DOCSLIB.ORG

The Nationa O Un Alt Man Har Man Di

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Nationa O Un Alt Man Har Man Di THE NATIONAUS009890430B2 O UN ALT MAN HAR MAN DI (12 ) United States Patent (10 ) Patent No. : US 9 ,890 ,430 B2 Ellis et al. ( 45 ) Date of Patent: Feb . 13 , 2018 (54 ) COPY NUMBER ABERRATION DRIVEN ( 58) Field of Classification Search ENDOCRINE RESPONSE GENE SIGNATURE None ( 71 ) Applicant : Washington University , Saint Louis , See application file for complete search history . MO (US ) (56 ) References Cited ( 72 ) Inventors: Matthew Ellis , Houston , TX (US ) ; U . S . PATENT DOCUMENTS Jingqin Luo , Saint Louis , MO (US ) 7 , 504 ,214 B2 3 / 2009 Erlander et al . ( 73 ) Assignee : Washington University , St. Louis , MO 7 , 569 ,345 B2 8 /2009 Cobleigh et al . (US ) ( Continued ) ( * ) Notice : Subject to any disclaimer , the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 U . S . C . 154 (b ) by 322 days . Wo 2011120984 Al 10 /2011 (21 ) Appl . No. : 14 /407 , 913 OTHER PUBLICATIONS (22 ) PCT Filed : Jun . 12 , 2013 M Dowsett et al. Meta - Analysis of Breast Cancer Outcomes in Adjuvant Trials of Aromatase Inhibitors Versus Tamoxifen . Journal ( 86 ) PCT No .: PCT/ US2013 / 045525 of Clinical Oncology, Jan . 2010 , vol . 28 , No. 3 , p . 509 -518 . * $ 371 ( c ) ( 1 ) , (Continued ) ( 2 ) Date : Dec. 12 , 2014 Primary Examiner — John S . Brusca ( 87 ) PCT Pub . No. : WO2013 / 188600 Assistant Examiner - Olivia M Wise PCT Pub. Date : Dec . 19 , 2013 (57 ) ABSTRACT (65 ) Prior Publication Data Disclosed are methods of predicting the likelihood of long term survival without recurrence of breast cancer for a US 2015 /0240312 A1 Aug. 27, 2015 subject having estrogen receptor -positive (ER + ) breast can Related U . S . Application Data cer treated with adjuvant endocrine monotherapy . In various embodiments , these methods comprise performing a gene (60 ) Provisional application No . 61/ 658 , 517 , filed on Jun . expression profile of a breast tissue sample of substantially 12 , 2012 . all of the genes of the “CADER set” described herein ; (51 ) Int. Ci. calculating a risk score using a regression model; and G06F 19 / 20 applying a double median cutoff classification to assign the ( 2011 . 01 ) subject to a sensitive , indeterminate or resistant group , C12Q 1 /68 ( 2006 . 01 ) wherein assignment to a sensitive group predicts longer ( Continued ) relapse - free survival compared to the median relapse - free (52 ) U . S . CI. survival of ER + breast cancer patients treated with adjuvant ??? .. C12Q 1 /6886 (2013 .01 ) ; B01J 19 /0046 endocrine monotherapy . ( 2013 .01 ) ; GOIN 33 /57415 ( 2013 .01 ) ; (Continued ) 11 Claims, 5 Drawing Sheets * Therapy * sensitive indeterminate ODOON Therapy indeterminate resistant X -axis : resistant gene centroid Y - axis : sensitive gene centroid US 9 ,890 , 430 B2 Page 2 ( 51 ) Int. Cl. Loi, S ., et al. , Definition of clinically distinct molecular subtypes in GOIN 33 /574 estrogen receptor- positive breast carcinomas through genomic ( 2006 .01 ) grade . , J . Clin . Oncol. , 25 ( 10 ) , 1239 - 1246 ( Apr. 2007 ) . B01J 19 / 00 (2006 . 01 ) Nielsen , T . O . , et al. , A comparison of PAM50 intrinsic subtyping G06F 19 /24 ( 2011. 01 ) with immunohistochemistry and clinical prognostic factors in G06F 19 / 00 ( 2011. 