Riikka, primary, Lehto, Minna, primary, Wolf, Maija, primary, Gjertsen, Bjorn Tore, primary, Mustjoki, Satu, primary, Aittokallio, Tero, primary, Wennerberg, Krister, primary, Heckman, Caroline A., primary, Kallioniemi, Olli, primary, and Porkka, Kimmo, primary

Published
2023
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17. Supplementary Figures S1-S3 from Drug-Sensitivity Screening and Genomic Characterization of 45 HPV-Negative Head and Neck Carcinoma Cell Lines for Novel Biomarkers of Drug Efficacy

Author

Lepikhova, Tatiana, primary, Karhemo, Piia-Riitta, primary, Louhimo, Riku, primary, Yadav, Bhagwan, primary, Murumägi, Astrid, primary, Kulesskiy, Evgeny, primary, Kivento, Mikko, primary, Sihto, Harri, primary, Grénman, Reidar, primary, Syrjänen, Stina M., primary, Kallioniemi, Olli, primary, Aittokallio, Tero, primary, Wennerberg, Krister, primary, Joensuu, Heikki, primary, and Monni, Outi, primary

Published
2023
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18. Data from Drug-Sensitivity Screening and Genomic Characterization of 45 HPV-Negative Head and Neck Carcinoma Cell Lines for Novel Biomarkers of Drug Efficacy

Author

Lepikhova, Tatiana, primary, Karhemo, Piia-Riitta, primary, Louhimo, Riku, primary, Yadav, Bhagwan, primary, Murumägi, Astrid, primary, Kulesskiy, Evgeny, primary, Kivento, Mikko, primary, Sihto, Harri, primary, Grénman, Reidar, primary, Syrjänen, Stina M., primary, Kallioniemi, Olli, primary, Aittokallio, Tero, primary, Wennerberg, Krister, primary, Joensuu, Heikki, primary, and Monni, Outi, primary

Published
2023
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19. Supplementary Table S2 from Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia

Author

Pemovska, Tea, primary, Kontro, Mika, primary, Yadav, Bhagwan, primary, Edgren, Henrik, primary, Eldfors, Samuli, primary, Szwajda, Agnieszka, primary, Almusa, Henrikki, primary, Bespalov, Maxim M., primary, Ellonen, Pekka, primary, Elonen, Erkki, primary, Gjertsen, Bjørn T., primary, Karjalainen, Riikka, primary, Kulesskiy, Evgeny, primary, Lagström, Sonja, primary, Lehto, Anna, primary, Lepistö, Maija, primary, Lundán, Tuija, primary, Majumder, Muntasir Mamun, primary, Marti, Jesus M. Lopez, primary, Mattila, Pirkko, primary, Murumägi, Astrid, primary, Mustjoki, Satu, primary, Palva, Aino, primary, Parsons, Alun, primary, Pirttinen, Tero, primary, Rämet, Maria E., primary, Suvela, Minna, primary, Turunen, Laura, primary, Västrik, Imre, primary, Wolf, Maija, primary, Knowles, Jonathan, primary, Aittokallio, Tero, primary, Heckman, Caroline A., primary, Porkka, Kimmo, primary, Kallioniemi, Olli, primary, and Wennerberg, Krister, primary

Published
2023
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20. Supplementary Figures from Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

Author

Malani, Disha, primary, Kumar, Ashwini, primary, Brück, Oscar, primary, Kontro, Mika, primary, Yadav, Bhagwan, primary, Hellesøy, Monica, primary, Kuusanmäki, Heikki, primary, Dufva, Olli, primary, Kankainen, Matti, primary, Eldfors, Samuli, primary, Potdar, Swapnil, primary, Saarela, Jani, primary, Turunen, Laura, primary, Parsons, Alun, primary, Västrik, Imre, primary, Kivinen, Katja, primary, Saarela, Janna, primary, Räty, Riikka, primary, Lehto, Minna, primary, Wolf, Maija, primary, Gjertsen, Bjorn Tore, primary, Mustjoki, Satu, primary, Aittokallio, Tero, primary, Wennerberg, Krister, primary, Heckman, Caroline A., primary, Kallioniemi, Olli, primary, and Porkka, Kimmo, primary

Published
2023
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21. Supplementary Figures, Tables and Methods from Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia

