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1. New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation

Author

Arwood, Matthew L., Liu, Yao, Harkins, Shannon K., Weinstock, David M., Yang, Lei, Stevenson, Kristen E., Plana, Olivia D., Dong, Jingyun, Cirka, Haley, Jones, Kristen L., Virtanen, Anniina T., Gupta, Dikshat G., Ceas, Amanda, Lawney, Brian, Yoda, Akinori, Leahy, Catharine, Hao, Mingfeng, He, Zhixiang, Choi, Hwan Geun, Wang, Yaning, Silvennoinen, Olli, Hubbard, Stevan R., Zhang, Tinghu, Gray, Nathanael S., and Li, Loretta S.

Published
2023
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2. The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice

Author

Townsend, Elizabeth C, Murakami, Mark A, Christodoulou, Alexandra, Christie, Amanda L, Köster, Johannes, DeSouza, Tiffany A, Morgan, Elizabeth A, Kallgren, Scott P, Liu, Huiyun, Wu, Shuo-Chieh, Plana, Olivia, Montero, Joan, Stevenson, Kristen E, Rao, Prakash, Vadhi, Raga, Andreeff, Michael, Armand, Philippe, Ballen, Karen K, Barzaghi-Rinaudo, Patrizia, Cahill, Sarah, Clark, Rachael A, Cooke, Vesselina G, Davids, Matthew S, DeAngelo, Daniel J, Dorfman, David M, Eaton, Hilary, Ebert, Benjamin L, Etchin, Julia, Firestone, Brant, Fisher, David C, Freedman, Arnold S, Galinsky, Ilene A, Gao, Hui, Garcia, Jacqueline S, Garnache-Ottou, Francine, Graubert, Timothy A, Gutierrez, Alejandro, Halilovic, Ensar, Harris, Marian H, Herbert, Zachary T, Horwitz, Steven M, Inghirami, Giorgio, Intlekofer, Andrew M, Ito, Moriko, Izraeli, Shai, Jacobsen, Eric D, Jacobson, Caron A, Jeay, Sébastien, Jeremias, Irmela, Kelliher, Michelle A, Koch, Raphael, Konopleva, Marina, Kopp, Nadja, Kornblau, Steven M, Kung, Andrew L, Kupper, Thomas S, LeBoeuf, Nicole R, LaCasce, Ann S, Lees, Emma, Li, Loretta S, Look, A Thomas, Murakami, Masato, Muschen, Markus, Neuberg, Donna, Ng, Samuel Y, Odejide, Oreofe O, Orkin, Stuart H, Paquette, Rachel R, Place, Andrew E, Roderick, Justine E, Ryan, Jeremy A, Sallan, Stephen E, Shoji, Brent, Silverman, Lewis B, Soiffer, Robert J, Steensma, David P, Stegmaier, Kimberly, Stone, Richard M, Tamburini, Jerome, Thorner, Aaron R, van Hummelen, Paul, Wadleigh, Martha, Wiesmann, Marion, Weng, Andrew P, Wuerthner, Jens U, Williams, David A, Wollison, Bruce M, Lane, Andrew A, Letai, Anthony, Bertagnolli, Monica M, Ritz, Jerome, Brown, Myles, Long, Henry, Aster, Jon C, Shipp, Margaret A, Griffin, James D, and Weinstock, David M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biotechnology, Clinical Trials and Supportive Activities, Orphan Drug, Clinical Research, Hematology, Cancer, Rare Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Good Health and Well Being, Animals, Antineoplastic Agents, Biomarkers, Tumor, Cell Lineage, Female, Gene Expression Profiling, Genes, p53, Heterografts, Humans, Internet, Isoquinolines, Leukemia, Leukemia, Experimental, Lymphoma, Male, Mice, Mice, Inbred NOD, Molecular Targeted Therapy, Neoplasm Proteins, Neoplasm Transplantation, Phenotype, Piperazines, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Proteome, Proto-Oncogene Proteins c-mdm2, Random Allocation, Randomized Controlled Trials as Topic, Research Design, Tissue Banks, Transcriptome, Xenograft Model Antitumor Assays, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease.