01 ) tamoxifen - treated estrogen receptor- positive breast cancer . , Clin . Cancer Res. , 16 ( 21) , 5222 - 5232 (Nov . 2010 ) . (52 ) U .S . CI. Olson , J . A . Jr . , et al. Improved surgical outcomes for breast cancer ??? G06F 19 / 20 ( 2013 .01 ) ; G06F 19 /24 patients receiving neoadjuvant aromatase inhibitor therapy : results ( 2013 .01 ) ; G06F 19 / 345 (2013 .01 ) ; C12Q from a multicenter phase II trial. , J . Am . Coll . Surg. , 208 ( 5 ) , 2600 / 112 ( 2013 . 01 ) ; C12Q 2600 / 118 906 - 914 (2009 ) . Paik , S . , et al. , A multigene assay to predict recurrence of tamoxifen ( 2013 .01 ) ; C12Q 2600 / 158 ( 2013 .01 ) ; C12Q treated , node- negative breast cancer ., N . Engl . J . Med ., 351 (27 ) , 2600 / 16 (2013 .01 ) ; GOIN 2800 /52 (2013 .01 ) ; 2817 - 2826 (Dec . 2004 ) . GOIN 2800 /60 (2013 .01 ) Parker, J . S . , et al. , Supervised risk predictor of breast cancer based on intrinsic subtypes . , J . Clin . Oncol ., 27 ( 8 ), 1160 - 1167 (Mar . ( 56 ) References Cited 2009 ) . Pawitan , Y ., et al. , Gene expression profiling spares early breast U . S . PATENT DOCUMENTS cancer patients from adjuvant therapy : derived and validated in two population -based cohorts . , Breast Cancer Res. , 7 (6 ) , R953 -R964 2007 / 0059720 A9 3 / 2007 Fuqua et al. (Oct . 2005 ) . 2008 /0014579 Al 1 / 2008 Liu et al. Ringner M . , et al . , GOBO : gene expression -based outcome for 2008/ 0032293 A1 2 / 2008 Szabo 2009 /0215033 A1 8 /2009 Khan et al . breast cancer online PLOS ONE , 6 ( 3 ) , E17911 (Mar . 2011) . 2011 / 0014191 A1 1 / 2011 Bertucci et al . Rupp , G . and Locker, J . , 395 , Lab Invest . , 56 ( 1 ) , A67 (Mar . 1987 ) . 2011/ 0130296 A1 6 / 2011 Benz et al. Schena , M ., et al ., A two - subunit type I DNA topoisomerase 2011/ 0145176 A16 /2011 Perou et al. ( reverse gyrase ) from an extreme hyperthermophile. , Proc . Natl . 2011 /0152113 Al * 6 /2011 Escudero .. .. C12Q 1 /6886 Acad . Sci. USA , 93 ( 2 ) , 106 - 149 (Oct . 1996 ) . 506 / 9 Sørlie T . et al. , Gene expression patterns of breast carcinomas 2011 /0230360 AL 9 / 2011 Stephan et al . distinguish tumor subclasses with clinical implications. , Proc . Natl . Acad . Sci. USA , 98 ( 19 ) , 10869 - 10874 (Sep . 2001 ) . Symmans , W . F . , et al . , Genomic index of sensitivity to endocrine OTHER PUBLICATIONS therapy for breast cancer ., J . Clin . Oncol. 28 (27 ) , 4111 -4119 (Sep . 2010 ) . La Korde et al . Gene expression pathway analysis to predict Van Tine , B . A . , et al ., ER and PI3K independently modulate response to neoadjuvant docetaxel and capecitabine for breast endocrine resistance in ER positive breast cancer ., Cancer Discov ., cancer . Breast Cancer Res Treat 2010 , vol. 119 , p . 685 -699 ( Year : 1 , 287 - 288 ( 2011) . 2010 ) . * Van De Vijver , M . J ., et al. , A gene -expression signature as a Affymetrix HG -U133 Plus 2 . 0 Array Search Results . Sep . 19 , 2017 , predictor of survival in breast cancer. , N . Engl . J . Med . , 347 ( 25 ) , www .affymetrix .com , pp . 1 - 8 . * 1999 - 2009 (Dec . 2002 ) . AGO2 GeneCard Entry. Sep . 19 , 2017, www . genecards. org , pp . Velculescu , V . E ., et al. , Serial analysis of gene expression . , Science 1 - 17 ; newly cited . * 270 ( 5235 ) , 484 - 487 (Oct . 1995 ) . RRNAD1 GeneCard Entry . RRNAD1 (Sep . 