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1. Microbiome preterm birth DREAM challenge: Crowdsourcing machine learning approaches to advance preterm birth research

Author

Golob, Jonathan L, Oskotsky, Tomiko T, Tang, Alice S, Roldan, Alennie, Chung, Verena, Ha, Connie WY, Wong, Ronald J, Flynn, Kaitlin J, Parraga-Leo, Antonio, Wibrand, Camilla, Minot, Samuel S, Oskotsky, Boris, Andreoletti, Gaia, Kosti, Idit, Bletz, Julie, Nelson, Amber, Gao, Jifan, Wei, Zhoujingpeng, Chen, Guanhua, Tang, Zheng-Zheng, Novielli, Pierfrancesco, Romano, Donato, Pantaleo, Ester, Amoroso, Nicola, Monaco, Alfonso, Vacca, Mirco, De Angelis, Maria, Bellotti, Roberto, Tangaro, Sabina, Kuntzleman, Abigail, Bigcraft, Isaac, Techtmann, Stephen, Bae, Daehun, Kim, Eunyoung, Jeon, Jongbum, Joe, Soobok, Community, The Preterm Birth DREAM, Theis, Kevin R, Ng, Sherrianne, Lee, Yun S, Diaz-Gimeno, Patricia, Bennett, Phillip R, MacIntyre, David A, Stolovitzky, Gustavo, Lynch, Susan V, Albrecht, Jake, Gomez-Lopez, Nardhy, Romero, Roberto, Stevenson, David K, Aghaeepour, Nima, Tarca, Adi L, Costello, James C, and Sirota, Marina

Subjects
Paediatrics, Biomedical and Clinical Sciences, Infant Mortality, Prevention, Genetics, Perinatal Period - Conditions Originating in Perinatal Period, Pediatric, Human Genome, Preterm, Low Birth Weight and Health of the Newborn, Reproductive health and childbirth, Good Health and Well Being, Pregnancy, Female, Infant, Newborn, Humans, Premature Birth, Crowdsourcing, Phylogeny, Vagina, Microbiota, Preterm Birth DREAM Community, 16S harmonization, DREAM challenge, crowdsourced, machine learning, microbiome, predictive modeling, preterm birth, vaginal microbiome, Biomedical and clinical sciences
Abstract

Every year, 11% of infants are born preterm with significant health consequences, with the vaginal microbiome a risk factor for preterm birth. We crowdsource models to predict (1) preterm birth (PTB;

Published
2024

2. AI Competitions and Benchmarks: The life cycle of challenges and benchmarks

Author

Stolovitzky, Gustavo, Saez-Rodriguez, Julio, Bletz, Julie, Albrecht, Jacob, Andreoletti, Gaia, Costello, James C., and Boutros, Paul

Subjects
Computer Science - Machine Learning
Abstract

Data Science research is undergoing a revolution fueled by the transformative power of technology, the Internet, and an ever increasing computational capacity. The rate at which sophisticated algorithms can be developed is unprecedented, yet they remain outpaced by the massive amounts of data that are increasingly available to researchers. Here we argue for the need to creatively leverage the scientific research and algorithm development community as an axis of robust innovation. Engaging these communities in the scientific discovery enterprise by critical assessments, community experiments, and/or crowdsourcing will multiply opportunities to develop new data driven, reproducible and well benchmarked algorithmic solutions to fundamental and applied problems of current interest. Coordinated community engagement in the analysis of highly complex and massive data has emerged as one approach to find robust methodologies that best address these challenges. When community engagement is done in the form of competitions, also known as challenges, the validation of the analytical methodology is inherently addressed, establishing performance benchmarks. Finally, challenges foster open innovation across multiple disciplines to create communities that collaborate directly or indirectly to address significant scientific gaps. Together, participants can solve important problems as varied as health research, climate change, and social equity. Ultimately, challenges can catalyze and accelerate the synthesis of complex data into knowledge or actionable information, and should be viewed a powerful tool to make lasting social and research contributions.

Published
2023

5. Crowdsourcing assessment of maternal blood multi-omics for predicting gestational age and preterm birth.

Author

Tarca, Adi L, Pataki, Bálint Ármin, Romero, Roberto, Sirota, Marina, Guan, Yuanfang, Kutum, Rintu, Gomez-Lopez, Nardhy, Done, Bogdan, Bhatti, Gaurav, Yu, Thomas, Andreoletti, Gaia, Chaiworapongsa, Tinnakorn, DREAM Preterm Birth Prediction Challenge Consortium, Hassan, Sonia S, Hsu, Chaur-Dong, Aghaeepour, Nima, Stolovitzky, Gustavo, Csabai, Istvan, and Costello, James C

Subjects
DREAM Preterm Birth Prediction Challenge Consortium, aptamers, collaborative competition, human transcriptome arrays, machine learning, plasma proteomics, predictive modeling, preterm labor and delivery, spontaneous preterm birth, whole blood transcriptomics
Abstract

Identification of pregnancies at risk of preterm birth (PTB), the leading cause of newborn deaths, remains challenging given the syndromic nature of the disease. We report a longitudinal multi-omics study coupled with a DREAM challenge to develop predictive models of PTB. The findings indicate that whole-blood gene expression predicts ultrasound-based gestational ages in normal and complicated pregnancies (r = 0.83) and, using data collected before 37 weeks of gestation, also predicts the delivery date in both normal pregnancies (r = 0.86) and those with spontaneous preterm birth (r = 0.75). Based on samples collected before 33 weeks in asymptomatic women, our analysis suggests that expression changes preceding preterm prelabor rupture of the membranes are consistent across time points and cohorts and involve leukocyte-mediated immunity. Models built from plasma proteomic data predict spontaneous preterm delivery with intact membranes with higher accuracy and earlier in pregnancy than transcriptomic models (AUROC = 0.76 versus AUROC = 0.6 at 27-33 weeks of gestation).

