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3. Paternal nicotine enhances fear memory, reduces nicotine administration, and alters hippocampal genetic and neural function in offspring

Author

Goldberg, Lisa R, Zeid, Dana, Kutlu, Munir Gunes, Cole, Robert D, Lallai, Valeria, Sebastian, Aswathy, Albert, Istvan, Fowler, Christie D, Parikh, Vinay, and Gould, Thomas J

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Tobacco Smoke and Health, Tobacco, Brain Disorders, Behavioral and Social Science, Mental Health, Basic Behavioral and Social Science, Substance Misuse, Genetics, Neurosciences, Post-Traumatic Stress Disorder (PTSD), Aetiology, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Animals, Conditioning, Psychological, Cues, Extinction, Psychological, Fear, Female, Hippocampus, Male, Memory, Mice, Mice, Inbred C57BL, Nicotine, Paternal Exposure, Up-Regulation, cholinergic, hippocampus, learning, multigenerational, nicotine, transgenerational, Medical and Health Sciences, Psychology and Cognitive Sciences, Substance Abuse, Biomedical and clinical sciences, Health sciences
Abstract

Nicotine use remains highly prevalent with tobacco and e-cigarette products consumed worldwide. However, increasing evidence of transgenerational epigenetic inheritance suggests that nicotine use may alter behavior and neurobiology in subsequent generations. We tested the effects of chronic paternal nicotine exposure in C57BL6/J mice on fear conditioning in F1 and F2 offspring, as well as conditioned fear extinction and spontaneous recovery, nicotine self-administration, hippocampal cholinergic functioning, RNA expression, and DNA methylation in F1 offspring. Paternal nicotine exposure was associated with enhanced contextual and cued fear conditioning and spontaneous recovery of extinguished fear memories. Further, nicotine reinforcement was reduced in nicotine-sired mice, as assessed in a self-administration paradigm. These behavioral phenotypes were coupled with altered response to nicotine, upregulated hippocampal nicotinic acetylcholine receptor binding, reduced evoked hippocampal cholinergic currents, and altered methylation and expression of hippocampal genes related to neural development and plasticity. Gene expression analysis suggests multigenerational effects on broader gene networks potentially involved in neuroplasticity and mental disorders. The changes in fear conditioning similarly suggest phenotypes analogous to anxiety disorders similar to post-traumatic stress.

Published
2021

10. First-Line Nivolumab Plus Ipilimumab Versus Chemotherapy in Advanced NSCLC With 1% or Greater Tumor PD-L1 Expression: Patient-Reported Outcomes From CheckMate 227 Part 1

Author

Reck, Martin, Ciuleanu, Tudor-Eliade, Lee, Jong-Seok, Schenker, Michael, Audigier-Valette, Clarisse, Zurawski, Bogdan, Linardou, Helena, Otterson, Gregory A., Salman, Pamela, Nishio, Makoto, de la Mora Jimenez, Emmanuel, Lesniewski-Kmak, Krysztof, Albert, István, Ahmed, Samreen, Syrigos, Konstantinos, Penrod, John R., Yuan, Yong, Blum, Steven I., Nathan, Faith E., Sun, Xiaowu, Moreno-Koehler, Alejandro, Taylor, Fiona, and O'Byrne, Kenneth John

Published
2021
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11. A critical role of RBM8a in proliferation and differentiation of embryonic neural progenitors

Author

Zou, Donghua, McSweeney, Colleen, Sebastian, Aswathy, Reynolds, Derrick James, Dong, Fengping, Zhou, Yijing, Deng, Dazhi, Wang, Yonggang, Liu, Long, Zhu, Jun, Zou, Jizhong, Shi, Yongsheng, Albert, Istvan, and Mao, Yingwei

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Psychology, Mental Health, Neurosciences, Intellectual and Developmental Disabilities (IDD), Autism, Stem Cell Research, Brain Disorders, Pediatric, Stem Cell Research - Embryonic - Non-Human, Aetiology, 2.1 Biological and endogenous factors, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Mental health, Animals, Brain, Cell Differentiation, Cell Proliferation, Cells, Cultured, Gene Expression Regulation, Developmental, Humans, Immunoblotting, Immunohistochemistry, Mice, Mice, Inbred C57BL, Microscopy, Confocal, Neural Stem Cells, Neurogenesis, RNA, Small Interfering, RNA-Binding Proteins, Transfection, RBM8a, Exon junction complex, Neurodevelopment, Neural progenitor cells, Psychiatric disorders, Nonsense mediated mRNA decay, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