19 , 2017 ; www . Velculescu , V . E ., et al. , Characterization of the yeast transcriptome. , genecards. org , pp . 1 - 14 ; newly cited ) . * Cell 88, 243 -51 ( Jan . 1997) . Chanrion , M . , et al ., A gene expression signature that can predict the Wang , Y ., et al . , Gene - expression profiles to predict distant metas recurrence of tamoxifen - treated primary breast cancer. , Clin Cancer tasis of lymph -node -negative primary breast cancer. , Lancet 365 , Res , 14 (6 ), 1744 - 1752 (2008 ) . 671 - 679 (Feb . 2005 ) . Cheang , M . C . U ., et al ., Ki67 Index , HER2 Status, and Prognosis of Zhang, Y . , et al. , The 76 - gene signature defines high - risk patients Patients with Luminal B Breast Cancer. , J . Natl . Cancer Inst . , that benefit from adjuvant tamoxifen therapy. , Breast Cancer Res. 101 ( 10 ) : 736 - 750 ( 2009 ) . Treat. , 116 , 303 -309 (2009 ) . Galanina , N . , et al . , Molecular Predictors of Response to Therapy for Breast Cancer. , Cancer J . , 17 ( 2 ), 96 - 103 (Mar . / Apr. 2011 ) . * cited by examiner atent Feb . 13 , 2018 Sheet 1 of 5 US 9 ,890 ,430 B2 FIG . 1 FL????? ???? ???????? [ reme= 1 (? .= meled ?????qa } of cost after?????? ? ? { { ?? Excised ?? ?? {{ 4 } { {ity ?? {22 - - - - * * - * - * - ? - - - - + * * * * * * ** - - - ???????? tise, ugY ?????? ? a3 Sucient { ssue , Hope s330d $ Du * * R & to c? ?? p???? $ notcpeted urer # ? fc ?????? expec????? at time of analysis cpt d?? analys fe of as = 4 {434 $ 1 1 = $ } { p = 23 $ { { } =??? ? away : ??????e ? { = ???? } e a? ?ppleted = 333 333 ??y ??? { { f } ? ?? ? ? } = { { 3 } & c - T a } ??type : 14 { } Faseline R ????2: $ = {41 S?? ? ? { fe? gene ????????? a??? ??? Arrays nuded $ ? ????? ?p???an anas?? + + + + + + + + + + + + + + + + + + + + + + + = 1 ? { 99 } 23 } 27 } }dentify ?ffenta }} { y Express g8? based on pat -t { ??tant Ki65 eva} ??? , C 2 - ????{ ???? ??? xt ; ? 1 ? + + + + + + ?27 s???????? gef?? + { { R??? ? + + - - - - + + + ? * * * * * * * * * * * - : * , * - ~ * * - + + + + + + + + - - * * * * * * Discover genes also associated with copy _ Z??????ey genes asked th & ? } { \ ber a?éatch breast cancer relapse chat , ???? FL 2 , 2 c & ??? ????? : ?? + ° & } ????? A???xx { } 23 = 9S5 :2 : { }, { } { {????? { if ! 1 S{ } } tes : { { Friyarat? . $ a 6? s??????? q? ? 43 $ sigr? -ant * - * - * gees ? ?? ??????.. ** ???????- ?? & ????tle - - - - - - - - - - - - 2 s???atgen???? { ? Resta 2 ???????? * * * * * - * * * * * * ???? Genec se??? nt and. …. *+ + 1 - " - - - - - - - - - - -- - - * ** * * e = = ? * * * * * * -gene signature* * * * * Res at 27 Sense Retrospective Validation Test ? 1 . ?? =???: ? ? ??es ? ??? ??1111 ? ? < p ? st?? ? U . S . Patent Feb . 13 , 2018 Sheet 2 of 5 US 9 ,890 , 430 B2 * HomeServer * * w *2 n w onewhowantedtheentertainment ka (VIAS12 setout RFSyrs) .* &A}vas P=1.82e-05 *. 0.0005 + ASUS eeuwelepu resistant }f?celeria?? resistant www meneranganna o materialismeoberen tot momenting moren doce N 0. 1 8. 0 6. 0 4. 0 2. 0 0. 0 0. 1 8. 0 6. 0 4. 0 2. 0 0. 0 FIG.2 Probability Survival
Load more

Recommended publications
  • Rule Mining on Microrna Expression Profiles For