Published
2016

3. Supplementary Table 5 from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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4. Supplementary Table 4 from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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5. Supplementary Table 2 from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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6. Data from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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7. Supplementary Table 6 from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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8. Supplementary Table 3 from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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9. Supplementary Table 7 from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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10. Supplementary Table 1 from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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11. Supplementary Figures and Methods from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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13. Mechanisms of lymphoma clearance induced by high-dose alkylating agents

Author

Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Massachusetts Institute of Technology. Department of Chemistry, Ragon Institute of MGH, MIT and Harvard, Lossos, Chen, Liu, Yunpeng, Kolb, Kellie E, Christie, Amanda L, van Scoyk, Alexandria, Prakadan, Sanjay M, Shigemori, Kay, Stevenson, Kristen E, Morrow, Sara, Plana, Olivia D, Fraser, Cameron, Jones, Kristen L, Liu, Huiyun, Pallasch, Christian P, Modiste, Rebecca, Nguyen, Quang-De, Craig, Jeffrey W, Morgan, Elizabeth A, Vega, Francisco, Aster, Jon C, Sarosiek, Kristopher A, Shalek, Alex K, Hemann, Michael T, Weinstock, David M, Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Massachusetts Institute of Technology. Department of Chemistry, Ragon Institute of MGH, MIT and Harvard, Lossos, Chen, Liu, Yunpeng, Kolb, Kellie E, Christie, Amanda L, van Scoyk, Alexandria, Prakadan, Sanjay M, Shigemori, Kay, Stevenson, Kristen E, Morrow, Sara, Plana, Olivia D, Fraser, Cameron, Jones, Kristen L, Liu, Huiyun, Pallasch, Christian P, Modiste, Rebecca, Nguyen, Quang-De, Craig, Jeffrey W, Morgan, Elizabeth A, Vega, Francisco, Aster, Jon C, Sarosiek, Kristopher A, Shalek, Alex K, Hemann, Michael T, and Weinstock, David M

Abstract

© 2019 American Association for Cancer Research. The extraordinary activity of high-dose cyclophosphamide against some high-grade lymphomas was described nearly 60 years ago. Here we address mechanisms that mediate cyclophosphamide activity in bona fide human double-hit lymphoma. We show that antibody resistance within the bone marrow (BM) is not present upon early engraftment but develops during lymphoma progression. This resistance required a high tumor:macrophage ratio, was recapitulated in spleen by partial macrophage depletion, and was overcome by multiple, high-dose alkylating agents. Cyclophosphamide induced endoplasmic reticulum (ER) stress in BM-resident lymphoma cells in vivo that resulted in ATF4-mediated paracrine secretion of VEGFA, massive macrophage infiltration, and clearance of alemtuzumab-opsonized cells. BM macrophages isolated after cyclophosphamide treatment had increased phagocytic capacity that was reversed by VEGFA blockade or SYK inhibition. Single-cell RNA sequencing of these macrophages identified a “super-phagocytic” subset that expressed CD36/FCGR4. Together, these findings define a novel mechanism through which high-dose alkylating agents promote macrophage-dependent lymphoma clearance. SIGNIFICANCE: mAbs are effective against only a small subset of cancers. Herein, we recapitulate compartment-specific antibody resistance and define an ER stress–dependent mechanism induced by high-dose alkylating agents that promotes phagocytosis of opsonized tumor cells. This approach induces synergistic effects with mAbs and merits testing across additional tumor types.

Published
2021

14. Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, additional, Kolb, Kellie E., additional, Christie, Amanda L., additional, Van Scoyk, Alexandria, additional, Prakadan, Sanjay M., additional, Shigemori, Kay, additional, Stevenson, Kristen E., additional, Morrow, Sara, additional, Plana, Olivia D., additional, Fraser, Cameron, additional, Jones, Kristen L., additional, Liu, Huiyun, additional, Pallasch, Christian P., additional, Modiste, Rebecca, additional, Nguyen, Quang-De, additional, Craig, Jeffrey W., additional, Morgan, Elizabeth A., additional, Vega, Francisco, additional, Aster, Jon C., additional, Sarosiek, Kristopher A., additional, Shalek, Alex K., additional, Hemann, Michael T., additional, and Weinstock, David M., additional