BackgroundNonsense mediated mRNA decay (NMD) is an RNA surveillance mechanism that controls RNA stability and ensures the speedy degradation of erroneous and unnecessary transcripts. This mechanism depends on several core factors in the exon junction complex (EJC), eIF4A3, RBM8a, Magoh, and BTZ, as well as peripheral factors to distinguish premature stop codons (PTCs) from normal stop codons in transcripts. Recently, emerging evidence has indicated that NMD factors are associated with neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). However, the mechanism in which these factors control embryonic brain development is not clear.ResultWe found that RBM8a is critical for proliferation and differentiation in cortical neural progenitor cells (NPCs). RBM8a is highly expressed in the subventricular zone (SVZ) of the early embryonic cortex, suggesting that RBM8a may play a role in regulating NPCs. RBM8a overexpression stimulates embryonic NPC proliferation and suppresses neuronal differentiation. Conversely, knockdown of RBM8a in the neocortex reduces NPC proliferation and promotes premature neuronal differentiation. Moreover, overexpression of RBM8a suppresses cell cycle exit and keeps cortical NPCs in a proliferative state. To uncover the underlying mechanisms of this phenotype, genome-wide RNAseq was used to identify potential downstream genes of RBM8a in the brain, which have been implicated in autism and neurodevelopmental disorders. Interestingly, autism and schizophrenia risk genes are highly represented in downstream transcripts of RBM8a. In addition, RBM8a regulates multiple alternative splicing genes and NMD targets that are implicated in ASD. Taken together, this data suggests a novel role of RBM8a in the regulation of neurodevelopment.ConclusionsOur studies provide some insight into causes of mental illnesses and will facilitate the development of new therapeutic strategies for neurodevelopmental illnesses.

Published
2015

13. Conserved network motifs allow protein-protein interaction prediction

Author

Albert, Istvan and Albert, Reka

Subjects
Quantitative Biology - Molecular Networks, Quantitative Biology - Genomics
Abstract

High-throughput protein interaction detection methods are strongly affected by false positive and false negative results. Focused experiments are needed to complement the large-scale methods by validating previously detected interactions but it is often difficult to decide which proteins to probe as interaction partners. Developing reliable computational methods assisting this decision process is a pressing need in bioinformatics. We show that we can use the conserved properties of the protein network to identify and validate interaction candidates. We apply a number of machine learning algorithms to the protein connectivity information and achieve a surprisingly good overall performance in predicting interacting proteins. Using a 'leave-one-out' approach we find average success rates between 20-50% for predicting the correct interaction partner of a protein. We demonstrate that the success of these methods is based on the presence of conserved interaction motifs within the network. A reference implementation and a table with candidate interacting partners for each yeast protein are available at http://www.protsuggest.org

Published
2004

14. Structural Vulnerability of the North American Power Grid

Author

Albert, Reka, Albert, Istvan, and Nakarado, Gary L.

Subjects
Condensed Matter - Disordered Systems and Neural Networks, Condensed Matter - Statistical Mechanics
Abstract

The magnitude of the August 2003 blackout affecting the United States has put the challenges of energy transmission and distribution into limelight. Despite all the interest and concerted effort, the complexity and interconnectivity of the electric infrastructure have so far precluded us from understanding why certain events happened. In this paper we study the power grid from a network perspective and determine its ability to transfer power between generators and consumers when certain nodes are disrupted. We find that the power grid is robust to most perturbations, yet disturbances affecting key transmision substations greatly reduce its ability to function. We emphasize that the global properties of the underlying network must be understood as they greatly affect local behavior., Comment: 10 pages, 4 figures, to appear in PRE

Published
2004
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20. Loss of selenoprotein W in murine macrophages alters the hierarchy of selenoprotein expression, redox tone, and mitochondrial functions during inflammation

