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TOMMUNEUS009952216B2TOUTTMANN (12 ) United States Patent ( 10 ) Patent No. : US 9 , 952 ,216 B2 Visel et al. (45 ) Date of Patent: Apr. 24 , 2018 ( 54 ) BRAIN - SPECIFIC ENHANCERS FOR C12N 15 / 86 (2006 .01 ) CELL -BASED THERAPY A61K 48 /00 (2006 .01 ) (52 ) U .S . CI. (71 ) Applicants :Axel Visel, El Cerrito , CA (US ) ; John CPC . .. .. GOIN 33 / 56966 (2013 .01 ) ; A61K 35 / 545 L . R . Rubenstein , San Francisco , CA ( 2013 .01 ) ; C12N 15 /85 ( 2013 .01 ) ; C12N (US ) ; Ying- Jiun ( Jasmine) Chen , 15 / 86 (2013 .01 ) ; GOIN 33/ 5014 ( 2013 .01 ) ; South San Francisco , CA ( US) ; Len A . A61K 48 / 00 ( 2013 .01 ) ; C12N 2830 /008 Pennacchio , Sebastopol, CA (US ) ; ( 2013 .01 ) Daniel Vogt, Burlingame, CA (US ) ; ( 58 ) Field of Classification Search Cory Nicholas, San Francisco , CA None (US ) ; Arnold Kriegstein , Mill Valley, See application file for complete search history . CA (US ) (56 ) References Cited ( 72 ) Inventors : Axel Visel , El Cerrito , CA ( US ) ; John L . R . Rubenstein , San Francisco , CA U . S . PATENT DOCUMENTS (US ) ; Ying - Jiun ( Jasmine ) Chen , 5 ,436 , 128 A * 7 /1995 Harpold . .. GOIN 33/ 6872 South San Francisco , CA (US ) ; Len A . 435 / 365 Pennacchio , Sebastopol, CA (US ) ; Daniel Vogt, Burlingame, CA (US ) ; OTHER PUBLICATIONS Cory Nicholas, San Francisco , CA (US ) ; Arnold Kriegstein , Mill Valley , Ferguson et al . The human synaptotagmin IV gene defines an CA (US ) evolutionary break point between syntenic mouse and human chro mosome regions but retains ligand inducibility and tissue specific ( 73 ) Assignee: The Regents of the University of ity . The Journal of Biological Chemistry , vol . 275 , No . 47 , pp . 36920 - 36926 , 2000 . * California , Oakland , CA (US ) Skottman et al . Gene expression signatures of seven individual human embryonic stem cell lines. Stem Cells , vol . 23 , pp . 1343 ( * ) Notice : Subject to any disclaimer , the term of this 1356 , 2005 . * patent is extended or adjusted under 35 De Vita et al. Flow cytometric and cytogenetic analyses in human U . S . C . 154 (b ) by 0 days . spontaneous abortions. Human Genetics , vol. 91, pp . 409 -415 , Jun . 1993 . * (21 ) Appl. No. : 14 /512 , 306 GenBank Accession No . AC044873 .13 , publicly available Oct . 2002 , printed as pp . 1 /40 -40 /40 . * (22 ) Filed : Oct . 10, 2014 * cited by examiner (65 ) Prior Publication Data Primary Examiner - Jennifer Dunston US 2015 /0044187 A1 Feb . 12 , 2015 ( 74 ) Attorney , Agent, or Firm — Kilpatrick Townsend & Stockton LLP Related U . S . Application Data (63 ) Continuation of application No . (57 ) ABSTRACT Herein are described a set of novel specific human enhancers PCT/ US2013 /036030 , filed on Apr. 10 , 2013 . for specific forebrain cell types used to study and select for (60 ) Provisional application No . 61 /622 ,467 , filed on Apr. human neural progenitor cells . This approach enables the 10 , 2012 , provisional application No . 61/676 , 606 , ability to generate interneurons from human ES , iPS and in filed on Jul. 27 , 2012 . cells , making them available for human transplantation and for molecular/ cellular analyzes. These approaches are also ( 51 ) Int. Ci. directly applicable to generating other neuronal cell types , C12N 15 /85 ( 2006 . 