    Faculty of Engineering and Information Technology University of Technology, Sydney Rule Mining on MicroRNA Expression Profiles for Human Disease Understanding A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy by Renhua Song July 2016 CERTIFICATE OF AUTHORSHIP/ORIGINALITY I certify that the work in this thesis has not previously been submitted for a degree nor has it been submitted as part of requirements for a degree except as fully acknowledged within the text. I also certify that the thesis has been written by me. Any help that I have received in my research work and the preparation of the thesis itself has been acknowledged. In addition, I certify that all information sources and literature used are indicated in the thesis. Signature of Candidate i Acknowledgments First, and foremost, I would like to express my gratitude to my chief supervisor, Assoc. Prof. Jinyan Li, and to my co-supervisors Assoc. Prof. Paul Kennedy and Assoc. Prof. Daniel Catchpoole. I am extremely grateful for all the advice and guidance so unselfishly given to me over the last three and half years by these three distinguished academics. This research would not have been possible without their high order supervision, support, assistance and leadership. The wonderful support and assistance provided by many people during this research is very much appreciated by me and my family. I am very grateful for the help that I received from all of these people but there are some special individuals that I must thank by name. A very sincere thank you is definitely owed to my loving husband Jing Liu, not only for his tremendous support during the last three and half years, but also his unfailing and often sorely tested patience.
    [Show full text]
  • Exploring Prostate Cancer Genome Reveals Simultaneous Losses of PTEN, FAS and PAPSS2 in Patients with PSA Recurrence After Radical Prostatectomy
    Int. J. Mol. Sci. 2015, 16, 3856-3869; doi:10.3390/ijms16023856 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Article Exploring Prostate Cancer Genome Reveals Simultaneous Losses of PTEN, FAS and PAPSS2 in Patients with PSA Recurrence after Radical Prostatectomy Chinyere Ibeawuchi 1, Hartmut Schmidt 2, Reinhard Voss 3, Ulf Titze 4, Mahmoud Abbas 5, Joerg Neumann 6, Elke Eltze 7, Agnes Marije Hoogland 8, Guido Jenster 9, Burkhard Brandt 10 and Axel Semjonow 1,* 1 Prostate Center, Department of Urology, University Hospital Muenster, Albert-Schweitzer-Campus 1, Gebaeude 1A, Muenster D-48149, Germany; E-Mail: [email protected] 2 Center for Laboratory Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Gebaeude 1A, Muenster D-48149, Germany; E-Mail: [email protected] 3 Interdisciplinary Center for Clinical Research, University of Muenster, Albert-Schweitzer-Campus 1, Gebaeude D3, Domagkstrasse 3, Muenster D-48149, Germany; E-Mail: [email protected] 4 Pathology, Lippe Hospital Detmold, Röntgenstrasse 18, Detmold D-32756, Germany; E-Mail: [email protected] 5 Institute of Pathology, Mathias-Spital-Rheine, Frankenburg Street 31, Rheine D-48431, Germany; E-Mail: [email protected] 6 Institute of Pathology, Klinikum Osnabrueck, Am Finkenhuegel 1, Osnabrueck D-49076, Germany; E-Mail: [email protected] 7 Institute of Pathology, Saarbrücken-Rastpfuhl, Rheinstrasse 2, Saarbrücken D-66113, Germany; E-Mail: [email protected] 8 Department
    [Show full text]
  • PARP-3 (B-7): Sc-390771