Author

Misra, Sougat, primary, Lee, Tai-Jung, additional, Sebastian, Aswathy, additional, McGuigan, John, additional, Liao, Chang, additional, Koo, Imhoi, additional, Patterson, Andrew D., additional, Rossi, Randall M., additional, Hall, Molly A., additional, Albert, Istvan, additional, and Prabhu, K. Sandeep, additional

Published
2023
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23. Piperaquine-resistant PfCRT mutations differentially impact drug transport, hemoglobin catabolism and parasite physiology in Plasmodium falciparum asexual blood stages

Author

Okombo, John, primary, Mok, Sachel, additional, Qahash, Tarrick, additional, Yeo, Tomas, additional, Bath, Jade, additional, Orchard, Lindsey M., additional, Owens, Edward, additional, Koo, Imhoi, additional, Albert, Istvan, additional, Llinás, Manuel, additional, and Fidock, David A., additional

Published
2022
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24. The clock genePer1expression may exert diurnal control over hippocampal memory consolidation

Author

Bellfy, Lauren, primary, Smies, Chad W., additional, Bernhardt, Alicia R., additional, Bodinayake, Kasuni K., additional, Sebastian, Aswathy, additional, Stuart, Emily M., additional, Wright, Destiny S., additional, Lo, Chen-Yu, additional, Murakami, Shoko, additional, Boyd, Hannah M., additional, von Abo, Megan J., additional, Albert, Istvan, additional, and Kwapis, Janine L., additional

Published
2022
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25. The clock gene Per1may exert diurnal control over hippocampal memory consolidation

Author

Bellfy, Lauren, Smies, Chad W., Bernhardt, Alicia R., Bodinayake, Kasuni K., Sebastian, Aswathy, Stuart, Emily M., Wright, Destiny S., Lo, Chen-Yu, Murakami, Shoko, Boyd, Hannah M., von Abo, Megan J., Albert, Istvan, and Kwapis, Janine L.

Abstract

The circadian system influences many different biological processes, including memory performance. While the suprachiasmatic nucleus (SCN) functions as the brain’s central pacemaker, downstream “satellite clocks” may also regulate local functions based on the time of day. Within the dorsal hippocampus (DH), for example, local molecular oscillations may contribute to time-of-day effects on memory. Here, we used the hippocampus-dependent Object Location Memory task to determine how memory is regulated across the day/night cycle in mice. First, we systematically determined which phase of memory (acquisition, consolidation, or retrieval) is modulated across the 24 h day. We found that mice show better long-term memory performance during the day than at night, an effect that was specifically attributed to diurnal changes in memory consolidation, as neither memory acquisition nor memory retrieval fluctuated across the day/night cycle. Using RNA-sequencing we identified the circadian clock gene Period1(Per1) as a key mechanism capable of supporting this diurnal fluctuation in memory consolidation, as learning-induced Per1oscillates in tandem with memory performance in the hippocampus. We then show that local knockdown of Per1within the DH impairs spatial memory without affecting either the circadian rhythm or sleep behavior. Thus, Per1may independently function within the DH to regulate memory in addition to its known role in regulating the circadian system within the SCN. Per1may therefore exert local diurnal control over memory consolidation within the DH.

Published
2023
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27. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease

Author

Jiang, Changtao, Xie, Cen, Li, Fei, Zhang, Limin, Nichols, Robert G., Krausz, Kristopher W., Cai, Jingwei, Qi, Yunpeng, Fang, Zhong-Ze, Takahashi, Shogo, Tanaka, Naoki, Desai, Dhimant, Amin, Shantu G., Albert, Istvan, Patterson, Andrew D., and Gonzalez, Frank J.