01 ) such as cortical and striatal projection neurons , which have GOIN 33/ 569 ( 2006 . 01) implications for many human diseases . GOIN 33 /50 ( 2006 .01 ) A61K 35 / 545 ( 2015 .01 ) 10 Claims, 32 Drawing Sheets U . S . Patent Apr . 24 , 2018 Sheet 1 of 32 US 9 ,952 , 216 B2 FIG . 1 ASSESSOSOS3126* 743624 * 59600 * 81224 fra 187 81161 * n8653 $ 1072 880 131025 $ 16604 9836 1987 15818 18103 $ * $ 1679 * 191537 ust z9 * hs 1626 * 98 10 : 9 * hs1230 183540 K $ 807 ks 1027 81092 6978 * $ 1187 $ 967 * * 1060 * 1166 .* h8923 ns1532 hs 156€ 1202181563 H: $622 69166* 1578 * * * 3102 880 1633 * 19914 1013 1546 81178 097588 4838 wiszyn ohsices usar genes pacated in thiencaphakor development or function : bbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbble Since www . Rhenis ) Swibo Serie 7817e hs0 & '7 '. ' ' ' ' 995' ' ' ' ' ' 'ASCUS ' ' W SchaeteW W -cute " " " " " "comodex " " " " " " " " " " "homoing " " " " 19 : 029 SMX ; Brasty sonces 3 : 09babox 3 391236 BMX erogty sprzdos koreobK 3433 25 En racerto . A $ 1823 FOXO forkvad 60X01 as : 983 resy Brairy and enhausMSX ? ta 1533 inhibics of ONA onda 457545 1. 68 minnoid arter binding factor 1 881361 EMOS L } & * orai Quixa as1024$ 177 ., ms16X15163714 . 24 rucea Fecior su 2 . Boom 9 : 579 07Xossistenticio horreddox 2 545 SOUZEY POUmair , Bass 3 . sünscricum factor } oCT in , f81035 68 ! 128 RU ones3 65x2 6181529 , 1481528 . $ POU 295 Xbox 3 Osta SOX2 SR box cordisaing go os1039 S2 353836 ansation facie ha1166 . 181538 WXXNX honaxx (31183 ) ht ? ? ? ? ? gea d & inte????????) see ? } \ $ 1873 2104 ac finger potes < $ * & Cazaust U . S . Patent Apr . 24 , 2018 Sheet 2 of 32 US 9 ,952 , 216 B2 FIG . 2 ? ? :*. 8886 09480 hs 192 F G DaDDOsim:;* VY.. VY - ns1050 h 1035 181345 h : 200 W M U 2002* * .. *! . *** 18218 hs 1358 8 969 81025 + 2 .000 S ns595 $ 123 h8871 19876 hs978 coac2mol . 0 229€115. 22 €13.5 h5840 1 81006 hs 1050 his 1172 MP, medial pallium ; OP, dorsal pallium ; LP, lateral pallium ; VP, ventralpallium ; LGE , lateral ganglionic eminence ; SeDES , septum U . S . Patent Apr. 24, 2018 Sheet 3 of 32 | US 9 ,952 ,216 B2 FiG . 3 |.3522 .22 . 2 . E*??? 3222285603 . animanawaran siations ?? . 22 . ? / * . ? ?? U . S . Patent Apr . 24 , 2018 Sheet 4 of 32 US 9 ,952 , 216 B2 FIG . 4 5 P = 0 . 0003 doenw en w ents 5 enhoe expected foldenrichment by ? naramenwwwwwwwwwwwwwwwwwwwwwwwwww ww WS AAYY .LYWW 10 709 408 103 norte overag of cr?? ??xpression and arcar activity ( forebrain subrogions , 1 * 81 enhancer. gene pairs ) wi :?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ? ??? ?? ?? ?? ?? ?? ?? ???? VUL4444444444444444444444 :. :. :. ooo rrrrrrrrrrr :. valdated hst16 QZ154$ 22 hs123 telencephalic * 1999999%mit enhancers gelos tiposPOLA1 chr : X * * * * * * * ** * * * ** * * Why www mwagana 25. OM0Mwana 26. M agnason25 28 . 2M21 yamanan 25 . 3M garan 25 AMAM U . S . Patent Apr . 24 , 2018 Sheet 5 of 32 US 9 ,952 , 216 B2 FIG . 4 . ' Lef1b81050 Wnt8b 181006 (ISH ) * (Lacz ) ( ISH ) (Lacz ) ES Nr211 08172 (ISH ) ( Lacz ) ( ISM ) * Lacz ) U . S . Patent Apr. 24, 2018 Sheet 6 of 32 | US 9 ,952 , 216 B2 FIG . 5A Telencephalon subregions -' * * ~ 2 2 ? ??? ?? 2_ ?}& {}"???? ?k ???? 