Published
2021

7. Mesenchymal and MAPK Expression Signatures Associate with Telomerase Promoter Mutations in Multiple Cancers

Author

Stern, Josh Lewis, Hibshman, Grace, Hu, Kevin, Ferrara, Sarah E, Costello, James C, Kim, William, Tamayo, Pablo, Cech, Thomas R, and Huang, Franklin W

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Generic health relevance, Cell Line, Tumor, Chromatin Immunoprecipitation, Epithelial-Mesenchymal Transition, Extracellular Signal-Regulated MAP Kinases, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Humans, Mutation, Neoplasms, Promoter Regions, Genetic, Sequence Analysis, RNA, Small Molecule Libraries, Telomerase, Tumor Microenvironment, Oncology and Carcinogenesis, Developmental Biology, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

In a substantial fraction of cancers TERT promoter (TERTp) mutations drive expression of the catalytic subunit of telomerase, contributing to their proliferative immortality. We conducted a pan-cancer analysis of cell lines and find a TERTp mutation expression signature dominated by epithelial-to-mesenchymal transition and MAPK signaling. These data indicate that TERTp mutants are likely to generate distinctive tumor microenvironments and intercellular interactions. Analysis of high-throughput screening tests of 546 small molecules on cell line growth indicated that TERTp mutants displayed heightened sensitivity to specific drugs, including RAS pathway inhibitors, and we found that inhibition of MEK1 and 2, key RAS/MAPK pathway effectors, inhibited TERT mRNA expression. Consistent with an enrichment of mesenchymal states in TERTp mutants, cell lines and some patient tumors displayed low expression of the central adherens junction protein E-cadherin, and we provide evidence that its expression in these cells is regulated by MEK1/2. Several mesenchymal transcription factors displayed elevated expression in TERTp mutants including ZEB1 and 2, TWIST1 and 2, and SNAI1. Of note, the developmental transcription factor SNAI2/SLUG was conspicuously elevated in a significant majority of TERTp-mutant cell lines, and knock-down experiments suggest that it promotes TERT expression. IMPLICATIONS: Cancers harboring TERT promoter mutations are often more lethal, but the basis for this higher mortality remains unknown. Our study identifies that TERTp mutants, as a class, associate with a distinct gene and protein expression signature likely to impact their biological and clinical behavior and provide new directions for investigating treatment approaches for these cancers.

Published
2020

8. Reducing overfitting in challenge-based competitions

Author

Neto, Elias Chaibub, Hoff, Bruce R, Bare, Chris, Bot, Brian M, Yu, Thomas, Magravite, Lara, Trister, Andrew D, Norman, Thea, Meyer, Pablo, Saez-Rodrigues, Julio, Costello, James C, Guinney, Justin, and Stolovitzky, Gustavo

Subjects
Statistics - Applications
Abstract

Over-fitting is a dreaded foe in challenge-based competitions. Because participants rely on public leaderboards to evaluate and refine their models, there is always the danger they might over-fit to the holdout data supporting the leaderboard. The recently published Ladder algorithm aims to address this problem by preventing the participants from exploiting willingly or inadvertently minor fluctuations in public leaderboard scores during model refinement. In this paper, we report a vulnerability of the Ladder that induces severe over-fitting of the leaderboard when the sample size is small. To circumvent this attack, we propose a variation of the Ladder that releases a bootstrapped estimate of the public leaderboard score instead of providing participants with a direct measure of performance. We also extend the scope of the Ladder to arbitrary performance metrics by relying on a more broadly applicable testing procedure based on the Bayesian bootstrap. Our method makes it possible to use a leaderboard, with the technical and social advantages that it provides, even in cases where data is scant.

Published
2016

9. ProstaMine: a bioinformatics tool for identifying subtype-specific co-alterations associated with aggressiveness in prostate cancer.

Author

Orman, Michael V., Sreekanth, Varsha, Laajala, Teemu D., Cramer, Scott D., and Costello, James C.

Subjects
PROSTATE cancer, CANCER invasiveness, BIOINFORMATICS software, ANTIGEN presentation, BIOINFORMATICS, METASTASIS
Abstract

Background: Prostate cancer is a leading cause of cancer-related deaths among men, marked by heterogeneous clinical and molecular characteristics. The complexity of the molecular landscape necessitates tools for identifying multigene co-alteration patterns that are associated with aggressive disease. The identification of such gene sets will allow for deeper characterization of the processes underlying prostate cancer progression and potentially lead to novel strategies for treatment. Methods: We developed ProstaMine to systematically identify co-alterations associated with aggressiveness in prostate cancer molecular subtypes defined by high-fidelity alterations in primary prostate cancer. ProstaMine integrates genomic, transcriptomic, and clinical data from five primary and one metastatic prostate cancer cohorts to prioritize co-alterations enriched in metastatic disease and associated with disease progression. Results: Integrated analysis of primary tumors defined a set of 17 prostate cancer alterations associated with aggressive characteristics. We applied ProstaMine to NKX3-1-loss and RB1-loss tumors and identified subtype-specific co-alterations associated with metastasis and biochemical relapse in these molecular subtypes. In NKX3-1-loss prostate cancer, ProstaMine identified novel subtype-specific coalterations known to regulate prostate cancer signaling pathways including MAPK, NF-kB, p53, PI3K, and Sonic hedgehog. In RB1-loss prostate cancer, ProstaMine identified novel subtype-specific co-alterations involved in p53, STAT6, and MHC class I antigen presentation. Co-alterations impacting autophagy were noted in both molecular subtypes. Conclusion: ProstaMine is a method to systematically identify novel subtypespecific co-alterations associated with aggressive characteristics in prostate cancer. The results from ProstaMine provide insights into potential subtypespecific mechanisms of prostate cancer progression which can be formed into testable experimental hypotheses. ProstaMine is publicly available at: https:// bioinformatics.cuanschutz.edu/prostamine. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Microbiome preterm birth DREAM challenge: Crowdsourcing machine learning approaches to advance preterm birth research