Author

Pemovska, Tea, primary, Kontro, Mika, primary, Yadav, Bhagwan, primary, Edgren, Henrik, primary, Eldfors, Samuli, primary, Szwajda, Agnieszka, primary, Almusa, Henrikki, primary, Bespalov, Maxim M., primary, Ellonen, Pekka, primary, Elonen, Erkki, primary, Gjertsen, Bjørn T., primary, Karjalainen, Riikka, primary, Kulesskiy, Evgeny, primary, Lagström, Sonja, primary, Lehto, Anna, primary, Lepistö, Maija, primary, Lundán, Tuija, primary, Majumder, Muntasir Mamun, primary, Marti, Jesus M. Lopez, primary, Mattila, Pirkko, primary, Murumägi, Astrid, primary, Mustjoki, Satu, primary, Palva, Aino, primary, Parsons, Alun, primary, Pirttinen, Tero, primary, Rämet, Maria E., primary, Suvela, Minna, primary, Turunen, Laura, primary, Västrik, Imre, primary, Wolf, Maija, primary, Knowles, Jonathan, primary, Aittokallio, Tero, primary, Heckman, Caroline A., primary, Porkka, Kimmo, primary, Kallioniemi, Olli, primary, and Wennerberg, Krister, primary

Published
2023
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27. Mechanical forces across compartments coordinate cell shape and fate transitions to generate tissue architecture

Author

Villeneuve, Clementine, primary, Hashmi, Ali, additional, Ylivinkka, Irene, additional, Lawson-Keister, Elizabeth, additional, Miroshnikova, Yekaterina A, additional, Perez-Gonzalez, Carlos, additional, Yadav, Bhagwan, additional, Zhang, Tao, additional, Matic Vignjevic, Danijela, additional, Mikkola, Marja L, additional, Manning, Lisa, additional, and Wickstrom, Sara A, additional

Published
2022
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28. IFN-α with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia

Author

Huuhtanen, Jani, primary, Ilander, Mette, additional, Yadav, Bhagwan, additional, Dufva, Olli M.J., additional, Lähteenmäki, Hanna, additional, Kasanen, Tiina, additional, Klievink, Jay, additional, Olsson-Strömberg, Ulla, additional, Stentoft, Jesper, additional, Richter, Johan, additional, Koskenvesa, Perttu, additional, Höglund, Martin, additional, Söderlund, Stina, additional, Dreimane, Arta, additional, Porkka, Kimmo, additional, Gedde-Dahl, Tobias, additional, Gjertsen, Björn T., additional, Stenke, Leif, additional, Myhr-Eriksson, Kristina, additional, Markevärn, Berit, additional, Lübking, Anna, additional, Dimitrijevic, Andreja, additional, Udby, Lene, additional, Bjerrum, Ole Weis, additional, Hjorth-Hansen, Henrik, additional, and Mustjoki, Satu, additional

Published
2022
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30. Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

Author

Malani, Disha, Kumar, Ashwini, Brück, Oscar, Kontro, Mika, Yadav, Bhagwan, Hellesøy, Monica, Kuusanmäki, Heikki, Dufva, Olli, Kankainen, Matti, Eldfors, Samuli, Potdar, Swapnil, Saarela, Jani, Turunen, Laura, Parsons, Alun, Västrik, Imre, Kivinen, Katja, Saarela, Janna, Räty, Riikka, Lehto, Minna, Wolf, Maija, Gjertsen, Bjorn Tore, Mustjoki, Satu, Aittokallio, Tero, Wennerberg, Krister, Heckman, Caroline A., Kallioniemi, Olli, Porkka, Kimmo, Malani, Disha, Kumar, Ashwini, Brück, Oscar, Kontro, Mika, Yadav, Bhagwan, Hellesøy, Monica, Kuusanmäki, Heikki, Dufva, Olli, Kankainen, Matti, Eldfors, Samuli, Potdar, Swapnil, Saarela, Jani, Turunen, Laura, Parsons, Alun, Västrik, Imre, Kivinen, Katja, Saarela, Janna, Räty, Riikka, Lehto, Minna, Wolf, Maija, Gjertsen, Bjorn Tore, Mustjoki, Satu, Aittokallio, Tero, Wennerberg, Krister, Heckman, Caroline A., Kallioniemi, Olli, and Porkka, Kimmo

