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51. sj-docx-2-cre-10.1177_02692155221138920 - Supplemental material for Economic evaluation of digitally enabled aged and neurological rehabilitation care in the Activity and MObility UsiNg Technology (AMOUNT) trial

Author

Pinheiro, Marina B, Hassett, Leanne, Sherrington, Catherine, Hayes, Alison, van den Berg, Maayken, Lindley, Richard I, Crotty, Maria, Chagpar, Sakina, Treacy, Daniel, Weber, Heather, Fairhall, Nicola, Wong, Siobhan, McCluskey, Annie, Togher, Leanne, Scrivener, Katharine, and Howard, Kirsten

Subjects
FOS: Clinical medicine, 110604 Sports Medicine, FOS: Health sciences, 110904 Neurology and Neuromuscular Diseases, 110314 Orthopaedics
Abstract

Supplemental material, sj-docx-2-cre-10.1177_02692155221138920 for Economic evaluation of digitally enabled aged and neurological rehabilitation care in the Activity and MObility UsiNg Technology (AMOUNT) trial by Marina B Pinheiro, Leanne Hassett, Catherine Sherrington, Alison Hayes and Maayken van den Berg, Richard I Lindley, Maria Crotty, Sakina Chagpar, Daniel Treacy, Heather Weber, Nicola Fairhall, Siobhan Wong, Annie McCluskey, Leanne Togher, Katharine Scrivener, Kirsten Howard in Clinical Rehabilitation

Published
2022
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52. CANCER GENOMICS: Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq

Author

Tirosh, Itay, Izar, Benjamin, Prakadan, Sanjay M., Wadsworth, Marc H., II, Treacy, Daniel, Trombetta, John J., Rotem, Asaf, Rodman, Christopher, Lian, Christine, Murphy, George, Fallahi-Sichani, Mohammad, Dutton-Regester, Ken, Lin, Jia-Ren, Cohen, Ofir, Shah, Parin, Lu, Diana, Genshaft, Alex S., Hughes, Travis K., Ziegler, Carly G. K., Kazer, Samuel W., Gaillard, Aleth, Kolb, Kellie E., Villani, Alexandra-Chloé, Johannessen, Cory M., Andreev, Aleksandr Y., Van Allen, Eliezer M., Bertagnolli, Monica, Sorger, Peter K., Sullivan, Ryan J., Flaherty, Keith T., Frederick, Dennie T., Jané-Valbuena, Judit, Yoon, Charles H., Rozenblatt-Rosen, Orit, Shalek, Alex K., Regev, Aviv, and Garraway, Levi A.

Published
2016
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53. 735 Identification of a small molecule that prevents T cell exhaustion using machine learning algorithms paired with high-resolution single cell RNAseq

Author

Mercier, Isabelle Le, primary, Sun, Sunny, additional, Xiao, Dongmei, additional, Isacco, Laura, additional, Treacy, Daniel, additional, Artru, Emilie, additional, Steelman, Scott, additional, Bradley, John, additional, Wolf, Alex, additional, Stewart, Morag, additional, and Tozzo, Effie, additional

Published
2021
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55. Mobility rehabilitation and measurement