Subjects
Fatty liver -- Analysis -- Risk factors -- Research, Cellular signal transduction -- Research, Cell receptors -- Physiological aspects -- Research, Health care industry
Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major worldwide health problem. Recent studies suggest that the gut microbiota influences NAFLD pathogenesis. Here, a murine model of high-fat diet-induced (HFD-induced) NAFLD was used, and the effects of alterations in the gut microbiota on NAFLD were determined. Mice treated with antibiotics or tempol exhibited altered bile acid composition, with a notable increase in conjugated bile acid metabolites that inhibited intestinal farnesoid X receptor (FXR) signaling. Compared with control mice, animals with intestine-specific Fxr disruption had reduced hepatic triglyceride accumulation in response to a HFD. The decrease in hepatic triglyceride accumulation was mainly due to fewer circulating ceramides, which was in part the result of lower expression of ceramide synthesis genes. The reduction of ceramide levels in the ileum and serum in tempol--or antibiotic-treated mice fed a HFD resulted in downregulation of hepatic SREBP1C and decreased de novo lipogenesis. Administration of C16:0 ceramide to antibiotic-treated mice fed a HFD reversed hepatic steatosis. These studies demonstrate that inhibition of an intestinal FXR/ceramide axis mediates gut microbiota- associated NAFLD development, linking the microbiome, nuclear receptor signaling, and NAFLD. This work suggests that inhibition of intestinal FXR is a potential therapeutic target for NAFLD treatment., Introduction Nonalcoholic fatty liver disease (NAFLD) is characterized by massive ectopic triglyceride accumulation in the liver in the absence of other liver disease or significant alcohol consumption (1). NAFLD is [...]

Published
2015
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28. Elioraea tepida, sp. nov., a Moderately Thermophilic Aerobic Anoxygenic Phototrophic Bacterium Isolated from the Mat Community of an Alkaline Siliceous Hot Spring in Yellowstone National Park, WY, USA

Author

Saini, Mohit Kumar, primary, Yoshida, Shohei, additional, Sebastian, Aswathy, additional, Hara, Eri, additional, Tamaki, Hideyuki, additional, Soulier, Nathan T., additional, Albert, Istvan, additional, Hanada, Satoshi, additional, Tank, Marcus, additional, and Bryant, Donald A., additional

Published
2021
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32. Genomic and Phenotypic Characterization of Chloracidobacterium Isolates Provides Evidence for Multiple Species

Author

Saini, Mohit Kumar, primary, Sebastian, Aswathy, additional, Shirotori, Yoshiki, additional, Soulier, Nathan T., additional, Garcia Costas, Amaya M., additional, Drautz-Moses, Daniela I., additional, Schuster, Stephan C., additional, Albert, Istvan, additional, Haruta, Shin, additional, Hanada, Satoshi, additional, Thiel, Vera, additional, Tank, Marcus, additional, and Bryant, Donald A., additional

Published
2021
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33. Adolescent Stress Reduces Adult Morphine-Induced Behavioral Sensitization in C57BL/6J Mice

Author

Kamens, Helen M., primary, Miller, Carley N., additional, Caulfield, Jasmine I., additional, Zeid, Dana, additional, Horton, William J., additional, Silva, Constanza P., additional, Sebastian, Aswathy, additional, Albert, Istvan, additional, Gould, Thomas J., additional, Fishbein, Diana, additional, Grigson, Patricia Sue, additional, and Cavigelli, Sonia A., additional

Published
2021
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34. Paternal nicotine enhances fear memory, reduces nicotine administration, and alters hippocampal genetic and neural function in offspring.

Author

Goldberg, Lisa, Goldberg, Lisa, Zeid, Dana, Kutlu, Munir, Cole, Robert, Sebastian, Aswathy, Albert, Istvan, Parikh, Vinay, Gould, Thomas, Fowler, Christie, Lallai, Valeria, Goldberg, Lisa, Goldberg, Lisa, Zeid, Dana, Kutlu, Munir, Cole, Robert, Sebastian, Aswathy, Albert, Istvan, Parikh, Vinay, Gould, Thomas, Fowler, Christie, and Lallai, Valeria

Abstract

Nicotine use remains highly prevalent with tobacco and e-cigarette products consumed worldwide. However, increasing evidence of transgenerational epigenetic inheritance suggests that nicotine use may alter behavior and neurobiology in subsequent generations. We tested the effects of chronic paternal nicotine exposure in C57BL6/J mice on fear conditioning in F1 and F2 offspring, as well as conditioned fear extinction and spontaneous recovery, nicotine self-administration, hippocampal cholinergic functioning, RNA expression, and DNA methylation in F1 offspring. Paternal nicotine exposure was associated with enhanced contextual and cued fear conditioning and spontaneous recovery of extinguished fear memories. Further, nicotine reinforcement was reduced in nicotine-sired mice, as assessed in a self-administration paradigm. These behavioral phenotypes were coupled with altered response to nicotine, upregulated hippocampal nicotinic acetylcholine receptor binding, reduced evoked hippocampal cholinergic currents, and altered methylation and expression of hippocampal genes related to neural development and plasticity. Gene expression analysis suggests multigenerational effects on broader gene networks potentially involved in neuroplasticity and mental disorders. The changes in fear conditioning similarly suggest phenotypes analogous to anxiety disorders similar to post-traumatic stress.