Published
2019
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15. Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, Liu, Yunpeng, Kolb, Kellie E., Christie, Amanda L., Van Scoyk, Alexandria, Prakadan, Sanjay M., Shigemori, Kay, Stevenson, Kristen E., Morrow, Sara, Plana, Olivia D., Fraser, Cameron, Jones, Kristen L., Liu, Huiyun, Pallasch, Christian P., Modiste, Rebecca, Craig, Jeffrey W., Morgan, Elizabeth A., Vega, Francisco, Aster, Jon C., Sarosiek, Kristopher A., Shalek, Alex K., Hemann, Michael T., Weinstock, David M., Lossos, Chen, Liu, Yunpeng, Kolb, Kellie E., Christie, Amanda L., Van Scoyk, Alexandria, Prakadan, Sanjay M., Shigemori, Kay, Stevenson, Kristen E., Morrow, Sara, Plana, Olivia D., Fraser, Cameron, Jones, Kristen L., Liu, Huiyun, Pallasch, Christian P., Modiste, Rebecca, Craig, Jeffrey W., Morgan, Elizabeth A., Vega, Francisco, Aster, Jon C., Sarosiek, Kristopher A., Shalek, Alex K., Hemann, Michael T., and Weinstock, David M.

Abstract

The extraordinary activity of high-dose cyclophosphamide against some high-grade lymphomas was described nearly 60 years ago. Here we address mechanisms that mediate cyclophosphamide activity in bona fide human double-hit lymphoma. We show that antibody resistance within the bone marrow (BM) is not present upon early engraftment but develops during lymphoma progression. This resistance required a high tumor:macrophage ratio, was recapitulated in spleen by partial macrophage depletion, and was overcome by multiple, high-dose alkylating agents. Cyclophosphamide induced endoplasmic reticulum (ER) stress in BM-resident lymphoma cells in vivo that resulted in ATF4-mediated paracrine secretion of VEGFA, massive macrophage infiltration, and clearance of alemtuzumab-opsonized cells. BM macrophages isolated after cyclophosphamide treatment had increased phagocytic capacity that was reversed by VEGFA blockade or SYK inhibition. Single-cell RNA sequencing of these macrophages identified a super-phagocytic subset that expressed CD36/FCGR4. Together, these findings define a novel mechanism through which high-dose alkylating agents promote macrophage-dependent lymphoma clearance. SIGNIFICANCE: mAbs are effective against only a small subset of cancers. Herein, we recapitulate compartment-specific antibody resistance and define an ER stress-dependent mechanism induced by high-dose alkylating agents that promotes phagocytosis of opsonized tumor cells. This approach induces synergistic effects with mAbs and merits testing across additional tumor types.

Published
2019

16. Alkylating Agent-Induced ER Stress Overcomes Microenvironmental Resistance to Lymphoma Therapy

Author

Lossos, Chen, primary, Kolb, Kellie E., additional, Christie, Amanda L., additional, Scoyk, Alexandria Van, additional, Prakadan, Sanjay, additional, Shigamori, Kay, additional, Stevenson, Kristen, additional, Morrow, Sara, additional, Plana, Olivia D., additional, Fraser, Cameron, additional, Liu, Huiyun, additional, Pallasch, Christian C., additional, Modiste, Rebecca, additional, Nguyen, Quang-De, additional, Craig, Jeffrey W., additional, Morgan, Elizabeth A., additional, Aster, Jon C., additional, Sarosiek, Kristopher A., additional, Shalek, Alex K., additional, Hemann, Michael T., additional, and Weinstock, David M., additional

Published
2018
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17. Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain

Author

Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Goff, Loyal A., Groff, Abigail F., Sauvageau, Martin, Trayes-Gibson, Zachary, Sanchez-Gomez, Diana B., Morse, Michael, Martin, Ryan D., Elcavage, Lara E., Liapis, Stephen C., Gonzalez-Celeiro, Meryem, Plana, Olivia, Li, Eric, Gerhardinger, Chiara, Tomassy, Giulio S., Arlotta, Paola, Rinn, John L., Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Goff, Loyal A., Groff, Abigail F., Sauvageau, Martin, Trayes-Gibson, Zachary, Sanchez-Gomez, Diana B., Morse, Michael, Martin, Ryan D., Elcavage, Lara E., Liapis, Stephen C., Gonzalez-Celeiro, Meryem, Plana, Olivia, Li, Eric, Gerhardinger, Chiara, Tomassy, Giulio S., Arlotta, Paola, and Rinn, John L.