Author

Golob, Jonathan L., primary, Oskotsky, Tomiko T., additional, Tang, Alice S., additional, Roldan, Alennie, additional, Chung, Verena, additional, Ha, Connie W.Y., additional, Wong, Ronald J., additional, Flynn, Kaitlin J., additional, Parraga-Leo, Antonio, additional, Wibrand, Camilla, additional, Minot, Samuel S., additional, Oskotsky, Boris, additional, Andreoletti, Gaia, additional, Kosti, Idit, additional, Bletz, Julie, additional, Nelson, Amber, additional, Gao, Jifan, additional, Wei, Zhoujingpeng, additional, Chen, Guanhua, additional, Tang, Zheng-Zheng, additional, Novielli, Pierfrancesco, additional, Romano, Donato, additional, Pantaleo, Ester, additional, Amoroso, Nicola, additional, Monaco, Alfonso, additional, Vacca, Mirco, additional, De Angelis, Maria, additional, Bellotti, Roberto, additional, Tangaro, Sabina, additional, Kuntzleman, Abigail, additional, Bigcraft, Isaac, additional, Techtmann, Stephen, additional, Bae, Daehun, additional, Kim, Eunyoung, additional, Jeon, Jongbum, additional, Joe, Soobok, additional, Theis, Kevin R., additional, Ng, Sherrianne, additional, Lee, Yun S., additional, Diaz-Gimeno, Patricia, additional, Bennett, Phillip R., additional, MacIntyre, David A., additional, Stolovitzky, Gustavo, additional, Lynch, Susan V., additional, Albrecht, Jake, additional, Gomez-Lopez, Nardhy, additional, Romero, Roberto, additional, Stevenson, David K., additional, Aghaeepour, Nima, additional, Tarca, Adi L., additional, Costello, James C., additional, and Sirota, Marina, additional

Published
2023
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11. Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate‐sparing anabolic therapy

Author

Jasuja, Ravi, Costello, James C, Singh, Rajan, Gupta, Vandana, Spina, Catherine S, Toraldo, Gianluca, Jang, Hyeran, Li, Hu, Serra, Carlo, Guo, Wen, Chauhan, Pratibha, Narula, Navjot S, Guarneri, Tyler, Ergun, Ayla, Travison, Thomas G, Collins, James J, and Bhasin, Shalender

Subjects
Prostate Cancer, Cancer, Biotechnology, Urologic Diseases, Aging, Anabolic Agents, Animals, Body Weight, Eflornithine, Enzyme Inhibitors, Follistatin, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Muscle, Skeletal, Oligonucleotide Array Sequence Analysis, Organ Size, Organ Sparing Treatments, Ornithine Decarboxylase, Ornithine Decarboxylase Inhibitors, Prostate, Recombinant Proteins, Signal Transduction, Testosterone, aging, anti-aging, sarcopenia, sex hormones, skeletal muscle, steroids, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Because of its anabolic effects on muscle, testosterone is being explored as a function-promoting anabolic therapy for functional limitations associated with aging; however, concerns about testosterone's adverse effects on prostate have inspired efforts to develop strategies that selectively increase muscle mass while sparing the prostate. Testosterone's promyogenic effects are mediated through upregulation of follistatin. We show here that the administration of recombinant follistatin (rFst) increased muscle mass in mice, but had no effect on prostate mass. Consistent with the results of rFst administration, follistatin transgenic mice with constitutively elevated follistatin levels displayed greater muscle mass than controls, but had similar prostate weights. To elucidate signaling pathways regulated differentially by testosterone and rFst in prostate and muscle, we performed microarray analysis of mRNAs from prostate and levator ani of castrated male mice treated with vehicle, testosterone, or rFst. Testosterone and rFst shared the regulation of many transcripts in levator ani; however, in prostate, 593 transcripts in several growth-promoting pathways were differentially expressed after testosterone treatment, while rFst showed a negligible effect with only 9 transcripts differentially expressed. Among pathways that were differentially responsive to testosterone in prostate, we identified ornithine decarboxylase (Odc1), an enzyme in polyamine biosynthesis, as a testosterone-responsive gene that is unresponsive to rFst. Accordingly, we administered testosterone with and without α-difluoromethylornithine (DFMO), an Odc1 inhibitor, to castrated mice. DFMO selectively blocked testosterone's effects on prostate, but did not affect testosterone's anabolic effects on muscle. Co-administration of testosterone and Odc1 inhibitor presents a novel therapeutic strategy for prostate-sparing anabolic therapy.