Published
2021

35. Nucleosome organization in the Drosophila genome

Author

Mavrich, Travis N., Jiang, Cizhong, Ioshikhes, Ilya P., Li, Xiaoyong, Venters, Bryan J., Zanton, Sara J., Tomsho, Lynn P., Qi, Ji, Glaser, Robert L., Schuster, Stephan C., Gilmour, David S., Albert, Istvan, and Pugh, B. Franklin

Subjects
Nucleosomes -- Genetic aspects, Drosophila -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation, Genetic aspects
Abstract

Comparative genomics of nucleosome positions provides a powerful means for understanding how the organization of chromatin and the transcription machinery co-evolve. Here we produce a high-resolution reference map of H2A.Z [...]

Published
2008

36. Translational and rotational settings of H2A.Z nucleosomes across the Saccharomyces cerevisiae genome

Author

Albert, Istvan, Mavrich, Travis N., Tomsho, Lynn P., Qi, Ji, Zanton, Sara J., Schuster, Stephan C., and Pugh, B. Franklin

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Istvan Albert [1]; Travis N. Mavrich [1, 2]; Lynn P. Tomsho [1]; Ji Qi [1]; Sara J. Zanton [1, 2]; Stephan C. Schuster [1]; B. Franklin Pugh (corresponding author) [...]

Published
2007
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37. Effect of Adolescent Stress on Adult Morphine-Induced Behavioral Sensitization is Dependent Upon Genetic Background

Author

Kamens, Helen M., primary, Miller, Carley N., additional, Caulfield, Jasmine I., additional, Zeid, Dana, additional, Horton, William J., additional, Silva, Constanza, additional, Sebastian, Aswathy, additional, Albert, Istvan, additional, Gould, Thomas J., additional, Fishbein, Diana, additional, Grigson, P. Sue, additional, and Cavigelli, Sonia A., additional

Published
2021
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38. Complete Genome Sequence of Mycobacterium orygis Strain 51145

Author

Rufai, Syed Beenish, primary, McIntosh, Fiona, additional, Poojary, Indira, additional, Chothe, Shubhada, additional, Sebastian, Aswathy, additional, Albert, Istvan, additional, Praul, Craig, additional, Venkatesan, Manigandan, additional, Mahata, Gibarni, additional, Maity, Hindol, additional, Dandapat, Premanshu, additional, Michael, Joy Sarojini, additional, Katani, Robab, additional, Kapur, Vivek, additional, and Behr, Marcel A., additional

Published
2021
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39. Genomic characterization of velogenic avian orthoavulavirus 1 isolates from poultry workers: Implications to emergence and its zoonotic potential towards public health

Author

Kuchipudi, SureshV, primary, Shabbir, MuhammadZubair, additional, Nissly, RuthHelmus, additional, Ahad, Abdul, additional, Rabbani, Masood, additional, Lim, Levina, additional, Chothe, ShubhadaK, additional, Subbiah, Murugan, additional, Sebastian, Aswathy, additional, Albert, Istvan, additional, Ul-Rahman, Aziz, additional, and Jayarao, BhushanM, additional

Published
2021
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41. FOCUS 1: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia

Author

File, Thomas M., Jr, Low, Donald E., Eckburg, Paul B., Talbot, George H., Friedland, H. David, Lee, Jon, Llorens, Lily, Critchley, Ian A., Thye, Dirk A., Pullman, John, Giordano, Philip, Welker, James, Manos, Paul, Mehra, Purvi, File, Thomas, Jr, De Santo, Joseph, Venkateswaralu, Bhaskar, Gerald Schrock, Christian, Tillis, William, Winetz, Jan Alan, Gonzalez, J. Mario, Ramage, Anthony, Eisenhower, Dwight D., Koegelenberg, Coenie, Engelbrecht, Ingrid, Jurgens, Jaco, Mitha, Ishmail, Breedt, Johannes, Gani, Mashra, Roos, Johannes, Basson, Matthys, Van Zyl, Louis, Meeding, Ronel, Fulat, Muhammed, Le Roux, Marius, Bonvehi, Pablo Eduardo, Ganaha, Maria Cristina, Gurini, Ana Leticia, Daniel Lopardo, Gustavo, Cristina, Lucia, Edwardo Prieto, Sergio, Rodiguez, Claudia Gabriela, Augusto Teijeiro, Ricardo, Carmen Pallone, Elida, Pryluka, Daniel Horacio, da Cunha, Clovis Arns, da Silva, Nilton Brandao, de Faria Freire, Antonio Tarcisio, Ferreira Starling, Carlos Ernesto, Costa Fiterman, Jussara, Góngora Rubio, Fernando, Carlos Losso, Luis, Patelli, Maria, Souza Lima, Juliani, Zimermann Teixeira, Paulo José, Carmo Moreira, Maria Auxiliadora, Abreu de Oliveira, Julio César, Roudas, Vsevolod, Gamal, Evgeny A., Leschenko, Igor, Rudnov, Vladimir A., Yevdokimova, Anna G., Vertkin, Arkadiy L., Ambalov, Yuriy M., Dvoryashina, Irina V., Zilber, Elmira, Khamitov, Rustem F., Galustyan, Anna N., Reshetko, Olga V., Senior, Victoria Arama, Grosan, Mihaela Flavia, Jimborean, Gabriela, Lupse, Mihaela, Aron, Gheorgita, Olteanu, Dan, Puschita, Maria, Gavris, Claudia, Tudorache, Voicu Mircea, Youroukova, Vania, Petkova, Mila, Troshanova, Evelina, Dzhabalyan, Mari, Kavtaradze, George, Makhviladze, Manana, Tabukashvili, Revaz, Pons, Marco, Garbino, Jorge, Genne, Daniel, Rothen, Madeleine, de Saracho, Juan Oriz, Capelastegui, Alberto, Menendez, Rosario, Torres, Antoni, Shum, Conrado, Falco, Vincenç, Bouza, Emilio, Bru, Jean-Pierre, Misset, Benoit, Megarbane, Bruno, Sollet, Jean Pierre, Molina, Jean-Michel, Dalhoff, Klaus, Lorenz, Joachim, Petermann, Wolfgang, Rohde, Gernot, Schumann, Christian, Tasci, Selcuk, Zerbst, Joachim, Auch-Schwelk, Wolfgang, Suttorp, Norbert, Henrich, Rolf, Fertl, Andreas, Grohe, Christian, Jakobeit, Christian, Deppermann, Karl-Matthius, Batura-Gabryel, Halina, Pupek-Musialik, Danuta, Piotrowicz, Pawe, Marcisz, Czeslaw, Czarnobilski, Krzysztof, Jankowska, Renata, Janik, Krzysztof, Gutowska-Jablonska, Malgorzata, Hamankiewicz, Maciej, Kus, Jan, Rydzewski, Andrzej, Dulawa, Jan, Ziolko, Ewa, Baranska, Eliza, Wendland, Marian, Trebas-Pietras, Ewa, Tyszkiewic, Ireneusz, Bonelli, Johannes, Balikó, Zoltán, Bisits, Márta, Losonczy, Gyorgy, Mark, Zsuzsa, Albert, Istvan, Francovszky, Eva, Fonay, Karoly, Tetiana Pertseva, Tetiana, Yefimov, Volodymyr, Havrysyuk, Volodymyr, Melnyk, Vasyl, Yashyna, Lyudmyla, Monogarova, Nadiya, Kolchyn, Yuriy, Dutka, Roman, Smolyanyi, Oleksandr, Tryshchuk, Nadiya, Kaydashev, Igor, Rodionova, Victoria, Neyko, Vasyl, Chopey, Ivan, Alekniene, Birute, Kramilius, Ginataras, Naudziunas, Stanislovas, Miliauskas, Skaidrius, Nausediene, Vitalija, Valavicius, Arvydas, Mitic-Milikic, Marija, Celeketic, Dusica, Lazic, Zorica, Milinic, Nikola, Pejcic, Tatjana, Sukles, Kai, Jaanus, Martti, Meriste, Sulev, Ahmad Mahayiddin, Datin Hjh Aziah, Bin Abdul Muttalif, Abdul Pazak, Kuang Kiat, Kiew, Binte, Roslina, Manap, Abdul, bt Tarekh, Noor Aliza, Anekthananon, Thanomsak, Mootsikapun, Piroon, Intalapaporn, Poj, Pothirat, Chaicharn, Horsin, Pinyo, Churchottaworn, Charoen, Wattanathum, Anan, Dukat, Andrej, and Plutinsky, Jan