Author

Treacy, Daniel John

Subjects
balance, Physiotherapy, mobility, frail, rehabilitation
Abstract

This thesis aimed to investigate strategies for mobility rehabilitation and measurement. Research methods used include: a randomised controlled trial (n=162) with a cost effectiveness analysis of a balance-focused exercise class; a validation study (n=166) of devices to measure step counts during inpatient rehabilitation and; a systematic review with meta-analysis of trials of exercise to enhance mobility in people with frailty (12 trials). An RCT was conducted to evaluate the impact of two weeks of additional standing balance circuit classes in an inpatient rehabilitation population. The intervention group improved their composite balance measure by 3.26 sec (95% CI 0.84 to 5.70, P = 0.009) at two weeks and 3.40 secs (95% CI -0.56 to 7.38, P = 0.092) at three months compared to the control group. The intervention group improved significantly on mobility with a difference in the SPPB of 1.19 (95% CI 0.52 to 1.87, P = 0.001) at two weeks and 1.00 at three months (95% CI 0.00 to 2.00, P = 0.049) compared to the control group. The median cost savings for those who received the intervention was $4,741 (95% CI $137 to $9,372); 94% of bootstraps showed that the intervention was both effective and cost saving. To determine the accuracy of activity monitors for measuring steps in people with mobility limitations, participants wore 16 activity monitors simultaneously during a 6-minute walk test. Overall, the ankle-worn StepWatch Activity Monitor showed the highest agreement with the observed step count (ICC2,1) (0.982, 95% CI 0.975 to 0.986), followed by the Fitbit One worn on the ankle (0.919, 95% CI 0.772 to 0.961) and the thigh-worn ActivPAL (0.781, 95% CI 0.231 to 0.911). All other devices showed poor agreement. To evaluate the evidence for mobility training on mobility and function for frail older people in the community a meta-analysis of RCTs was performed (12 trials, 1,317 participants). Overall mobility training resulted in an improvement in mobility with a 0.47 SMD (95% CI 0.24 to 0.71). At 6 months post intervention there was an improvement of 0.32 SMD (95% CI 0.1 to 0.54). Overall, mobility training resulted in an improvement in function of 0.60 SMD (95% CI 0.21 to 1.00). At 6 months post intervention there was little to no difference with an improvement of 1.29 SMD (95% CI -0.38 to 2.96).

Published
2021

57. Physical activity coaching for adults with mobility limitations: protocol for the ComeBACK pragmatic hybrid effectiveness-implementation type 1 randomised controlled trial

Author

Hassett, Leanne, primary, Tiedemann, Anne, additional, Hinman, Rana S, additional, Crotty, Maria, additional, Hoffmann, Tammy, additional, Harvey, Lisa, additional, Taylor, Nicholas F, additional, Greaves, Colin, additional, Treacy, Daniel, additional, Jennings, Matthew, additional, Milat, Andrew, additional, Bennell, Kim L, additional, Howard, Kirsten, additional, van den Berg, Maayken, additional, Pinheiro, Marina, additional, Wong, Siobhan, additional, Kirkham, Catherine, additional, Ramsay, Elizabeth, additional, O'Rourke, Sandra, additional, and Sherrington, Catherine, additional

Published
2020
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58. Digitally enabled aged care and neurological rehabilitation to enhance outcomes with Activity and MObility UsiNg Technology (AMOUNT) in Australia: A randomised controlled trial

Author

Hassett, Leanne, primary, van den Berg, Maayken, additional, Lindley, Richard I., additional, Crotty, Maria, additional, McCluskey, Annie, additional, van der Ploeg, Hidde P., additional, Smith, Stuart T., additional, Schurr, Karl, additional, Howard, Kirsten, additional, Hackett, Maree L., additional, Killington, Maggie, additional, Bongers, Bert, additional, Togher, Leanne, additional, Treacy, Daniel, additional, Dorsch, Simone, additional, Wong, Siobhan, additional, Scrivener, Katharine, additional, Chagpar, Sakina, additional, Weber, Heather, additional, Pinheiro, Marina, additional, Heritier, Stephane, additional, and Sherrington, Catherine, additional

Published
2020
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59. Digitally enabled aged care and neurological rehabilitation to enhance outcomes with Activity and MObility UsiNg Technology (AMOUNT) in Australia: A randomised controlled trial

Author

Hassett, Leanne, van den Berg, Maayken, Lindley, Richard I., Crotty, Maria, McCluskey, Annie, van der Ploeg, Hidde P., Smith, Stuart T., Schurr, Karl, Howard, Kirsten, Hackett, Maree, Killington, Maggie, Bongers, Bert, Togher, Leanne, Treacy, Daniel, Dorsch, Simone, Wong, Siobhan, Scrivener, Katharine, Chagpar, Sakina, Weber, Heather, Pinheiro, Marina, Heritier, Stephane, Sherrington, Catherine, Hassett, Leanne, van den Berg, Maayken, Lindley, Richard I., Crotty, Maria, McCluskey, Annie, van der Ploeg, Hidde P., Smith, Stuart T., Schurr, Karl, Howard, Kirsten, Hackett, Maree, Killington, Maggie, Bongers, Bert, Togher, Leanne, Treacy, Daniel, Dorsch, Simone, Wong, Siobhan, Scrivener, Katharine, Chagpar, Sakina, Weber, Heather, Pinheiro, Marina, Heritier, Stephane, and Sherrington, Catherine