Published
2014

13. Differential splicing across immune system lineages

Author

Ergun, Ayla, Doran, Graeme, Costello, James C, Paik, Henry H, Collins, James J, Mathis, Diane, Benoist, Christophe, Blair, David A, Dustin, Michael L, Shinton, Susan A, Hardy, Richard R, Shay, Tal, Regevc, Aviv, Cohen, Nadia, Brennan, Patrick, Brenner, Michael, Kim, Francis, Rao, Tata Nageswara, Wagers, Amy, Heng, Tracy, Ericson, Jeffrey, Rothamel, Katherine, Ortiz-Lopez, Adriana, Kreslavsky, Taras, Fletcher, Anne, Elpek, Kutlu, Bellemare-Pelletier, Angelique, Malhotra, Deepali, Turley, Shannon, Miller, Jennifer, Brown, Brian, Merad, Miriam, Gautier, Emmanuel L, Jakubzick, Claudia, Randolph, Gwendalyn J, Monach, Paul, Best, Adam J, Knell, Jamie, Goldrath, Ananda, Jojic, Vladimir, Koller, Daphne, Laidlaw, David, Collins, Jim, Gazit, Roi, Rossi, Derrick J, Malhotra, Nidhi, Sylvia, Katelyn, Kang, Joonsoo, Bezman, Natalie A, Sun, Joseph C, Min-Oo, Gundula, Kim, Charlie C, and Lanier, Lewis L

Subjects
Genetics, Human Genome, 1.1 Normal biological development and functioning, Underpinning research, Inflammatory and immune system, Alternative Splicing, B-Lymphocytes, Cell Lineage, Humans, T-Lymphocytes, ImmGen Consortium
Abstract

Alternative splicing (AS) allows increased diversity and orthogonal regulation of the transcriptional products of mammalian genomes. To assess the distribution and variation of alternative splicing across cell lineages of the immune system, we comprehensively analyzed RNA sequencing and microarray data generated by the Immunological Genome Project Consortium. AS is pervasive: 60% of genes showed frequent AS isoforms in T or B lymphocytes, with 7,599 previously unreported isoforms. Distinct cell specificity was observed, with differential exon skipping in 5% of genes otherwise coexpressed in both B and T cells. The distribution of isoforms was mostly all or none, suggesting on/off switching as a frequent mode of AS regulation in lymphocytes. From the identification of differential exon use in the microarray data, clustering of exon inclusion/exclusion patterns across all Immunological Genome Project cell types showed that ∼70% of AS exons are distributed along a common pattern linked to lineage differentiation and cell cycling. Other AS events distinguished myeloid from lymphoid cells or affected only a small set of exons without clear lineage specificity (e.g., Ptprc). Computational analysis predicted specific associations between AS exons and splicing regulators, which were verified by detection of the hnRPLL/Ptprc connection.

Published
2013

15. Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors

Author

Powers, Rani K., Culp-Hill, Rachel, Ludwig, Michael P., Smith, Keith P., Waugh, Katherine A., Minter, Ross, Tuttle, Kathryn D., Lewis, Hannah C., Rachubinski, Angela L., Granrath, Ross E., Carmona-Iragui, María, Wilkerson, Rebecca B., Kahn, Darcy E., Joshi, Molishree, Lleó, Alberto, Blesa, Rafael, Fortea, Juan, D’Alessandro, Angelo, Costello, James C., Sullivan, Kelly D., and Espinosa, Joaquin M.

Published
2019
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16. Eya3 promotes breast tumor-associated immune suppression via threonine phosphatase-mediated PD-L1 upregulation

Author

Vartuli, Rebecca L., Zhou, Hengbo, Zhang, Lingdi, Powers, Rani K., Klarquist, Jared, Rudra, Pratyaydipta, Vincent, Melanie Y., Ghosh, Debashis, Costello, James C., Kedl, Ross M., Slansky, Jill E., Zhao, Rui, and Ford, Heide L.

Subjects
Immune response regulation -- Health aspects, Breast tumors -- Development and progression -- Genetic aspects, Membrane proteins -- Physiological aspects -- Health aspects, Transcriptional coactivators -- Physiological aspects -- Health aspects, Health care industry
Abstract

Eya proteins are critical developmental regulators that are highly expressed in embryogenesis but downregulated after development. Amplification and/or re-expression of Eyas occurs in many tumor types. In breast cancer, Eyas regulate tumor progression by acting as transcriptional cofactors and tyrosine phosphatases. Intriguingly, Eyas harbor a separate threonine (Thr) phosphatase activity, which was previously implicated in innate immunity. Here we describe what we believe to be a novel role for Eya3 in mediating triple-negative breast cancer-associated immune suppression. Eya3 loss decreases tumor growth in immune-competent mice and is associated with increased numbers of infiltrated [CD8.sup.+] T cells, which, when depleted, reverse the effects of Eya3 knockdown. Mechanistically, Eya3 utilizes its Thr phosphatase activity to dephosphorylate Myc at pT58, resulting in a stabilized form. We show that Myc is required for Eya3-mediated increases in PD-L1, and that rescue of PD-L1 in Eya3-knockdown cells restores tumor progression. Finally, we demonstrate that Eya3 significantly correlates with PD-L1 in human breast tumors, and that tumors expressing high levels of Eya3 have a decreased [CD8.sup.+] T cell signature. Our data uncover a role for Eya3 in mediating tumor-associated immune suppression, and suggest that its inhibition may enhance checkpoint therapies., Introduction The eyes absent family of proteins (Eyas 1-4) are crucial regulators of embryogenesis, contributing to the development of diverse tissues such as the ear (1, 2), eye (3), craniofacial [...]