Abstract

We generated ex vivo drug-response and multiomics profiling data for a prospective series of 252 samples from 186 patients with acute myeloid leukemia (AML). A functional precision medicine tumor board (FPMTB) integrated clinical, molecular, and functional data for application in clinical treatment decisions. Actionable drugs were found for 97% of patients with AML, and the recommendations were clinically implemented in 37 relapsed or refractory patients. We report a 59% objective response rate for the individually tailored therapies, including 13 complete responses, as well as bridging five patients with AML to allogeneic hematopoietic stem cell transplantation. Data integration across all cases enabled the identification of drug response biomarkers, such as the association of IL15 overexpression with resistance to FLT3 inhibitors. Integration of molecular profiling and large-scale drug response data across many patients will enable continuous improvement of the FPMTB recommen-dations, providing a paradigm for individualized implementation of functional precision cancer medicine.

Published
2022

31. Ruthenium (II) complexes bearing N‐heterocyclic carbene‐based C^N donor sets in dye‐sensitized solar cells.

Author

Mary, Angelina, Jain, Nimisha, Sakla, Rahul, Jose, D. Amilan, Yadav, Bhagwan Sahai, and Naziruddin, Abbas Raja

Subjects
DYE-sensitized solar cells, RUTHENIUM, CHARGE exchange, VISIBLE spectra, ELECTRON density, PHOTOINDUCED electron transfer, CHARGE transfer
Abstract

We present the syntheses of ruthenium (II) complexes bearing an N‐heterocyclic carbene (NHC)‐based C^N donor set and an NCS ligand and evaluate their use as photosensitizers in dye‐sensitized solar cells (DSSCs). These complexes deploy a monocarboxylic acid‐functionalized terpyridine (tpy)/phenyl‐tpy to anchor with the TiO2 of the photoanodes. Results show that the complexes devoid of the phenyl spacer between the acid anchor and the tpy harvest the visible light more effectively. Absorption of the visible light transfers the electron density from the ruthenium, NHC, and the NCS donors to the tpy acceptor (1MRuLdonorLacceptorCT). Stronger MRuLdonorσ‐bonds in the complexes with opposite NHC and tpy ligand configuration render facile ruthenium‐centered oxidation. In contrast, the metal‐centered oxidation of complexes with trans‐oriented NHC and NCS ligands is relatively difficult. However, these complexes display higher photon conversion efficiency (PCE) in DSSCs. One of them shows PCE of 3.44%, which is ~70% of the standard N3 dye, under similar conditions. A longer electron lifetime and the lowest charge transfer resistance at the TiO2/electrolyte interface derived from the electrochemical impedance spectra accounts for the enhanced PCE. Insights into the oxidized dye regeneration in a DSSC setup, obtained from the computed Hirshfeld charges and spin density, depict the essential role of iodide anion in dye regeneration. This report summarizes our investigation of photophysics, electronic structure calculations, and the electrochemical study of all newly prepared complexes and their use as photosensitizers in DSSCs. [ABSTRACT FROM AUTHOR]

Published
2023
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32. A cross-sectional study on the role of hematological and inflammatory biomarkers as predictor of mortality at the time of admission among COVID-19 patients.

Author

Totade, Sanjay Kumar, Daheria, Chanchlesh, Morya, Rajesh Kumar, Yadav, Bhagwan Singh, Varma, Amit, and Toppo, Neelam

Subjects
COVID-19, NEUTROPHIL lymphocyte ratio, MEDICAL personnel, COVID-19 pandemic, BIOMARKERS, MEDULLARY thyroid carcinoma
Abstract