Abstract

Background: Digitally enabled rehabilitation may lead to better outcomes but has not been tested in large pragmatic trials. We aimed to evaluate a tailored prescription of affordable digital devices in addition to usual care for people with mobility limitations admitted to aged care and neurological rehabilitation. Methods and findings: We conducted a pragmatic, outcome-assessor-blinded, parallel-group randomised trial in 3 Australian hospitals in Sydney and Adelaide recruiting adults 18 to 101 years old with mobility limitations undertaking aged care and neurological inpatient rehabilitation. Both the intervention and control groups received usual multidisciplinary inpatient and post-hospital rehabilitation care as determined by the treating rehabilitation clinicians. In addition to usual care, the intervention group used devices to target mobility and physical activity problems, individually prescribed by a physiotherapist according to an intervention protocol, including virtual reality video games, activity monitors, and handheld computer devices for 6 months in hospital and at home. Co-primary outcomes were mobility (performance-based Short Physical Performance Battery [SPPB]; continuous version; range 0 to 3; higher score indicates better mobility) and upright time as a proxy measure of physical activity (proportion of the day upright measured with activPAL) at 6 months. The dataset was analysed using intention-to-treat principles. The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000936628). Between 22 September 2014 and 10 November 2016, 300 patients (mean age 74 years, SD 14; 50% female; 54% neurological condition causing activity limitation) were randomly assigned to intervention (n = 149) or control (n = 151) using a secure online database (REDCap) to achieve allocation concealment. Six-month assessments were completed by 258 participants (129 intervention, 129 control). Intervention participants rec

Published
2020

60. Transcriptome alterations in myotonic dystrophy skeletal muscle and heart

Author

Wang, Eric T, primary, Treacy, Daniel, additional, Eichinger, Katy, additional, Struck, Adam, additional, Estabrook, Joseph, additional, Olafson, Hailey, additional, Wang, Thomas T, additional, Bhatt, Kirti, additional, Westbrook, Tony, additional, Sedehizadeh, Sam, additional, Ward, Amanda, additional, Day, John, additional, Brook, David, additional, Berglund, J Andrew, additional, Cooper, Thomas, additional, Housman, David, additional, Thornton, Charles, additional, and Burge, Christopher, additional

Published
2018
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62. Systematic genomic and translational efficiency studies of uveal melanoma

Author

Johnson, Chelsea Place, primary, Kim, Ivana K., additional, Esmaeli, Bita, additional, Amin-Mansour, Ali, additional, Treacy, Daniel J., additional, Carter, Scott L., additional, Hodis, Eran, additional, Wagle, Nikhil, additional, Seepo, Sara, additional, Yu, Xiaoxing, additional, Lane, Anne Marie, additional, Gragoudas, Evangelos S., additional, Vazquez, Francisca, additional, Nickerson, Elizabeth, additional, Cibulskis, Kristian, additional, McKenna, Aaron, additional, Gabriel, Stacey B., additional, Getz, Gad, additional, Van Allen, Eliezer M., additional, ‘t Hoen, Peter A. C., additional, Garraway, Levi A., additional, and Woodman, Scott E., additional

Published
2017
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65. Abstract 4380: Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-sequencing

Author

Izar, Benjamin, primary, Tirsh, Itay, additional, Prakadan, Sanjay, additional, Wadsworth, Marc, additional, Treacy, Daniel, additional, Trombetta, John, additional, Rotem, Asaf, additional, Lian, Christine, additional, Murphy, George, additional, Fallahi-Sichani, Mohammad, additional, Dutton-Regester, Ken, additional, Lin, Jia-Ren, additional, Jane-Valbuena, Judit, additional, Rozenblatt-Rosen, Orit, additional, Yoon, Charles, additional, Shalek, Alex, additional, Regev, Aviv, additional, and Garraway, Levi, additional

Published
2016
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66. Effect of affordable technology on physical activity levels and mobility outcomes in rehabilitation: a protocol for the Activity and MObility UsiNg Technology (AMOUNT) rehabilitation trial

Author

Hassett, Leanne, primary, van den Berg, Maayken, additional, Lindley, Richard I, additional, Crotty, Maria, additional, McCluskey, Annie, additional, van der Ploeg, Hidde P, additional, Smith, Stuart T, additional, Schurr, Karl, additional, Killington, Maggie, additional, Bongers, Bert, additional, Howard, Kirsten, additional, Heritier, Stephane, additional, Togher, Leanne, additional, Hackett, Maree, additional, Treacy, Daniel, additional, Dorsch, Simone, additional, Wong, Siobhan, additional, Scrivener, Katharine, additional, Chagpar, Sakina, additional, Weber, Heather, additional, Pearson, Ross, additional, and Sherrington, Catherine, additional