Published
2018
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18. Abstract IA020: Reprogramming of myogenic transcription factors in rhabdomyosarcoma

Author

Ford, Heide L., primary, Hsu, Jessica Y., additional, Danis, Etienne P., additional, Nance, Stephanie, additional, O’Brien, Jenean H., additional, Gustafson, Annika L., additional, Wessells, Veronica M., additional, Goodspeed, Andrew E., additional, Talbot, Jared C., additional, Amacher, Sharon L., additional, Jedlicka, Paul, additional, Black, Joshua C., additional, Costello, James C., additional, Durbin, Adam D., additional, and Artinger, Kristin B., additional

Published
2022
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22. SIX1 reprograms myogenic transcription factors to maintain the rhabdomyosarcoma undifferentiated state

Author

Hsu, Jessica Y., primary, Danis, Etienne P., additional, Nance, Stephanie, additional, O'Brien, Jenean H., additional, Gustafson, Annika L., additional, Wessells, Veronica M., additional, Goodspeed, Andrew E., additional, Talbot, Jared C., additional, Amacher, Sharon L., additional, Jedlicka, Paul, additional, Black, Joshua C., additional, Costello, James C., additional, Durbin, Adam D., additional, Artinger, Kristin B., additional, and Ford, Heide L., additional

Published
2022
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25. IL13Rα2 Promotes Proliferation and Outgrowth of Breast Cancer Brain Metastases

Author

Márquez-Ortiz, R. Alejandro, primary, Contreras-Zárate, Maria J., additional, Tesic, Vesna, additional, Alvarez-Eraso, Karen L.F., additional, Kwak, Gina, additional, Littrell, Zachary, additional, Costello, James C., additional, Sreekanth, Varsha, additional, Ormond, D. Ryan, additional, Karam, Sana D., additional, Kabos, Peter, additional, and Cittelly, Diana M., additional

Published
2021
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26. Antigens Expressed by Breast Cancer Cells Undergoing EMT Stimulate Cytotoxic CD8 + T Cell Immunity.

Author

Camp, Faye A., Brunetti, Tonya M., Williams, Michelle M., Christenson, Jessica L., Sreekanth, Varsha, Costello, James C., Hay, Zachary L. Z., Kedl, Ross M., Richer, Jennifer K., and Slansky, Jill E.

Subjects
FLOW cytometry, BIOLOGICAL models, REVERSE transcriptase polymerase chain reaction, SEQUENCE analysis, ANIMAL experimentation, WESTERN immunoblotting, EPITHELIAL-mesenchymal transition, TUMOR antigens, CELL lines, T cells, CANCER vaccines, CELL surface antigens, BREAST tumors, MICE, IMMUNODIAGNOSIS
Published
2022
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27. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma

Author

Kwong, Lawrence N., Costello, James C., Liu, Huiyun, Jiang, Shan, Helms, Timothy L., Langsdorf, Aliete E., Jakubosky, David, Genovese, Giannicola, Muller, Florian L., Jeong, Joseph H., Bender, Ryan P., Chu, Gerald C., Flaherty, Keith T., Wargo, Jennifer A., Collins, James J., and Chin, Lynda

Subjects
Cellular signal transduction -- Physiological aspects -- Genetic aspects -- Research, Melanoma -- Analysis -- Health aspects -- Genetic aspects -- Drug therapy -- Research, Ras genes -- Physiological aspects -- Research, Biological sciences, Health
Abstract

The discovery of potent inhibitors of the BRAF proto-oncogene has revolutionized therapy for melanoma harboring mutations in BRAF, yet NRAS-mutant melanoma remains without an effective therapy. Because direct pharmacological inhibition of the RAS proto-oncogene has thus far been unsuccessful, we explored systems biology approaches to identify synergistic drug combination(s) that can mimic RAS inhibition. Here, leveraging an inducible mouse model of NRAS-mutant melanoma, we show that pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) activates apoptosis but not cell-cycle arrest, which is in contrast to complete genetic neuroblastoma RAS homolog (NRAS) extinction, which triggers both of these effects. Network modeling pinpointed cyclin-dependent kinase 4 (CDK4) as a key driver of this differential phenotype. Accordingly, combined pharmacological inhibition of MEK and CDK4 in vivo led to substantial synergy in therapeutic efficacy. We suggest a gradient model of oncogenic NRAS signaling in which the output is gated, resulting in the decoupling of discrete downstream biological phenotypes as a result of incomplete inhibition. Such a gated signaling model offers a new framework to identify nonobvious coextinction target(s) for combined pharmacological inhibition in NRAS-mutant melanomas., The RAS proto-oncogene is activated across a diverse range of human cancers (1), including 15-20% of the melanomas that harbor activating NRAS mutations (2). Agents that block canonical mitogen-activated protein [...]

Published
2012
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30. MAP3K7 Loss Drives Enhanced Androgen Signaling and Independently Confers Risk of Recurrence in Prostate Cancer with Joint Loss of CHD1

Author

Jillson, Lauren K., primary, Rider, Leah C., additional, Rodrigues, Lindsey U., additional, Romero, Lina, additional, Karimpour-Fard, Anis, additional, Nieto, Cera, additional, Gillette, Claire, additional, Torkko, Kathleen, additional, Danis, Etienne, additional, Smith, Elizabeth E., additional, Nolley, Rosalie, additional, Peehl, Donna M., additional, Lucia, M. Scott, additional, Costello, James C., additional, and Cramer, Scott D., additional

Published
2021
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32. Induction of ADAM10 by Radiation Therapy Drives Fibrosis, Resistance, and Epithelial-to-Mesenchyal Transition in Pancreatic Cancer

Author

Mueller, Adam C., primary, Piper, Miles, additional, Goodspeed, Andrew, additional, Bhuvane, Shiv, additional, Williams, Jason S., additional, Bhatia, Shilpa, additional, Phan, Andy V., additional, Van Court, Benjamin, additional, Zolman, Kathryn L., additional, Peña, Brisa, additional, Oweida, Ayman J., additional, Zakem, Sara, additional, Meguid, Cheryl, additional, Knitz, Michael W., additional, Darragh, Laurel, additional, Bickett, Thomas E., additional, Gadwa, Jacob, additional, Mestroni, Luisa, additional, Taylor, Matthew R.G., additional, Jordan, Kimberly R., additional, Dempsey, Peter, additional, Lucia, M. Scott, additional, McCarter, Martin D., additional, Del Chiaro, Marco, additional, Messersmith, Wells A., additional, Schulick, Richard D., additional, Goodman, Karyn A., additional, Gough, Michael J., additional, Greene, Casey S., additional, Costello, James C., additional, Neto, Antonio Galveo, additional, Lagares, David, additional, Hansen, Kirk C., additional, Van Bokhoven, Adrie, additional, and Karam, Sana D., additional