    SANTA CRUZ BIOTECHNOLOGY, INC. PARP-3 (B-7): sc-390771 BACKGROUND RECOMMENDED SUPPORT REAGENTS Poly(ADP-ribose) polymerase-3 (PARP-3) is part of the base excision repair To ensure optimal results, the following support reagents are recommended: (BER) pathway, catalyzing the poly(ADP-ribosyl)ation of nuclear proteins. 1) Western Blotting: use m-IgGk BP-HRP: sc-516102 or m-IgGk BP-HRP (Cruz Poly(ADP-ribosyl)ation, a post-translational modification following DNA Marker): sc-516102-CM (dilution range: 1:1000-1:10000), Cruz Marker™ damage, appears as an obligatory step in a detection/signaling pathway Molecular Weight Standards: sc-2035, UltraCruz® Blocking Reagent: leading to the reparation of DNA strand breaks. PARP-3 is a nuclear, DNA- sc-516214 and Western Blotting Luminol Reagent: sc-2048. 2) Immunopre- binding protein, which interacts with PARP-1. PARP-3 is present in actively cipitation: use Protein A/G PLUS-Agarose: sc-2003 (0.5 ml agarose/2.0 ml). dividing tissues with highest levels in the kidney, skeletal muscle, liver, heart 3) Immunofluorescence: use m-IgGk BP-FITC: sc-516140 or m-IgGk BP-PE: and spleen. Human PARP-3 maps to chromosome 3p21.2, a gene region that sc-516141 (dilution range: 1:50-1:200) with UltraCruz® Mounting Medium: undergoes alteration in solid malignant tumors. sc-24941 or UltraCruz® Hard-set Mounting Medium: sc-359850. CHROMOSOMAL LOCATION DATA Genetic locus: PARP3 (human) mapping to 3p21.2; Parp3 (mouse) mapping to 9 F1. AB 132 K – < PARP-3 90 K – 50 K – SOURCE < PARP-3 55 K – PARP-3 (B-7) is a mouse monoclonal antibody raised against amino acids 43 K – 139-219 mapping within an internal region of PARP-3 of human origin.
    [Show full text]
  • Modulating Hallmarks of Cholangiocarcinoma
    University of Nebraska Medical Center DigitalCommons@UNMC Theses & Dissertations Graduate Studies Fall 12-14-2018 Modulating Hallmarks of Cholangiocarcinoma Cody Wehrkamp University of Nebraska Medical Center Follow this and additional works at: https://digitalcommons.unmc.edu/etd Part of the Molecular Biology Commons Recommended Citation Wehrkamp, Cody, "Modulating Hallmarks of Cholangiocarcinoma" (2018). Theses & Dissertations. 337. https://digitalcommons.unmc.edu/etd/337 This Dissertation is brought to you for free and open access by the Graduate Studies at DigitalCommons@UNMC. It has been accepted for inclusion in Theses & Dissertations by an authorized administrator of DigitalCommons@UNMC. For more information, please contact [email protected]. MODULATING HALLMARKS OF CHOLANGIOCARCINOMA by Cody J. Wehrkamp A DISSERTATION Presented to the Faculty of the University of Nebraska Graduate College in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Biochemistry and Molecular Biology Graduate Program Under the Supervision of Professor Justin L. Mott University of Nebraska Medical Center Omaha, Nebraska November 2018 Supervisory Committee: Kaustubh Datta, Ph.D. Melissa Teoh‐Fitzgerald, Ph.D. Richard G. MacDonald, Ph.D. Acknowledgements This endeavor has led to scientific as well as personal growth for me. I am indebted to many for their knowledge, influence, and support along the way. To my mentor, Dr. Justin L. Mott, you have been an incomparable teacher and invaluable guide. You upheld for me the concept that science is intrepid, even when the experience is trying. Through my training, and now here at the end, I can say that it has been an honor to be your protégé. When you have shaped your future graduates to be and do great, I will be privileged to say that I was your first one.