Abstract

Long noncoding RNAs (lncRNAs) have been implicated in numerous cellular processes including brain development. However, the in vivo expression dynamics and molecular pathways regulated by these loci are not well understood. Here, we leveraged a cohort of 13 lncRNA-null mutant mouse models to investigate the spatiotemporal expression of lncRNAs in the developing and adult brain and the transcriptome alterations resulting from the loss of these lncRNA loci. We show that several lncRNAs are differentially expressed both in time and space, with some presenting highly restricted expression in only selected brain regions. We further demonstrate altered regulation of genes for a large variety of cellular pathways and processes upon deletion of the lncRNA loci. Finally, we found that 4 of the 13 lncRNAs significantly affect the expression of several neighboring protein-coding genes in a cis-like manner. By providing insight into the endogenous expression patterns and the transcriptional perturbations caused by deletion of the lncRNA locus in the developing and postnatal mammalian brain, these data provide a resource to facilitate future examination of the specific functional relevance of these genes in neural development, brain function, and disease., National Science Foundation (U.S.) (Postdoctoral Research Fellowship in Biology DBI-0905973)

Published
2016

18. In Vivo Characterization of Linc-p21 Reveals Functional cis -Regulatory DNA Elements

Author

Groff, Abigail F., primary, Sanchez-Gomez, Diana B., additional, Soruco, Marcela M.L., additional, Gerhardinger, Chiara, additional, Barutcu, A. Rasim, additional, Li, Eric, additional, Elcavage, Lara, additional, Plana, Olivia, additional, Sanchez, Lluvia V., additional, Lee, James C., additional, Sauvageau, Martin, additional, and Rinn, John L., additional

Published
2016
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20. Male Contraception: Research, New Methods, and Implications for Marginalized Populations.

Author

Plana, Olivia

Abstract

The majority of research on contraception has focused on manipulating the female reproductive system. Recent studies have identified novel contraceptives for males, including hormonal- and nonhormonal-based therapeutics. Although these new contraceptives are still undergoing clinical trials, their development and potential future use in society necessitate serious consideration of their implications for reproductive health. Through my analysis of the research conducted on male contraception over time and the current therapeutics available, it is clear that male contraception has the potential to shift societal gender dynamics and provide males with greater control over their own reproduction. This article also identifies the implications of these novel contraceptives for marginalized populations, especially men of color and men of lower socioeconomic positions. To overcome barriers to contraception among these populations, public policy efforts are needed in order to motivate the development of programs that facilitate coverage of these new male contraceptives by health plans and to increase their availability to underserved communities. Health care providers will be responsible for educating patients about these novel male contraception options and the need to continue using existing methods (e.g., condoms) in order to prevent sexually transmitted infections. This article analyzes the research conducted on male contraception and identifies the implications of these novel therapeutics for marginalized groups of men in the United States to identify the interventions that will be necessary to help ensure that all men have access to these promising scientific innovations. [ABSTRACT FROM AUTHOR]

Published
2017
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21. In Vivo Characterization of Linc-p21Reveals Functional cis-Regulatory DNA Elements

Author

Groff, Abigail F., Sanchez-Gomez, Diana B., Soruco, Marcela M.L., Gerhardinger, Chiara, Barutcu, A. Rasim, Li, Eric, Elcavage, Lara, Plana, Olivia, Sanchez, Lluvia V., Lee, James C., Sauvageau, Martin, and Rinn, John L.

Abstract

The Linc-p21locus, encoding a long non-coding RNA, plays an important role in p53 signaling, cell-cycle regulation, and tumor suppression. However, despite extensive study, confusion exists regarding its mechanism of action: is activity driven by the transcript acting in trans, in cis, or by an underlying functional enhancer? Here, using a knockout mouse model and a massively parallel enhancer assay, we delineate the functional elements at this locus. We observe that, even in tissues with no detectable Linc-p21transcript, deletion of the locus significantly affects local gene expression, including of the cell-cycle regulator Cdkn1a. To characterize this RNA-independent regulatory effect, we systematically interrogated the underlying DNA sequence for enhancer activity at nucleotide resolution and confirmed the existence of multiple enhancer elements. Together, these data suggest that, in vivo, the cis-regulatory effects mediated by Linc-p21, in the presence or absence of transcription, are due to DNA enhancer elements.

Published
2016
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