Published
2021
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33. Evolution of genes and genomes on the Drosophila phylogeny

Author

Clark, Andrew G., Eisen, Michael B., Smith, Douglas R., Bergman, Casey M., Oliver, Brian, Markow, Therese A., Kaufman, Thomas C., Kellis, Manolis, Gelbart, William, Iyer, Venky N., Pollard, Daniel A., Sackton, Timothy B., Larracuente, Amanda M., Singh, Nadia D., Abad, Jose P., Abt, Dawn N., Adryan, Boris, Aguade, Montserrat, Akashi, Hiroshi, Anderson, Wyatt W., Aquadro, Charles F., Ardell, David H., Arguello, Roman, Artieri, Carlo G., Barbash, Daniel A., Barker, Daniel, Barsanti, Paolo, Batterham, Phil, Batzoglou, Serafim, Begun, Dave, Bhutkar, Arjun, Blanco, Enrico, Bosak, Stephanie A., Bradley, Robert K., Brand, Adrianne D., Brent, Michael R., Brooks, Angela N., Brown, Randall H., Butlin, Roger K., Caggese, Corrado, Calvi, Brian R., Bernardo de Carvalho, A., Caspi, Anat, Castrezana, Sergio, Celniker, Susan E., Chang, Jean L., Chapple, Charles, Chatterji, Sourav, Chinwalla, Asif, Civetta, Alberto, Clifton, Sandra W., Comeron, Josep M., Costello, James C., Coyne, Jerry A., Daub, Jennifer, David, Robert G., Delcher, Arthur L., Delehaunty, Kim, Do, Chuong B., Ebling, Heather, Edwards, Kevin, Eickbush, Thomas, Evans, Jay D., Filipski, Alan, Findeiß, Sven, Freyhult, Eva, Fulton, Lucinda, Fulton, Robert, Garcia, Ana C. L., Gardiner, Anastasia, Garfield, David A., Garvin, Barry E., Gibson, Greg, Gilbert, Don, Gnerre, Sante, Godfrey, Jennifer, Good, Robert, Gotea, Valer, Gravely, Brenton, Greenberg, Anthony J., Griffiths-Jones, Sam, Gross, Samuel, Guigo, Roderic, Gustafson, Erik A., Haerty, Wilfried, Hahn, Matthew W., Halligan, Daniel L., Halpern, Aaron L., Halter, Gillian M., Han, Mira V., Heger, Andreas, Hillier, LaDeana, Hinrichs, Angie S., Holmes, Ian, Hoskins, Roger A., Hubisz, Melissa J., Hultmark, Dan, Huntley, Melanie A., Jaffe, David B., Jagadeeshan, Santosh, Jeck, William R., Johnson, Justin, Jones, Corbin D., Jordan, William C., Karpen, Gary H., Kataoka, Eiko, Keightley, Peter D., Kheradpour, Pouya, Kirkness, Ewen F., Koerich, Leonardo B., Kristiansen, Karsten, Kudrna, Dave, Kulathinal, Rob J., Kumar, Sudhir, Kwok, Roberta, Lander, Eric, Langley, Charles H., Lapoint, Richard, Lazzaro, Brian P., Lee, So-Jeong, Levesque, Lisa, Li, Ruiqiang, Lin, Chiao-Feng, Lin, Michael F., Lindblad-Toh, Kerstin, Llopart, Ana, Long, Manyuan, Low, Lloyd, Lozovsky, Elena, Lu, Jian, Luo, Meizhong, Machado, Carlos A., Makalowski, Wojciech, Marzo, Mar, Matsuda, Muneo, Matzkin, Luciano, McAllister, Bryant, McBride, Carolyn S., McKernan, Brendan, McKernan, Kevin, Mendez-Lago, Maria, Minx, Patrick, Mollenhauer, Michael U., Montooth, Kristi, Mount, Stephen M., Mu, Xu, Myers, Eugene, Negre, Barbara, Newfeld, Stuart, Nielsen, Rasmus, Noor, Mohamed A. F., O'Grady, Patrick, Pachter, Lior, Papaceit, Montserrat, Parisi, Matthew J., Parisi, Michael, Parts, Leopold, Pedersen, Jakob S., Pesole, Graziano, Phillippy, Adam M., Ponting, Chris P., Pop, Mihai, Porcelli, Damiano, Powell, Jeffrey R., Prohaska, Sonja, Pruitt, Kim, Puig, Marta, Quesneville, Hadi, Ravi Ram, Kristipati, Rand, David, Rasmussen, Matthew D., Reed, Laura K., Reenan, Robert, Reily, Amy, Remington, Karin A., Rieger, Tania T., Ritchie, Michael G., Robin, Charles, Rogers, Yu-Hui, Rohde, Claudia, Rozas, Julio, Rubenfield, Marc J., Ruiz, Alfredo, Russo, Susan, Salzberg, Steven L., Sanchez-Gracia, Alejandro, Saranga, David J., Sato, Hajime, Schaeffer, Stephen W., Schatz, Michael C., Schlenke, Todd, Schwartz, Russell, Segarra, Carmen, Singh, Rama S., Sirot, Laura, Sirota, Marina, Sisneros, Nicholas B., Smith, Chris D., Smith, Temple F., Spieth, John, Stage, Deborah E., Stark, Alexander, Stephan, Wolfgang, Strausberg, Robert