Whole world experienced COVID-19 pandemic with more than 155 million cases and >3.4 million deaths. Vasculitis and immune system activation plays a critical role in pathogenesis, especially in severely ill and non-survivors COVID-19 patients. Aims and Objectives: The aim of the study was to establish the role of hematological indices and inflammatory biomarker as predictors of mortality among non-survivor and survivor COVID-19 cases at the time of admission. Materials and Methods: The cross-sectional study was conducted at a dedicated COVID-19 referral hospital from July 2020 to August 2020, among 300 real time-polymerase chain reaction confirmed COVID-19 cases. Demographic, clinical, comorbidity, laboratory investigation, and outcome data were collected from patient's medical record. Outcome variables -- discharged (survived) or death (non-survived) were considered for comparison of various hematological indices and inflammatory biomarkers. Data are represented as median, IQR (Q1-Q3) and difference between median and proportions were calculated by Mann--Whitney U-test and χ² test. A predictive power of laboratory parameters between survivors and non-survivors was evaluated using receiver operant curve (ROC) analysis and area under the ROC curve (AUC). Results: The median age of non-survivors was significantly higher than survivors. Hypertension was significantly associated with non-survivors. Hematological parameters such as total leukocyte count, absolute neutrophil count, Neutrophil: Lymphocyte ratio were significantly increased with lymphocytopenia (P=0.001), and Inflammatory biomarkers such as C-reactive protein (CRP), lactate dehydrogenase, D-dimer, ferritin, procalcitonin, and NT-Pro BNP, all were significantly increased in non-survivors patients (P=0.001). CRP and neutrophil lymphocyte ratio (NLR) showed "Good" predictive value for mortality with cutoff value of 74.0 mg/l (AUC=0.841, Sensitivity=80.4%, Specificity=73.0%) and 5.65 (AUC=0.805, Sensitivity=76.1%, Specificity=73.0%), respectively. Pro-BNP showed "Fair" predictive value for mortality with cutoff value of 330.5 pg/ml (AUC=0.726, Sensitivity=73.9%, Specificity=58.2%). Conclusion: We suggest that CRP, NLR, and Pro-BNP can be used as a screening tool to predict mortality in COVID-19 patients for timely intervention to save valuable life, especially when sensitivity toward severity of COVID-19 among medical health professionals and general public is on decline. [ABSTRACT FROM AUTHOR]

Published
2023
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33. Anti-COX-2 Autoantibody is a Novel Marker of Immune Aplastic Anemia

Author

Kelkka, Tiina, primary, Tyster, Mikko, additional, Lundgren, Sofie, additional, Feng, Xingmin, additional, Kerr, Cassandra, additional, Hosokawa, Kohei, additional, Huuhtanen, Jani, additional, Keränen, Mikko, additional, Kawakami, Toru, additional, Patel, Bhavisha, additional, Maeda, Yuka, additional, Nieminen, Otso, additional, Kasanen, Tiina, additional, Aronen, Pasi, additional, Yadav, Bhagwan, additional, Rajala, Hanna, additional, Nakazawa, Hideyuki, additional, Jaatinen, Taina, additional, Hellstrom-Lindberg, Eva, additional, Ogawa, Seishi, additional, Ishida, Fumihiro, additional, Nishikawa, Hiroyoshi, additional, Nakao, Shinji, additional, Maciejewski, Jaroslaw, additional, Young, Neal S., additional, and Mustjoki, Satu, additional

Published
2022
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35. Targeting Apoptosis Pathways With BCL2 and MDM2 Inhibitors in Adult B-cell Acute Lymphoblastic Leukemia

Author

Hohtari, Helena, primary, Kankainen, Matti, additional, Adnan-Awad, Shady, additional, Yadav, Bhagwan, additional, Potdar, Swapnil, additional, Ianevski, Aleksandr, additional, Dufva, Olli, additional, Heckman, Caroline, additional, Sexl, Veronika, additional, Kytölä, Soili, additional, Mustjoki, Satu, additional, and Porkka, Kimmo, additional

Published
2022
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36. Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

Author

Malani, Disha, primary, Kumar, Ashwini, additional, Brück, Oscar, additional, Kontro, Mika, additional, Yadav, Bhagwan, additional, Hellesøy, Monica, additional, Kuusanmäki, Heikki, additional, Dufva, Olli, additional, Kankainen, Matti, additional, Eldfors, Samuli, additional, Potdar, Swapnil, additional, Saarela, Jani, additional, Turunen, Laura, additional, Parsons, Alun, additional, Västrik, Imre, additional, Kivinen, Katja, additional, Saarela, Janna, additional, Räty, Riikka, additional, Lehto, Minna, additional, Wolf, Maija, additional, Gjertsen, Bjorn Tore, additional, Mustjoki, Satu, additional, Aittokallio, Tero, additional, Wennerberg, Krister, additional, Heckman, Caroline A., additional, Kallioniemi, Olli, additional, and Porkka, Kimmo, additional