Published
2011
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47. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer

Author

Hellmann, Matthew, Paz-Ares, Luis, Bernabe Caro, Reyes, Zurawski, Bogdan, Kim, Sang-We, Carcereny Costa, Enric, Park, Keunchil, Alexandru, Aurelia, Lupinacci, Lorena, de La Mora Jimenez, Emmanuel, Sakai, Hiroshi, Albert, Istvan, Vergnenègre, Alain, Peters, Solange, Syrigos, Konstantinos, Barlesi, Fabrice, Reck, Martin, Borghaei, Hossein, Brahmer, Julie, O'Byrne, Kenneth, Geese, William, Bhagavatheeswaran, Prabhu, Rabindran, Sridhar, Kasinathan, Ravi, Nathan, Faith, Ramalingam, Suresh, O’byrne, Kenneth, Samsung Medical Center Sungkyunkwan University School of Medicine, Institute Division of Hematology/Oncology, Bioinformatics Consulting Center, Pennsylvania State University (Penn State), Penn State System-Penn State System, Service de Pathologie respiratoire et allergologie [CHU Limoges], CHU Limoges, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), National and Kapodistrian University of Athens (NKUA), Assistance Publique - Hôpitaux de Marseille (APHM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AstraZeneca, Bristol-Myers Squibb, and Ono Pharmaceutical

Subjects
Oncology, Male, Lung Neoplasms, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, B7-H1 Antigen, law.invention, MESH: Ipilimumab, 0302 clinical medicine, Antineoplastic Agents, Immunological, MESH: Aged, 80 and over, Randomized controlled trial, law, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, MESH: B7-H1 Antigen, 030212 general & internal medicine, Response rate (survey), Aged, 80 and over, MESH: Aged, MESH: Middle Aged, General Medicine, Middle Aged, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, Nivolumab, MESH: Survival Analysis, MESH: Nivolumab, Female, medicine.drug, Adult, medicine.medical_specialty, Ipilimumab, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 03 medical and health sciences, Internal medicine, Carcinoma, medicine, Humans, Lung cancer, Survival analysis, Aged, MESH: Humans, business.industry, MESH: Adult, medicine.disease, Survival Analysis, MESH: Antineoplastic Agents, Immunological, MESH: Male, respiratory tract diseases, MESH: Lung Neoplasms, Clinical trial, business, MESH: Female, MESH: Carcinoma, Non-Small-Cell Lung
Abstract

[Background] In an early-phase study involving patients with advanced non–small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC., [Methods] In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1% or more., [Results] Among the patients with a PD-L1 expression level of 1% or more, the median duration of overall survival was 17.1 months (95% confidence interval [CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (P=0.007), with 2-year overall survival rates of 40.0% and 32.8%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy. The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy., [Conclusions] First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826. opens in new tab.), Funded by Bristol-Myers Squibb and Ono Pharmaceutical.

Published
2019

48. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer

Author

Hellmann, Matthew D. Paz-Ares, Luis Bernabe Caro, Reyes Zurawski, Bogdan Kim, Sang-We Carcereny Costa, Enric Park, Keunchil Alexandru, Aurelia Lupinacci, Lorena de la Mora Jimenez, Emmanuel Sakai, Hiroshi Albert, Istvan Vergnenegre, Alain Peters, Solange Syrigos, Konstantinos Barlesi, Fabrice Reck, Martin Borghaei, Hossein Brahmer, Julie R. O'Byrne, Kenneth J. Geese, William J. Bhagavatheeswaran, Prabhu Rabindran, Sridhar K. Kasinathan, Ravi S. Nathan, Faith E. Ramalingam, Suresh S.