    [Show full text]
  • An Evaluation of Host Factors As Novel Therapeutic Targets During Influenza Infection Using RNA Technologies
    California State University, San Bernardino CSUSB ScholarWorks Electronic Theses, Projects, and Dissertations Office of aduateGr Studies 6-2018 An Evaluation of Host Factors as Novel Therapeutic Targets During Influenza Infection Using RNA Technologies Michael Ryan Haden Thompson California State University - San Bernardino Follow this and additional works at: https://scholarworks.lib.csusb.edu/etd Part of the Virology Commons Recommended Citation Thompson, Michael Ryan Haden, "An Evaluation of Host Factors as Novel Therapeutic Targets During Influenza Infection Using RNA Technologies" (2018). Electronic Theses, Projects, and Dissertations. 721. https://scholarworks.lib.csusb.edu/etd/721 This Thesis is brought to you for free and open access by the Office of aduateGr Studies at CSUSB ScholarWorks. It has been accepted for inclusion in Electronic Theses, Projects, and Dissertations by an authorized administrator of CSUSB ScholarWorks. For more information, please contact [email protected]. AN EVALUATION OF HOST FACTORS AS NOVEL THERAPEUTIC TARGETS DURING INFLUENZA INFECTION USING RNA TECHNOLOGIES _____________________ A Thesis Presented to the Faculty of California State University, San Bernardino _____________________ In Partial Fulfillment of the Requirements for the Degree Master of Science in Biology _____________________ by Michael Ryan Haden Thompson June 2018 AN EVALUATION OF HOST FACTORS AS NOVEL THERAPEUTIC TARGETS DURING INFLUENZA INFECTION USING RNA TECHNOLOGIES _____________________ A Thesis Presented to the Faculty of California State University, San Bernardino _____________________ By Michael Ryan Haden Thompson June 2018 Approved by: Dr. Laura L Newcomb, Committee Chair, Biology Dr. Nicole Bournias-Vardiabasis, Committee Member Dr. Daniel Nickerson, Committee Member © 2018 Michael Ryan Haden Thompson ABSTRACT Influenza A is a single-stranded, multi-segmented, negative sense RNA virus of the family Orthomyxoviridae and is the causative agent of seasonal Influenza.
    [Show full text]
  • Molecular Effects of Isoflavone Supplementation Human Intervention Studies and Quantitative Models for Risk Assessment
    Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis committee Promotors Prof. Dr Pieter van ‘t Veer Professor of Nutritional Epidemiology Wageningen University Prof. Dr Evert G. Schouten Emeritus Professor of Epidemiology and Prevention Wageningen University Co-promotors Dr Anouk Geelen Assistant professor, Division of Human Nutrition Wageningen University Dr Lydia A. Afman Assistant professor, Division of Human Nutrition Wageningen University Other members Prof. Dr Jaap Keijer, Wageningen University Dr Hubert P.J.M. Noteborn, Netherlands Food en Consumer Product Safety Authority Prof. Dr Yvonne T. van der Schouw, UMC Utrecht Dr Wendy L. Hall, King’s College London This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences). Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis submitted in fulfilment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. Dr M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Friday 20 June 2014 at 13.30 p.m. in the Aula. Vera van der Velpen Molecular effects of isoflavone supplementation: Human intervention studies and quantitative models for risk assessment 154 pages PhD thesis, Wageningen University, Wageningen, NL (2014) With references, with summaries in Dutch and English ISBN: 978-94-6173-952-0 ABSTRact Background: Risk assessment can potentially be improved by closely linked experiments in the disciplines of epidemiology and toxicology.