Published
2021
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37. Consistency in drug response profiling

Author

Mpindi, John Patrick, Yadav, Bhagwan, Östling, Päivi, Gautam, Prson, Malani, Disha, Murumägi, Astrid, Hirasawa, Akira, Kangaspeska, Sara, Wennerberg, Krister, Kallioniemi, Olli, and Aittokallio, Tero

Published
2016
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39. High miR-30 Expression Associates with Improved Breast Cancer Patient Survival and Treatment Outcome

Author

Jamshidi, Maral, primary, Fagerholm, Rainer, additional, Muranen, Taru A., additional, Kaur, Sippy, additional, Potdar, Swapnil, additional, Khan, Sofia, additional, Netti, Eliisa, additional, Mpindi, John-Patrick, additional, Yadav, Bhagwan, additional, Kiiski, Johanna I., additional, Aittomäki, Kristiina, additional, Heikkilä, Päivi, additional, Saarela, Jani, additional, Bützow, Ralf, additional, Blomqvist, Carl, additional, and Nevanlinna, Heli, additional

Published
2021
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40. Corrigendum: Adult-Onset Anti-Citrullinated Peptide Antibody-Negative Destructive Rheumatoid Arthritis Is Characterized by a Disease-Specific CD8+ T Lymphocyte Signature (vol 11, 578848, 2020)

Author

Kelkka, Tiina, Savola, Paula, Bhattacharya, Dipabarna, Huuhtanen, Jani, Lönnberg, Tapio, Kankainen, Matti, Paalanen, Kirsi, Tyster, Mikko, Lepisto, Maija, Ellonen, Pekka, Smolander, Johannes, Eldfors, Samuli, Yadav, Bhagwan, Khan, Sofia, Koivuniemi, Riitta, Sjöwall, Christopher, Elo, Laura L., Lähdesmäki, Harri, Maeda, Yuka, Nishikawa, Hiroyoshi, Leirisalo-Repo, Marjatta, Sokka-Isler, Tuulikki, and Mustjoki, Satu

Subjects
rheumatoid arthritis, seronegative, ACPA-negative, CD8+lymphocyte, T cell receptor, somatic mutation
Abstract

n/a

Published
2021

41. Corrigendum: Adult-Onset Anti-Citrullinated Peptide Antibody-Negative Destructive Rheumatoid Arthritis Is Characterized by a Disease-Specific CD8+ T Lymphocyte Signature

Author

Kelkka, Tiina, primary, Savola, Paula, additional, Bhattacharya, Dipabarna, additional, Huuhtanen, Jani, additional, Lönnberg, Tapio, additional, Kankainen, Matti, additional, Paalanen, Kirsi, additional, Tyster, Mikko, additional, Lepistö, Maija, additional, Ellonen, Pekka, additional, Smolander, Johannes, additional, Eldfors, Samuli, additional, Yadav, Bhagwan, additional, Khan, Sofia, additional, Koivuniemi, Riitta, additional, Sjöwall, Christopher, additional, Elo, Laura L., additional, Lähdesmäki, Harri, additional, Maeda, Yuka, additional, Nishikawa, Hiroyoshi, additional, Leirisalo-Repo, Marjatta, additional, Sokka-Isler, Tuulikki, additional, and Mustjoki, Satu, additional

Published
2021
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43. Breeze

Author

Potdar, Swapnil, Ianevski, Aleksandr, Mpindi, John Patrick, Bychkov, Dmitrii, Fiere, Clément, Ianevski, Philipp, Yadav, Bhagwan, Wennerberg, Krister, Aittokallio, Tero, Kallioniemi, Olli, Saarela, Jani, Östling, Päivi, University of Helsinki, Department of Computer Science, Aalto-yliopisto, and Aalto University