13_S1_c F_502 -EZ! 1 S_5v2 d DAZAS? 13 *???? Enhances dC1a d) ? ?? 13 - ?| Z9S d????? ? -FOXSZ hs17 15112 ???152 his122014 , h?? ?????zs } s :}3hG322 } 1 2 }} } ? } 42 ? 32 22 ? } 39 452 48. ++ ?????{ ++ { ? ? ? 233 } _ ses } ?15 ?????7 1998 83 541??? ???33) t 2s886555 $ * . * * . * , h53? hs{ ?? ? 8? $ Fg! ! ! s5 s ? sts192 c , ?9 322? S123 }{ } { 4 h 2 ta 325 htts 21 } ht hs ; & S2 Y? ?? 3 ? ? htsS55 53 211 ???19 : 23 . .: : : 1 h687 1 11 242 -*: ?542 5 :: :: :: :: :: : 2 . 72. S341 s????????? + ? ?? ? $ $ - Sicilit s56 57 $ 435 ) 1 hs24 437328???$ 352?? 49 ? ht? 48 32 324 hs2444 44 . { \ c ak18 if; text U . S . Patent Apr . 24 , 2018 Sheet 7 of 32 US 9 ,952 , 216 B2 FIG . 5B Balliumwanaos OTX2_ Q3 CAT ;.. ?? . * LUKE OT . * . LI MKI_ CI . * . * . IL $T COAFP1_ 08 ** ersagsod-1} . 115 UM 01 * ..* * * .. !. 9801 ! wangunanna. $3 _ 01 ** !! wiwiwitinin AUC080 0 000 0004 0 .008 0 .012 Faise positive iste . 30 } ?1i { {{c ice Pallium and Subpallium? ?????????????????????????????????????????????????????????????????????????????????????????????????????? MZF \_ 04 Ceca 1 . 0 ** * ** * ** * ** , AP 1 , , , , , , SIE).BAISO-33351 , MZFL_ 02 , }, , , , , LH- X61, 01 , LUL - XB1_ 01 , { , HMBOX . 01 es , AVO - 092 0 .010 0. 0200 .080 * * * * * * * * * * * * * * * * * * * *. *. *. *. * . * . *. *. * *. * * # if 3 " : 0. 080 False -positive rate 10 ' ' ' ' ' ' ' ' ' ' ' ' ' Subpallium C CT mmmmmmmmmmmmmmmmmmmNEWROC_ 02 iiiiiiiiiiiiiiiiiiiinnnnnn *. *. LOT MOXAYO *. *. *. * *. ITT DLXZG OLEJBAINSoden *. *. 08 *. *. CACCIOLPQ6 . *. I MKX83_ 01 *. AUC078 . 0 000 2 .002 0 .001 0. 00€ 03. * * * * * * * * * * * * * * * * * * * * * * * * ** * * * * Modi portare 0 Faise positive rate 10 viiiiiiiiiiiiiiiiiiiiiiii VYYYYYYYYYYYYYYYYYYYYYYY View U . S . Patent Apr . 24 , 2018 Sheet 8 of 32 US 9 ,952 , 216 B2 FIG . 5C version Near D4/ SOXH : : : - fiear Es : : : 97ac2/siri gasverandi ein near GSX1 : : : : : : : : : : : : : m .near FOXG1 : * Luciferaseactivityfoldchangenormalizedtonegativecontrol : vor innear SPG/ SP8 : : : * ** vas auto the near ARX : *TRY : : : : : : : : 2 : L ana Positivens1340 ns304 4$ 669 1s532 8342 hs110 #$1321 His545 hs1052 1$1041 1151226 bs1027 His1007 TTELSE h9408 tys1187 69704 hs1019 Control Enhancer Enhancer Reporter Construct emancantho PGL4 .23 Luciferase Dlx2 Co - transfected with activator TF Ascl1 in PCAGGS, P19 cells U . S . Patent Apr . 24 , 2018 Sheet 9 of 32 US 9 ,952 , 216 B2 FIG . 6 plane a { rostral) plane b (caudal ) on www n . irene *** o LGE * SA? . :,-** OS-rti???? * * pallial ( dorsal structures : diencephalon : Memedial pallium Ththalamus OP dorsal pallium EMT errinentia thalami Plateral palium Vo ventral pallun CP choroid plexus differntatiof zics: Subpaliel ( ventral) structures mante zone (MZ ) UGE - latera gangliomic eminence subventricular zona (SVZ ) NGE medial ganglionio ainence Se Septum verticular zona (VZ ) POA - preoptic area U . S . Patent Apr. 24 , 2018 Sheet 10 of 32 US 9 , 952 , 216 B2 FIG . 7 pallium pallium and subpalliumn
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    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
  • Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?

    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.