    [Show full text]
  • Variation in Protein Coding Genes Identifies Information
    bioRxiv preprint doi: https://doi.org/10.1101/679456; this version posted June 21, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Animal complexity and information flow 1 1 2 3 4 5 Variation in protein coding genes identifies information flow as a contributor to 6 animal complexity 7 8 Jack Dean, Daniela Lopes Cardoso and Colin Sharpe* 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Institute of Biological and Biomedical Sciences 25 School of Biological Science 26 University of Portsmouth, 27 Portsmouth, UK 28 PO16 7YH 29 30 * Author for correspondence 31 [email protected] 32 33 Orcid numbers: 34 DLC: 0000-0003-2683-1745 35 CS: 0000-0002-5022-0840 36 37 38 39 40 41 42 43 44 45 46 47 48 49 Abstract bioRxiv preprint doi: https://doi.org/10.1101/679456; this version posted June 21, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Animal complexity and information flow 2 1 Across the metazoans there is a trend towards greater organismal complexity. How 2 complexity is generated, however, is uncertain. Since C.elegans and humans have 3 approximately the same number of genes, the explanation will depend on how genes are 4 used, rather than their absolute number.
    [Show full text]
  • Mir-17-92 Fine-Tunes MYC Expression and Function to Ensure
    ARTICLE Received 31 Mar 2015 | Accepted 22 Sep 2015 | Published 10 Nov 2015 DOI: 10.1038/ncomms9725 OPEN miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth Marija Mihailovich1, Michael Bremang1, Valeria Spadotto1, Daniele Musiani1, Elena Vitale1, Gabriele Varano2,w, Federico Zambelli3, Francesco M. Mancuso1,w, David A. Cairns1,w, Giulio Pavesi3, Stefano Casola2 & Tiziana Bonaldi1 The synergism between c-MYC and miR-17-19b, a truncated version of the miR-17-92 cluster, is well-documented during tumor initiation. However, little is known about miR-17-19b function in established cancers. Here we investigate the role of miR-17-19b in c-MYC-driven lymphomas by integrating SILAC-based quantitative proteomics, transcriptomics and 30 untranslated region (UTR) analysis upon miR-17-19b overexpression. We identify over one hundred miR-17-19b targets, of which 40% are co-regulated by c-MYC. Downregulation of a new miR-17/20 target, checkpoint kinase 2 (Chek2), increases the recruitment of HuR to c- MYC transcripts, resulting in the inhibition of c-MYC translation and thus interfering with in vivo tumor growth. Hence, in established lymphomas, miR-17-19b fine-tunes c-MYC activity through a tight control of its function and expression, ultimately ensuring cancer cell homeostasis. Our data highlight the plasticity of miRNA function, reflecting changes in the mRNA landscape and 30 UTR shortening at different stages of tumorigenesis. 1 Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy. 2 Units of Genetics of B cells and lymphomas, IFOM, FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy.