Published
2016
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67. The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma

Author

Van Allen, Eliezer M. Wagle, Nikhil Sucker, Antje Treacy, Daniel J. Johannessen, Cory M. Goetz, Eva M. Place, Chelsea S. Taylor-Weiner, Amaro Whittaker, Steven Kryukov, Gregory V. Hodis, Eran Rosenberg, Mara McKenna, Aaron Cibulskis, Kristian Farlow, Deborah Zimmer, Lisa Hillen, Uwe and Gutzmer, Ralf Goldinger, Simone M. Ugurel, Selma Gogas, Helen J. Egberts, Friederike Berking, Carola Trefzer, Uwe and Loquai, Carmen Weide, Benjamin Hassel, Jessica C. and Gabriel, Stacey B. Carter, Scott L. Getz, Gad Garraway, Levi A. Schadendorf, Dirk Dermatologic Cooperative Oncology

Abstract

Most patients with BRAF(V600)-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAF(V600)-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a “long tail” of new mitogen-activated protein kinase (MAPK) pathway alterations (MAP2K2, MITF) that confer RAF inhibitor resistance. In three cases, multiple resistance gene alterations were observed within the same tumor biopsy. Overall, RAF inhibitor therapy leads to diverse clinical genetic resistance mechanisms, mostly involving MAPK pathway reactivation. Novel therapeutic combinations may be needed to achieve durable clinical control of BRAF(V600)-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies. SIGNIFICANCE: The use of RAF inhibitors for BRAF(V600)-mutant metastatic melanoma improves patient outcomes, but most patients demonstrate early or acquired resistance to this targeted therapy. We reveal the genetic landscape of clinical resistance mechanisms to RAF inhibitors from patients using whole-exome sequencing, and experimentally assess new observed mechanisms to define potential subsequent treatment strategies. (C)2013 AACR.

Published
2014

69. Antagonistic regulation of mRNA expression and splicing by CELF and MBNL proteins

Author

Massachusetts Institute of Technology. Computational and Systems Biology Program, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Wang, Eric Tzy-shi, Ward, Amanda, Cherone, Jennifer Michelle, Wang, Thomas T., Treacy, Daniel J., Lambert, Nicole J., Freese, Peter Dale, Saxena, Tanvi, Burge, Christopher B., Giudice, Jimena, Cooper, Thomas A., Wang, Thomas, Lambert, Nicole, Burge, Christopher B, Wang, Eric T, Massachusetts Institute of Technology. Computational and Systems Biology Program, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Wang, Eric Tzy-shi, Ward, Amanda, Cherone, Jennifer Michelle, Wang, Thomas T., Treacy, Daniel J., Lambert, Nicole J., Freese, Peter Dale, Saxena, Tanvi, Burge, Christopher B., Giudice, Jimena, Cooper, Thomas A., Wang, Thomas, Lambert, Nicole, Burge, Christopher B, and Wang, Eric T

Abstract

RNA binding proteins of the conserved CUGBP1, Elav-like factor (CELF) family contribute to heart and skeletal muscle development and are implicated in myotonic dystrophy (DM). To understand their genome-wide functions, we analyzed the transcriptome dynamics following induction of CELF1 or CELF2 in adult mouse heart and of CELF1 in muscle by RNA-seq, complemented by crosslinking/immunoprecipitation-sequencing (CLIP-seq) analysis of mouse cells and tissues to distinguish direct from indirect regulatory targets. We identified hundreds of mRNAs bound in their 3′ UTRs by both CELF1 and the developmentally induced MBNL1 protein, a threefold greater overlap in target messages than expected, including messages involved in development and cell differentiation. The extent of 3′ UTR binding by CELF1 and MBNL1 predicted the degree of mRNA repression or stabilization, respectively, following CELF1 induction. However, CELF1's RNA binding specificity in vitro was not detectably altered by coincubation with recombinant MBNL1. These findings support a model in which CELF and MBNL proteins bind independently to mRNAs but functionally compete to specify down-regulation or localization/stabilization, respectively, of hundreds of mRNA targets. Expression of many alternative 3′ UTR isoforms was altered following CELF1 induction, with 3′ UTR binding associated with down-regulation of isoforms and genes. The splicing of hundreds of alternative exons was oppositely regulated by these proteins, confirming an additional layer of regulatory antagonism previously observed in a handful of cases. The regulatory relationships between CELFs and MBNLs in control of both mRNA abundance and splicing appear to have evolved to enhance developmental transitions in major classes of heart and muscle genes., Myotonic Dystrophy Foundation, National Institutes of Health (U.S.) (Grant OD017865-02), National Science Foundation (U.S.) (Award 0821391), National Institutes of Health (U.S.) (Grant R01GM085319), National Institutes of Health (U.S.) (Grant RC2HG005624)