Abstract

BACKGROUND: In an early-phase study involving patients with advanced non-small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC. METHODS: In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1\% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a PD-L1 expression level of less than 1\% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1\% or more. RESULTS: Among the patients with a PD-L1 expression level of 1\% or more, the median duration of overall survival was 17.1 months (95\% confidence interval [CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95\% CI, 12.7 to 16.7) with chemotherapy (P = 0.007), with 2-year overall survival rates of 40.0\% and 32.8\%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1\%, with a median duration of 17.2 months (95\% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95\% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95\% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95\% CI, 12.2 to 15.1) with chemotherapy. The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8\% with nivolumab plus ipilimumab and 36.0\% with chemotherapy. CONCLUSIONS: First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826.).

Published
2019

49. Nivolumab plus Ipilimumab in Advanced Non–Small-Cell Lung Cancer

Author

Bristol-Myers Squibb, Ono Pharmaceutical, Hellmann, Matthew D., Paz-Ares, Luis, Bernabé Caro, Reyes, Zurawski, Bogdan, Kim, Sang-We, Carcereny Costa, Enric, Park, Keunchil, Alexandru, Aurelia, Lupinacci, Lorena, Mora Jiménez, Emmanuel de la, Sakai, Hiroshi, Albert, Istvan, Vergnenegre, Alain, Peters, Solange, Syrigos, Konstantinos, Barlesi, Fabrice, Reck, Martin, Borghaei, Hossein, Brahmer, Julie R., O'Byrne, Kenneth J., Geese, William J., Bhagavatheeswaran, Prabhu, Rabindran, Sridhar K., Kasinathan, Ravi S., Nathan, Faith Ellen, Ramalingam, Suresh S., Bristol-Myers Squibb, Ono Pharmaceutical, Hellmann, Matthew D., Paz-Ares, Luis, Bernabé Caro, Reyes, Zurawski, Bogdan, Kim, Sang-We, Carcereny Costa, Enric, Park, Keunchil, Alexandru, Aurelia, Lupinacci, Lorena, Mora Jiménez, Emmanuel de la, Sakai, Hiroshi, Albert, Istvan, Vergnenegre, Alain, Peters, Solange, Syrigos, Konstantinos, Barlesi, Fabrice, Reck, Martin, Borghaei, Hossein, Brahmer, Julie R., O'Byrne, Kenneth J., Geese, William J., Bhagavatheeswaran, Prabhu, Rabindran, Sridhar K., Kasinathan, Ravi S., Nathan, Faith Ellen, and Ramalingam, Suresh S.

Abstract

[Background] In an early-phase study involving patients with advanced non–small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC., [Methods] In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1% or more., [Results] Among the patients with a PD-L1 expression level of 1% or more, the median duration of overall survival was 17.1 months (95% confidence interval [CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (P=0.007), with 2-year overall survival rates of 40.0% and 32.8%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy. The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy., [Conclusions] First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826. opens in new tab.)

Published
2019

50. Galaxy: A platform for interactive large-scale genome analysis

Author

Giardine, Belinda, Hardison, Ross C., Elnitski, Laura, Albert, Istvan, Kent, W. James, Riemer, Cathy, Burhans, Richard, Shah, Prachi, Yi Zhang, Blakenberg, Daniel, Taylor, James, Nekrutenko, Anton, and Miller, Webb

Subjects
Interactive computer systems -- Evaluation, Interactive media -- Evaluation, Electronic publishing -- Evaluation, Interactive technology, Electronic publication, Electronic publishing, Health
Abstract

An interactive system, Galaxy, that combines the power of existing genome annotation databases with a simple Web portal to enable users to search remote resources, combine data from independent queries and visualize the results, is presented. The heart of Galaxy is a flexible history system that stores the queries from each user, performs operations such as intersections unions and subtractions and links to other computational tools.

Published
2005

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