Abstract

Funding Information: The FIMM High-Throughput Biomedicine Unit is financially supported by the University of Helsinki and Biocenter Finland. The work has received funding from the Sigrid Juselius Foundation, Cancer Society of Finland, Academy of Finland [292611, 326238 and 310507 to T.A.], the Magnus Ehrnrooth Foundation, Biocentrum Helsinki and St. Baldrick’s Foundation. Publisher Copyright: © 2020 The Author(s) 2020. Published by Oxford University Press. High-throughput screening (HTS) enables systematic testing of thousands of chemical compounds for potential use as investigational and therapeutic agents. HTS experiments are often conducted in multi-well plates that inherently bear technical and experimental sources of error. Thus, HTS data processing requires the use of robust quality control procedures before analysis and interpretation. Here, we have implemented an open-source analysis application, Breeze, an integrated quality control and data analysis application for HTS data. Furthermore, Breeze enables a reliable way to identify individual drug sensitivity and resistance patterns in cell lines or patient-derived samples for functional precision medicine applications. The Breeze application provides a complete solution for data quality assessment, dose-response curve fitting and quantification of the drug responses along with interactive visualization of the results. Contact: swapnil.potdar@helsinki.fi

Published
2020

44. Phosphoproteome and drug-response effects mediated by the three protein phosphatase 2A inhibitor proteins CIP2A, SET, and PME-1

Author

Kauko, Otto, Imanishi, Susumu Y., Kulesskiy, Evgeny, Yetukuri, Laxman, Laajala, Teemu Daniel, Sharma, Mukund, Pavic, Karolina, Aakula, Anna, Rupp, Christian, Jumppanen, Mikael, Haapaniemi, Pekka, Ruan, Luyao, Yadav, Bhagwan, Suni, Veronika, Varila, Taru, Corthals, Garry L., Reimand, Jüri, Wennerberg, Krister, Aittokallio, Tero, and Westermarck, Jukka

Subjects
Proteome, LMNA, Apoptosis, macromolecular substances, Autoantigens, Proto-Oncogene Mas, environment and public health, Neoplasms, Humans, cancer, Histone Chaperones, Protein Phosphatase 2, drug screening, Enzyme Inhibitors, Phosphorylation, RNA, Small Interfering, Cell Proliferation, Nuclear Lamina, protein phosphatase 2 (PP2A), Intracellular Signaling Peptides and Proteins, Membrane Proteins, phosphoproteomics, systems biology, Phosphoproteins, phosphatase activation-responsive site (PARS), phosphatase inhibition-responsive site (PIRS), DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, enzymes and coenzymes (carbohydrates), AURK inhibitor, nucleophosmin, Carboxylic Ester Hydrolases, Signal Transduction, HeLa Cells
Abstract

Protein phosphatase 2A (PP2A) critically regulates cell signaling and is a human tumor suppressor. PP2A complexes are modulated by proteins such as cancerous inhibitor of protein phosphatase 2A (CIP2A), protein phosphatase methylesterase 1 (PME-1), and SET nuclear proto-oncogene (SET) that often are deregulated in cancers. However, how they impact cellular phosphorylation and how redundant they are in cellular regulation is poorly understood. Here, we conducted a systematic phosphoproteomics screen for phosphotargets modulated by siRNA-mediated depletion of CIP2A, PME-1, and SET (to reactivate PP2A) or the scaffolding A-subunit of PP2A (PPP2R1A) (to inhibit PP2A) in HeLa cells. We identified PP2A-modulated targets in diverse cellular pathways, including kinase signaling, cytoskeleton, RNA splicing, DNA repair, and nuclear lamina. The results indicate nonredundancy among CIP2A, PME-1, and SET in phosphotarget regulation. Notably, PP2A inhibition or reactivation affected largely distinct phosphopeptides, introducing a concept of nonoverlapping phosphatase inhibition- and activation-responsive sites (PIRS and PARS, respectively). This phenomenon is explained by the PPP2R1A inhibition impacting primarily dephosphorylated threonines, whereas PP2A reactivation results in dephosphorylation of clustered and acidophilic sites. Using comprehensive drug-sensitivity screening in PP2A-modulated cells to evaluate the functional impact of PP2A across diverse cellular pathways targeted by these drugs, we found that consistent with global phosphoproteome effects, PP2A modulations broadly affect responses to more than 200 drugs inhibiting a broad spectrum of cancer-relevant targets. These findings advance our understanding of the phosphoproteins, pharmacological responses, and cellular processes regulated by PP2A modulation and may enable the development of combination therapies.