Published
2015

70. Abstract CN07-04: Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq

Author

Tirosh, Itay, primary, Izar, Benjamin, additional, Prakadan, Sanjay M., additional, Wadsworth, Marc H., additional, Treacy, Daniel, additional, Trombetta, John J., additional, Lu, Diana, additional, Rotem, Asaf, additional, Lian, Christine, additional, Murphy, George, additional, Cohen, Ofir, additional, Allen, Eli van, additional, Bertagnolli, Monica, additional, Genshaft, Alex, additional, Hughes, Travis K., additional, Ziegler, Carly G. K., additional, Kazer, Samuel W., additional, Gaillard, Aleth, additional, Kolb, Kellie E., additional, Valbuena1, Judit, additional, Yoon, Charles, additional, Rozenblatt-Rosen, Orit, additional, Shalek, Alex K., additional, Regev, Aviv, additional, and Garraway, Levi, additional

Published
2015
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71. Abstract A2-11: PLZF, a tumor suppressor genetically lost in metastatic castration resistant prostate cancer, is a mediator of resistance to androgen deprivation therapy

Author

Hsieh, Chen-Lin, primary, Botta, Ginevra, additional, Gao, Shuai, additional, Li, Tiantian, additional, Allen, Eliezer M. Van, additional, Treacy, Daniel J., additional, Cai, Changmeng, additional, He, Housheng Hansen, additional, Sweeney, Christopher J., additional, Brown, Myles, additional, Balk, Steven P., additional, Nelson, Peter S., additional, Garraway, Levi A., additional, and Kantoff, Philip W., additional

Published
2015
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72. Abstract A1-15: Systematic genomic characterization of uveal melanoma

Author

Place, Chelsea S., primary, Kim, Ivana K., additional, Esmaeli, Bita, additional, Amin-Mansour, Ali, additional, Treacy, Daniel J., additional, Carter, Scott L., additional, Hodis, Eran, additional, Wagle, Nikhil, additional, Seepo, Sara, additional, Yu, Xiaoxing, additional, Vazquez, Francisca, additional, Nickerson, Elizabeth, additional, Cibulskis, Kristian, additional, McKenna, Aaron, additional, Gabriel, Stacey B., additional, Getz, Gad, additional, Allen, Eliezer M. Van, additional, Garraway, Levi A., additional, and Woodman, Scott E., additional

Published
2015
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73. PLZF, a Tumor Suppressor Genetically Lost in Metastatic Castration-Resistant Prostate Cancer, Is a Mediator of Resistance to Androgen Deprivation Therapy

Author

Hsieh, Chen-Lin, primary, Botta, Ginevra, additional, Gao, Shuai, additional, Li, Tiantian, additional, Van Allen, Eliezer M., additional, Treacy, Daniel J., additional, Cai, Changmeng, additional, He, Housheng Hansen, additional, Sweeney, Christopher J., additional, Brown, Myles, additional, Balk, Steven P., additional, Nelson, Peter S., additional, Garraway, Levi A., additional, and Kantoff, Philip W., additional

Published
2015
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76. Transcriptome-wide Regulation of Pre-mRNA Splicing and mRNA Localization by Muscleblind Proteins

Author

Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Wang, Eric Tzy-shi, Wang, Thomas, Treacy, Daniel J., Housman, David E., Burge, Christopher B., Cody, Neal A. L., Jog, Sonali, Biancolella, Michela, Wang, Thomas T., Luo, Shujun, Schroth, Gary P., Reddy, Sita, Lécuyer, Eric, Housman, David E, Burge, Christopher B, Wang, Eric T, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Wang, Eric Tzy-shi, Wang, Thomas, Treacy, Daniel J., Housman, David E., Burge, Christopher B., Cody, Neal A. L., Jog, Sonali, Biancolella, Michela, Wang, Thomas T., Luo, Shujun, Schroth, Gary P., Reddy, Sita, Lécuyer, Eric, Housman, David E, Burge, Christopher B, and Wang, Eric T