    [Show full text]
  • Enhancer-Derived Noncoding RNA in the Regulation of Gnrh1 Gene Expression
    UNIVERSITY OF CALIFORNIA, SAN DIEGO A Novel Gonadotropin-Releasing Hormone 1 (Gnrh1) Enhancer-Derived Noncoding RNA in the Regulation of Gnrh1 Gene Expression A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biomedical Sciences by Polly Pu Huang Committee in charge: Professor Pamela L. Mellon, Chair Professor Alexander S. Kauffman Professor Nicholas J. G. Webster Professor Miles F. Wilkinson Professor Eugene W. Yeo 2016 Copyright Polly Pu Huang, 2016 All rights reserved SIGNATURE PAGE The Dissertation of Polly Pu Huang is approved, and it is acceptable in quality and form for publication on microfilm and electronically. Chair University of California, San Diego 2016 iii DEDICATION I dedicate my dissertation to my best friend and the love of my life, Steffan McMurrin, for his support, encouragement, guidance, empathy, and unwavering love. iv TABLE OF CONTENTS SIGNATURE PAGE ........................................................................................................ iii DEDICATION ................................................................................................................. iv TABLE OF CONTENTS .................................................................................................. v LIST OF FIGURES ......................................................................................................... vi LIST OF TABLES .......................................................................................................... vii LIST OF
    [Show full text]
  • Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
    Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement.
    [Show full text]
  • Therapeutic Targeting of Nuclear Transport
    cells Review Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport Friederike K. Kosyna * and Reinhard Depping Institute of Physiology, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, D-23562 Lübeck, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-451-3101-7322; Fax: +49-451-3101-7304 Received: 25 October 2018; Accepted: 17 November 2018; Published: 21 November 2018 Abstract: Nuclear transport receptors of the karyopherin superfamily of proteins transport macromolecules from one compartment to the other and are critical for both cell physiology and pathophysiology. The nuclear transport machinery is tightly regulated and essential to a number of key cellular processes since the spatiotemporally expression of many proteins and the nuclear transporters themselves is crucial for cellular activities. Dysregulation of the nuclear transport machinery results in localization shifts of specific cargo proteins and associates with the pathogenesis of disease states such as cancer, inflammation, viral illness and neurodegenerative diseases. Therefore, inhibition of the nuclear transport system has future potential for therapeutic intervention and could contribute to the elucidation of disease mechanisms. In this review, we recapitulate clue findings in the pathophysiological significance of nuclear transport processes and describe the development of nuclear transport inhibitors. Finally, clinical implications and results of the first clinical trials are discussed for the most promising nuclear transport inhibitors. Keywords: nuclear transport; exportin; importin; karyopherin; chromosome region maintenance 1 (CRM1); cancer; drug; nuclear transport inhibitor 1. Introduction The cytoplasm and the nucleoplasm are separated by the nuclear envelope in eukaryotic cells. Spatially segregation of essential cellular processes requires tight control of large molecule exchange such as RNAs, proteins, or ribonucleoprotein particles through this double membrane.
    [Show full text]
  • Downloaded the “Top Edge” Version
    bioRxiv preprint doi: https://doi.org/10.1101/855338; this version posted December 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Drosophila models of pathogenic copy-number variant genes show global and 2 non-neuronal defects during development 3 Short title: Non-neuronal defects of fly homologs of CNV genes 4 Tanzeen Yusuff1,4, Matthew Jensen1,4, Sneha Yennawar1,4, Lucilla Pizzo1, Siddharth 5 Karthikeyan1, Dagny J. Gould1, Avik Sarker1, Yurika Matsui1,2, Janani Iyer1, Zhi-Chun Lai1,2, 6 and Santhosh Girirajan1,3* 7 8 1. Department of Biochemistry and Molecular Biology, Pennsylvania State University, 9 University Park, PA 16802 10 2. Department of Biology, Pennsylvania State University, University Park, PA 16802 11 3. Department of Anthropology, Pennsylvania State University, University Park, PA 16802 12 4 contributed equally to work 13 14 *Correspondence: 15 Santhosh Girirajan, MBBS, PhD 16 205A Life Sciences Building 17 Pennsylvania State University 18 University Park, PA 16802 19 E-mail: [email protected] 20 Phone: 814-865-0674 21 1 bioRxiv preprint doi: https://doi.org/10.1101/855338; this version posted December 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 22 ABSTRACT 23 While rare pathogenic copy-number variants (CNVs) are associated with both neuronal and non- 24 neuronal phenotypes, functional studies evaluating these regions have focused on the molecular 25 basis of neuronal defects.
    [Show full text]