Published
2020
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45. Adult-Onset Anti-Citrullinated Peptide Antibody-Negative Destructive Rheumatoid Arthritis Is Characterized by a Disease-Specific CD8+T Lymphocyte Signature

Author

Kelkka, Tiina, Savola, Paula, Bhattacharya, Dipabarna, Huuhtanen, Jani, Lonnberg, Tapio, Kankainen, Matti, Paalanen, Kirsi, Tyster, Mikko, Lepisto, Maija, Ellonen, Pekka, Smolander, Johannes, Eldfors, Samuli, Yadav, Bhagwan, Khan, Sofia, Koivuniemi, Riitta, Sjöwall, Christopher, Elo, Laura L., Lahdesmaki, Harri, Maeda, Yuka, Nishikawa, Hiroyashi, Leirisalo-Repo, Marjatta, Sokka-Isler, Tuulikki, Mustjoki, Satu, Kelkka, Tiina, Savola, Paula, Bhattacharya, Dipabarna, Huuhtanen, Jani, Lonnberg, Tapio, Kankainen, Matti, Paalanen, Kirsi, Tyster, Mikko, Lepisto, Maija, Ellonen, Pekka, Smolander, Johannes, Eldfors, Samuli, Yadav, Bhagwan, Khan, Sofia, Koivuniemi, Riitta, Sjöwall, Christopher, Elo, Laura L., Lahdesmaki, Harri, Maeda, Yuka, Nishikawa, Hiroyashi, Leirisalo-Repo, Marjatta, Sokka-Isler, Tuulikki, and Mustjoki, Satu

Abstract

Rheumatoid arthritis (RA) is a complex autoimmune disease targeting synovial joints. Traditionally, RA is divided into seropositive (SP) and seronegative (SN) disease forms, the latter consisting of an array of unrelated diseases with joint involvement. Recently, we described a severe form of SN-RA that associates with characteristic joint destruction. Here, we sought biological characteristics to differentiate this rare but aggressive anti-citrullinated peptide antibody-negative destructive RA (CND-RA) from early seropositive (SP-RA) and seronegative rheumatoid arthritis (SN-RA). We also aimed to study cytotoxic CD8+ lymphocytes in autoimmune arthritis. CND-RA, SP-RA and SN-RA were compared to healthy controls to reveal differences in T-cell receptor beta (TCR beta) repertoire, cytokine levels and autoantibody repertoires. Whole-exome sequencing (WES) followed by single-cell RNA-sequencing (sc-RNA-seq) was performed to study somatic mutations in a clonally expanded CD8+ lymphocyte population in an index patient. A unique TCR beta signature was detected in CND-RA patients. In addition, CND-RA patients expressed higher levels of the bone destruction-associated TNFSF14 cytokine. Blood IgG repertoire from CND-RA patients recognized fewer endogenous proteins than SP-RA patients repertoires. Using WES, we detected a stable mutation profile in the clonally expanded CD8+ T-cell population characterized by cytotoxic gene expression signature discovered by sc-RNA-sequencing. Our results identify CND-RA as an independent RA subset and reveal a CND-RA specific TCR signature in the CD8+ lymphocytes. Improved classification of seronegative RA patients underlines the heterogeneity of RA and also, facilitates development of improved therapeutic options for the treatment resistant patients., Funding Agencies|European Research CouncilEuropean Research Council (ERC) [M-IMM 647355, STRATIFY 862011, DynaOmics 677943]; Academy of Finland Heal-Art consortium [314442]; ERA PerMed (JAKSTAT-TARGET consortium); Finnish Medical foundation; Instrumentarium Science foundation; Biomedicum Helsinki foundation; Orion research foundation; Juhani Aho foundation; K. Albin Johansson foundation; Paulo foundation; Region Ostergotland (ALF grants); European UnionEuropean Union (EU) [675395]; Tekes the Finnish Funding Agency for InnovationFinnish Funding Agency for Technology & Innovation (TEKES) [1877/31/2016]; Sigrid Juselius FoundationSigrid Juselius Foundation; Finska Lakaresallskapet; Liv ochHalsa Foundation; Maire Lisko foundation

Published
2020
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46. Breeze: an integrated quality control and data analysis application for high-throughput drug screening