L., Strempel, Sebastian, Sturgill, David, Sutton, Granger, Sutton, Granger G., Tao, Wei, Teichmann, Sarah, Tobari, Yoshiko N., Tomimura, Yoshihiko, Tsolas, Jason M., Valente, Vera L. S., Venter, Eli, Craig Venter, J., Vicario, Saverio, Vieira, Filipe G., Vilella, Albert J., Villasante, Alfredo, Walenz, Brian, Wang, Jun, Wasserman, Marvin, Watts, Thomas, Wilson, Derek, Wilson, Richard K., Wing, Rod A., Wolfner, Mariana F., Wong, Alex, Ka-Shu Wong, Gane, Wu, Chung-I, Wu, Gabriel, Yamamoto, Daisuke, Yang, Hsiao-Pei, Yang, Shiaw-Pyng, Yorke, James A., Yoshida, Kiyohito, Zdobnov, Evgeny, Zhang, Peili, Zhang, Yu, Zimin, Aleksey V., Baldwin, Jennifer, Abdouelleil, Amr, Abdulkadir, Jamal, Abebe, Adal, Abera, Brikti, Abreu, Justin, Christophe Acer, St, Aftuck, Lynne, Alexander, Allen, An, Peter, Anderson, Erica, Anderson, Scott, Arachi, Harindra, Azer, Marc, Bachantsang, Pasang, Barry, Andrew, Bayul, Tashi, Berlin, Aaron, Bessette, Daniel, Bloom, Toby, Blye, Jason, Boguslavskiy, Leonid, Bonnet, Claude, Boukhgalter, Boris, Bourzgui, Imane, Brown, Adam, Cahill, Patrick, Channer, Sheridon, Cheshatsang, Yama, Chuda, Lisa, Citroen, Mieke, Collymore, Alville, Cooke, Patrick, Costello, Maura, D'Aco, Katie, Daza, Riza, De Haan, Georgius, DeGray, Stuart, DeMaso, Christina, Dhargay, Norbu, Dooley, Kimberly, Dooley, Erin, Doricent, Missole, Dorje, Passang, Dorjee, Kunsang, Dupes, Alan, Elong, Richard, Falk, Jill, Farina, Abderrahim, Faro, Susan, Ferguson, Diallo, Fisher, Sheila, Foley, Chelsea D., Franke, Alicia, Friedrich, Dennis, Gadbois, Loryn, Gearin, Gary, Gearin, Christina R., Giannoukos, Georgia, Goode, Tina, Graham, Joseph, Grandbois, Edward, Grewal, Sharleen, Gyaltsen, Kunsang, Hafez, Nabil, Hagos, Birhane, Hall, Jennifer, Henson, Charlotte, Hollinger, Andrew, Honan, Tracey, Huard, Monika D., Hughes, Leanne, Hurhula, Brian, Erii Husby, M, Kamat, Asha, Kanga, Ben, Kashin, Seva, Khazanovich, Dmitry, Kisner, Peter, Lance, Krista, Lara, Marcia, Lee, William, Lennon, Niall, Letendre, Frances, LeVine, Rosie, Lipovsky, Alex, Liu, Xiaohong, Liu, Jinlei, Liu, Shangtao, Lokyitsang, Tashi, Lokyitsang, Yeshi, Lubonja, Rakela, Lui, Annie, MacDonald, Pen, Magnisalis, Vasilia, Maru, Kebede, Matthews, Charles, McCusker, William, McDonough, Susan, Mehta, Teena, Meldrim, James, Meneus, Louis, Mihai, Oana, Mihalev, Atanas, Mihova, Tanya, Mittelman, Rachel, Mlenga, Valentine, Montmayeur, Anna, Mulrain, Leonidas, Navidi, Adam, Naylor, Jerome, Negash, Tamrat, Nguyen, Thu, Nguyen, Nga, Nicol, Robert, Norbu, Choe, Norbu, Nyima, Novod, Nathaniel, O'Neill, Barry, Osman, Sahal, Markiewicz, Eva, Oyono, Otero L., Patti, Christopher, Phunkhang, Pema, Pierre, Fritz, Priest, Margaret, Raghuraman, Sujaa, Rege, Filip, Reyes, Rebecca, Rise, Cecil, Rogov, Peter, Ross, Keenan, Ryan, Elizabeth, Settipalli, Sampath, Shea, Terry, Sherpa, Ngawang, Shi, Lu, Shih, Diana, Sparrow, Todd, Spaulding, Jessica, Stalker, John, Stange-Thomann, Nicole, Stavropoulos, Sharon, Stone, Catherine, Strader, Christopher, Tesfaye, Senait, Thomson, Talene, Thoulutsang, Yama, Thoulutsang, Dawa, Topham, Kerri, Topping, Ira, Tsamla, Tsamla, Vassiliev, Helen, Vo, Andy, Wangchuk, Tsering, Wangdi, Tsering, Weiand, Michael, Wilkinson, Jane, Wilson, Adam, Yadav, Shailendra, Young, Geneva, Yu, Qing, Zembek, Lisa, Zhong, Danni, Zimmer, Andrew, Zwirko, Zac, Alvarez, Pablo, Brockman, Will, Butler, Jonathan, Chin, CheeWhye, Grabherr, Manfred, Kleber, Michael, Mauceli, Evan, and MacCallum, Iain

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

Author(s): Drosophila 12 Genomes Consortium; Project Leaders; Andrew G. Clark (corresponding author) [1]; Michael B. Eisen (corresponding author) [2, 3]; Douglas R. Smith (corresponding author) [4]; Casey M. Bergman (corresponding [...]