Abstract

The muscleblind-like (Mbnl) family of RNA-binding proteins plays important roles in muscle and eye development and in myotonic dystrophy (DM), in which expanded CUG or CCUG repeats functionally deplete Mbnl proteins. We identified transcriptome-wide functional and biophysical targets of Mbnl proteins in brain, heart, muscle, and myoblasts by using RNA-seq and CLIP-seq approaches. This analysis identified several hundred splicing events whose regulation depended on Mbnl function in a pattern indicating functional interchangeability between Mbnl1 and Mbnl2. A nucleotide resolution RNA map associated repression or activation of exon splicing with Mbnl binding near either 3′ splice site or near the downstream 5′ splice site, respectively. Transcriptomic analysis of subcellular compartments uncovered a global role for Mbnls in regulating localization of mRNAs in both mouse and Drosophila cells, and Mbnl-dependent translation and protein secretion were observed for a subset of mRNAs with Mbnl-dependent localization. These findings hold several new implications for DM pathogenesis., Massachusetts Institute of Technology (Poitras Fellowship), National Science Foundation (U.S.) (equipment grant no. 082139), National Institutes of Health (U.S.)

Published
2014

78. The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma

Author

Van Allen, Eliezer M., primary, Wagle, Nikhil, additional, Sucker, Antje, additional, Treacy, Daniel J., additional, Johannessen, Cory M., additional, Goetz, Eva M., additional, Place, Chelsea S., additional, Taylor-Weiner, Amaro, additional, Whittaker, Steven, additional, Kryukov, Gregory V., additional, Hodis, Eran, additional, Rosenberg, Mara, additional, McKenna, Aaron, additional, Cibulskis, Kristian, additional, Farlow, Deborah, additional, Zimmer, Lisa, additional, Hillen, Uwe, additional, Gutzmer, Ralf, additional, Goldinger, Simone M., additional, Ugurel, Selma, additional, Gogas, Helen J., additional, Egberts, Friederike, additional, Berking, Carola, additional, Trefzer, Uwe, additional, Loquai, Carmen, additional, Weide, Benjamin, additional, Hassel, Jessica C., additional, Gabriel, Stacey B., additional, Carter, Scott L., additional, Getz, Gad, additional, Garraway, Levi A., additional, and Schadendorf, Dirk, additional

Published
2014
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79. MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition

Author

Wagle, Nikhil, primary, Van Allen, Eliezer M., additional, Treacy, Daniel J., additional, Frederick, Dennie T., additional, Cooper, Zachary A., additional, Taylor-Weiner, Amaro, additional, Rosenberg, Mara, additional, Goetz, Eva M., additional, Sullivan, Ryan J., additional, Farlow, Deborah N., additional, Friedrich, Dennis C., additional, Anderka, Kristin, additional, Perrin, Danielle, additional, Johannessen, Cory M., additional, McKenna, Aaron, additional, Cibulskis, Kristian, additional, Kryukov, Gregory, additional, Hodis, Eran, additional, Lawrence, Donald P., additional, Fisher, Sheila, additional, Getz, Gad, additional, Gabriel, Stacey B., additional, Carter, Scott L., additional, Flaherty, Keith T., additional, Wargo, Jennifer A., additional, and Garraway, Levi A., additional

Published
2014
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81. Whole exome and whole transcriptome sequencing in melanoma patients to identify mechanisms of resistance to combined RAF/MEK inhibition.

Author

Wagle, Nikhil, primary, Van Allen, Eliezer Mendel, additional, Frederick, Dennie T., additional, Cooper, Zachary A., additional, Farlow, Deborah Norman, additional, Treacy, Daniel, additional, Goetz, Eva M., additional, Johannessen, Cory M., additional, Carter, Scott L., additional, Taylor-Weiner, Amaro, additional, Hodis, Eran, additional, Lawrence, Donald P., additional, Sullivan, Ryan J., additional, Getz, Gad, additional, Gabriel, Stacey B., additional, Flaherty, Keith, additional, Wargo, Jennifer Ann, additional, and Garraway, Levi A., additional