Author

Potdar, Swapnil, Ianevski, Aleksandr, Mpindi, John-patrick, Bychkov, Dmitrii, Fiere, Clément, Ianevski, Philipp, Yadav, Bhagwan, Wennerberg, Krister, Aittokallio, Tero, Kallioniemi, Olli, Saarela, Jani, Östling, Päivi, Potdar, Swapnil, Ianevski, Aleksandr, Mpindi, John-patrick, Bychkov, Dmitrii, Fiere, Clément, Ianevski, Philipp, Yadav, Bhagwan, Wennerberg, Krister, Aittokallio, Tero, Kallioniemi, Olli, Saarela, Jani, and Östling, Päivi

Published
2020

47. Adult-Onset Anti-Citrullinated Peptide Antibody-Negative Destructive Rheumatoid Arthritis Is Characterized by a Disease-Specific CD8+ T Lymphocyte Signature

Author

Kelkka, Tiina, primary, Savola, Paula, additional, Bhattacharya, Dipabarna, additional, Huuhtanen, Jani, additional, Lönnberg, Tapio, additional, Kankainen, Matti, additional, Paalanen, Kirsi, additional, Tyster, Mikko, additional, Lepistö, Maija, additional, Ellonen, Pekka, additional, Smolander, Johannes, additional, Eldfors, Samuli, additional, Yadav, Bhagwan, additional, Khan, Sofia, additional, Koivuniemi, Riitta, additional, Sjöwall, Christopher, additional, Elo, Laura L., additional, Lähdesmäki, Harri, additional, Maeda, Yuka, additional, Nishikawa, Hiroyoshi, additional, Leirisalo-Repo, Marjatta, additional, Sokka-Isler, Tuulikki, additional, and Mustjoki, Satu, additional

Published
2020
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48. Breeze: an integrated quality control and data analysis application for high-throughput drug screening

Author

Potdar, Swapnil, primary, Ianevski, Aleksandr, additional, Mpindi, John-Patrick, additional, Bychkov, Dmitrii, additional, Fiere, Clément, additional, Ianevski, Philipp, additional, Yadav, Bhagwan, additional, Wennerberg, Krister, additional, Aittokallio, Tero, additional, Kallioniemi, Olli, additional, Saarela, Jani, additional, and Östling, Päivi, additional

Published
2020
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49. Phosphoproteome and drug-response effects mediated by the three protein phosphatase 2A inhibitor proteins CIP2A, SET, and PME-1

Author

Kauko, Otto, primary, Imanishi, Susumu Y., additional, Kulesskiy, Evgeny, additional, Yetukuri, Laxman, additional, Laajala, Teemu Daniel, additional, Sharma, Mukund, additional, Pavic, Karolina, additional, Aakula, Anna, additional, Rupp, Christian, additional, Jumppanen, Mikael, additional, Haapaniemi, Pekka, additional, Ruan, Luyao, additional, Yadav, Bhagwan, additional, Suni, Veronika, additional, Varila, Taru, additional, Corthals, Garry L., additional, Reimand, Jüri, additional, Wennerberg, Krister, additional, Aittokallio, Tero, additional, and Westermarck, Jukka, additional

Published
2020
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50. Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

Author

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 A., 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, Gonen, Mehmet, 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 T., 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, and Computer Science

Subjects
health care economics and organizations
Abstract

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. AstraZeneca European Union Horizon 2020 research [668858 PrECISE] Joint Research Center for Computational Biomedicine (Bayer AG) National Institute for Health Research (NIHR) Sheffield Biomedical Research Center, Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences Wellcome Trust [102696, 206194] We thank the Genomics of Drug Sensitivity in Cancer and COSMIC teams at the Wellcome Trust Sanger Institute for help with the preparation of the molecular data, Denes Turei for help with Omnipath, and Katjusa Koler for help with matching drug names across combination screens. We thank AstraZeneca for funding and provision of data to the DREAM Consortium to run the challenge, and funding from the European Union Horizon 2020 research (under grant agreement No 668858 PrECISE to J.S.R.), the Joint Research Center for Computational Biomedicine (which is partially funded by Bayer AG) to J.S.R., National Institute for Health Research (NIHR) Sheffield Biomedical Research Center, Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences. M.G lab is supported by Wellcome Trust (102696 and 206194).

Published
2019

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