Published
2007
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34. The Capacity of the Ovarian Cancer Tumor Microenvironment to Integrate Inflammation Signaling Conveys a Shorter Disease-free Interval

Author

Jordan, Kimberly R., primary, Sikora, Matthew J., additional, Slansky, Jill E., additional, Minic, Angela, additional, Richer, Jennifer K., additional, Moroney, Marisa R., additional, Hu, Junxiao, additional, Wolsky, Rebecca J., additional, Watson, Zachary L., additional, Yamamoto, Tomomi M., additional, Costello, James C., additional, Clauset, Aaron, additional, Behbakht, Kian, additional, Kumar, T. Rajendra, additional, and Bitler, Benjamin G., additional

Published
2020
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37. KDM5A and PHF2 positively control expression of pro-metastatic genes repressed by EWS/Fli1, and promote growth and metastatic properties in Ewing sarcoma

Author

McCann, Tyler S., primary, Parrish, Janet K., additional, Hsieh, Joseph, additional, Sechler, Marybeth, additional, Sobral, Lays M., additional, Self, Chelsea, additional, Jones, Kenneth L., additional, Goodspeed, Andrew, additional, Costello, James C., additional, and Jedlicka, Paul, additional

Published
2020
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39. Abstract 4091: Functional genomic screening in gemcitabine and cisplatin resistant bladder cancer cell lines identifies DNA repair pathways as mediators of chemosensitivity

Author

Jones, Robert T., primary, Zuiverloon, Tahlita C., additional, Vekony, Hedvig, additional, Goodspeed, Andrew, additional, Laajala, Teemu D., additional, Joshi, Molishree, additional, Sempeck, Colin, additional, Jean, Annie, additional, Tu, Megan, additional, Wulfkuhle, Julia D., additional, Petricoin, Emanuel F., additional, Costello, James C., additional, and Theodorescu, Dan, additional

Published
2020
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41. Abstract IA10: Developing rational combination therapy with checkpoint inhibitors

Author

Tu, Megan M., primary, Lee, Francis Y. F., additional, Jones, Robert T., additional, Kimball, Abigail K., additional, Saravia, Elizabeth, additional, Graziano, Robert F., additional, Coleman, Brianne, additional, Menard, Krista, additional, Yan, Jun, additional, Michaud, Erin, additional, Chang, Han, additional, Abdel-Hafiz, Hany A., additional, Rozhok, Andrii I., additional, Duex, Jason E., additional, Agarwal, Neeraj, additional, Chauca-Diaz, Ana, additional, Johnson, Linda K., additional, Ng, Terry L., additional, Cambier, John C., additional, Clambey, Eric T., additional, Costello, James C., additional, Korman, Alan J., additional, and Theodorescu, Dan, additional

Published
2020
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43. Abstract B11: Multi-omic interrogation of gemcitabine and cisplatin-resistant bladder cancer cell lines identifies unique and shared mediators of chemosensitivity and resistance

Author

Jones, Robert T., primary, Zuiverloon, Tahlita C. M., additional, Vekony, Hedvig, additional, Goodspeed, Andrew, additional, Laajala, Teemu D., additional, Joshi, Molishree, additional, Sempeck, Colin, additional, Jean, Annie, additional, Tu, Megan, additional, Wulfkuhle, Julia D., additional, Petricoin, Emanuel F., additional, Costello, James C., additional, and Theodorescu, Dan, additional

Published
2020
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44. Identification of a Small-Molecule Inhibitor That Disrupts the SIX1/EYA2 Complex, EMT, and Metastasis

Author

Zhou, Hengbo, primary, Blevins, Melanie A., additional, Hsu, Jessica Y., additional, Kong, Deguang, additional, Galbraith, Matthew D., additional, Goodspeed, Andrew, additional, Culp-Hill, Rachel, additional, Oliphant, Michael U.J., additional, Ramirez, Dominique, additional, Zhang, Lingdi, additional, Trinidad-Pineiro, Jennyvette, additional, Mathews Griner, Lesley, additional, King, Rebecca, additional, Barnaeva, Elena, additional, Hu, Xin, additional, Southall, Noel T., additional, Ferrer, Marc, additional, Gustafson, Daniel L., additional, Regan, Daniel P., additional, D'Alessandro, Angelo, additional, Costello, James C., additional, Patnaik, Samarjit, additional, Marugan, Juan, additional, Zhao, Rui, additional, and Ford, Heide L., additional

Published
2020
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49. SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program

Author

Oliphant, Michael U.J., primary, Vincent, Melanie Y., additional, Galbraith, Matthew D., additional, Pandey, Ahwan, additional, Zaberezhnyy, Vadym, additional, Rudra, Pratyaydipta, additional, Johnson, Katherine R., additional, Costello, James C., additional, Ghosh, Debashis, additional, DeGregori, James, additional, Espinosa, Joaquin M., additional, and Ford, Heide L., additional

Published
2019
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50. Targeting DDR2 enhances tumor response to anti–PD-1 immunotherapy

Author

Tu, Megan M., primary, Lee, Francis Y. F., additional, Jones, Robert T., additional, Kimball, Abigail K., additional, Saravia, Elizabeth, additional, Graziano, Robert F., additional, Coleman, Brianne, additional, Menard, Krista, additional, Yan, Jun, additional, Michaud, Erin, additional, Chang, Han, additional, Abdel-Hafiz, Hany A., additional, Rozhok, Andrii I., additional, Duex, Jason E., additional, Agarwal, Neeraj, additional, Chauca-Diaz, Ana, additional, Johnson, Linda K., additional, Ng, Terry L., additional, Cambier, John C., additional, Clambey, Eric T., additional, Costello, James C., additional, Korman, Alan J., additional, and Theodorescu, Dan, additional

Published
2019
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