Published
2013
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84. Systematic genomic and translational efficiency studies of uveal melanoma

Author

Johnson, Chelsea Place, Kim, Ivana K., Esmaeli, Bita, Amin-Mansour, Ali, Treacy, Daniel J., Carter, Scott L., Hodis, Eran, Wagle, Nikhil, Seepo, Sara, Yu, Xiaoxing, Lane, Anne Marie, Gragoudas, Evangelos S., Vazquez, Francisca, Nickerson, Elizabeth, Cibulskis, Kristian, McKenna, Aaron, Gabriel, Stacey B., Getz, Gad, Van Allen, Eliezer M., ‘t Hoen, Peter A. C., Garraway, Levi A., and Woodman, Scott E.

Subjects
Biology and Life Sciences, Genetics, Mutation, Somatic Mutation, Medicine and Health Sciences, Oncology, Cancers and Neoplasms, Melanomas, Gene Expression, Protein Translation, Frameshift Mutation, Biochemistry, Ribosomes, Polyribosomes, Cell Biology, Cellular Structures and Organelles, Biology and life sciences, Nucleic acids, RNA, Messenger RNA, Metastasis, Basic Cancer Research
Abstract

To further our understanding of the somatic genetic basis of uveal melanoma, we sequenced the protein-coding regions of 52 primary tumors and 3 liver metastases together with paired normal DNA. Known recurrent mutations were identified in GNAQ, GNA11, BAP1, EIF1AX, and SF3B1. The role of mutated EIF1AX was tested using loss of function approaches including viability and translational efficiency assays. Knockdown of both wild type and mutant EIF1AX was lethal to uveal melanoma cells. We probed the function of N-terminal tail EIF1AX mutations by performing RNA sequencing of polysome-associated transcripts in cells expressing endogenous wild type or mutant EIF1AX. Ribosome occupancy of the global translational apparatus was sensitive to suppression of wild type but not mutant EIF1AX. Together, these studies suggest that cells expressing mutant EIF1AX may exhibit aberrant translational regulation, which may provide clonal selective advantage in the subset of uveal melanoma that harbors this mutation.

Published
2017
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85. ERK Mutations Confer Resistance to Mitog en-Activated Protein Kinase Pathway Inhibitors.

Author

Goetz, Eva M., Ghandi, Mahmoud, Treacy, Daniel J., Wagle, Nikhil, and Garraway, Levi A.

Subjects
*PROTEIN kinase inhibitors, *MELANOMA, *CANCER invasiveness, *CANCER genetics, *GENETIC mutation
Abstract

The use of targeted therapeutics directed against BRAFV600-mutant metastatic melanoma improves progression-free survival in many patients; however, acquired drug resistance remains a major medical challenge. By far, the most common clinical resistance mechanism involves reactivation of the MAPK (RAF/MEK/ERK) pathway by a variety of mechanisms. Thus, targeting ERK itself has emerged as an attractive therapeutic concept, and several ERK inhibitors have entered clinical trials. We sought to preemptively determine mutations in ERK1/2 that confer resistance to either ERK inhibitors or combined RAF/MEK inhibition in BRAFV600-mutant melanoma. Using a random mutagenesis screen, we identified multiple point mutations in ERK1 (MAPK3) and ERK2 (MAPK1) that could confer resistance to ERK or RAF/MEK inhibitors. ERK inhibitor-resistant alleles were sensitive to RAF/MEK inhibitors and vice versa, suggesting that the future development of alternating RAF/MEK and ERK inhibitor regimens might help circumvent resistance to these agents. [ABSTRACT FROM AUTHOR]

Published
2014
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86. PLZF, a Tumor Suppressor Genetically Lost in Metastatic Castration-Resistant Prostate Cancer, Is a Mediator of Resistance to Androgen Deprivation Therapy.

Author

Chen-Lin Hsieh, Botta, Ginevra, Shuai Gao, Tiantian Li, Van Allen, Eliezer M., Treacy, Daniel J., Changmeng Cai, Housheng Hansen He, Sweeney, Christopher J., Brown, Myles, Balk, Steven P., Nelson, Peter S., Garraway, Levi A., and Kantoff, PhilipW.

Subjects
*PROSTATE cancer, *ZINC-finger proteins, *DRUG resistance in cancer cells, *TUMOR growth, *MITOGEN-activated protein kinases, *CELLULAR signal transduction
Abstract

Whole-exome sequencing of metastatic castration-resistant prostate cancer (mCRPC) reveals that 5% to 7% of tumors harbor promyelocytic leukemia zinc finger (PLZF) protein homozygous deletions. PLZF is a canonical androgen-regulated putative tumor suppressor gene whose expression is inhibited by androgen deprivation therapy (ADT). Here, we demonstrate that knockdown of PLZF expression promotes a CRPC and enzalutamide-resistant phenotype in prostate cancer cells. Reintroduction of PLZF expression is sufficient to reverse androgen-independent growth mediated by PLZF depletion. PLZF loss enhances CRPC tumor growth in a xenograft model. Bioinformatic analysis of the PLZF cistrome shows that PLZF negatively regulates multiple pathways, including the MAPK pathway. Accordingly, our data support an oncogenic program activated by ADT. This acquired mechanism together with the finding of genetic loss in CRPC implicates PLZF inactivation as a mechanism promoting ADT resistance and the CRPC phenotype. [ABSTRACT FROM AUTHOR]

Published
2015
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87. Antagonistic regulation of mRNA expression and splicing by CELF and MBNL proteins

Author

Thomas A. Cooper, Daniel J. Treacy, Amanda J. Ward, Christopher B. Burge, Eric T. Wang, Tanvi Saxena, Peter Freese, Jennifer M. Cherone, Jimena Giudice, Nicole J. Lambert, Thomas T. Wang, Massachusetts Institute of Technology. Computational and Systems Biology Program, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Wang, Eric Tzy-shi, Ward, Amanda, Cherone, Jennifer Michelle, Wang, Thomas T., Treacy, Daniel J., Lambert, Nicole J., Freese, Peter Dale, Saxena, Tanvi, and Burge, Christopher B.

Subjects
Untranslated region, RNA Splicing, Down-Regulation, RNA-binding protein, Mice, Transgenic, Nerve Tissue Proteins, Biology, CELF1 Protein, 03 medical and health sciences, Exon, Mice, 0302 clinical medicine, Genetics, Animals, CELF Proteins, Humans, Myotonic Dystrophy, Protein Isoforms, RNA, Messenger, Muscle, Skeletal, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Messenger RNA, Sequence Analysis, RNA, Research, RNA, Gene Expression Regulation, Developmental, RNA-Binding Proteins, Heart, Exons, 3. Good health, Gene Expression Regulation, RNA splicing, Transcriptome, 030217 neurology & neurosurgery
Abstract

RNA binding proteins of the conserved CUGBP1, Elav-like factor (CELF) family contribute to heart and skeletal muscle development and are implicated in myotonic dystrophy (DM). To understand their genome-wide functions, we analyzed the transcriptome dynamics following induction of CELF1 or CELF2 in adult mouse heart and of CELF1 in muscle by RNA-seq, complemented by crosslinking/immunoprecipitation-sequencing (CLIP-seq) analysis of mouse cells and tissues to distinguish direct from indirect regulatory targets. We identified hundreds of mRNAs bound in their 3′ UTRs by both CELF1 and the developmentally induced MBNL1 protein, a threefold greater overlap in target messages than expected, including messages involved in development and cell differentiation. The extent of 3′ UTR binding by CELF1 and MBNL1 predicted the degree of mRNA repression or stabilization, respectively, following CELF1 induction. However, CELF1's RNA binding specificity in vitro was not detectably altered by coincubation with recombinant MBNL1. These findings support a model in which CELF and MBNL proteins bind independently to mRNAs but functionally compete to specify down-regulation or localization/stabilization, respectively, of hundreds of mRNA targets. Expression of many alternative 3′ UTR isoforms was altered following CELF1 induction, with 3′ UTR binding associated with down-regulation of isoforms and genes. The splicing of hundreds of alternative exons was oppositely regulated by these proteins, confirming an additional layer of regulatory antagonism previously observed in a handful of cases. The regulatory relationships between CELFs and MBNLs in control of both mRNA abundance and splicing appear to have evolved to enhance developmental transitions in major classes of heart and muscle genes., Myotonic Dystrophy Foundation, National Institutes of Health (U.S.) (Grant OD017865-02), National Science Foundation (U.S.) (Award 0821391), National Institutes of Health (U.S.) (Grant R01GM085319), National Institutes of Health (U.S.) (Grant RC2HG005624)

Published
2015

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