Cancer:
`Researc
`
`bie sebeeard Miltenyi Ex. 1003 Page1
`
`a Reeca)
`Piel
`Mr)oo
`Wane)
`
`
`
`W@Wti\cere)
`EL eeelifts
`MEtteTa
`MRTeT)|
`Page 2581
`
`3
`reast CAFS and
`TCFs Display
`Neoplastic.
`Meus
`Page 2717
`
`Bilao aae] CRette]
`
`ANC2 American Association tor CancerResearch
`
`Miltenyi Ex. 1003 Page 1
`
`

`

`Cancer Research
`A Journal of the American Association for Cancer Research
`
`April 15, 2008 - Pages 2551-3076
`Volume 68 - Number8
`
`
`The Questfor the 1p36 Tumor Suppressor. Anindya Bagchi
`and Alea A. Mills vs.sssssscsesssossssessscsssseserstssneesessaessseessesssanseseseecenesessenesnes2551
`
`Role of the Aggresome Pathwayin Cancer: Targeting Histone Deacetylase
`6-DependentProtein Degradation. Agustin Rodriguez-Gonzalez,
`tara Lin, Alan K. Ikeda,Tiffany Simms-Waldrip,Cecilia Fu,
`and Kathleen M. Sakamot0o.sssessesscssssssensersesenscnssenseesessseenesesneeneneseenetetse2557
`
`Tumor Escape Mechanism Governed by Myeloid-Derived Suppressor
`Cells. Srinivas Nagaraj and Dimitry I. Gabrilovich ...ssessscssersesessercnenees2561
`
`| Priority Reports
`
`Identification of p18'%«¢ as a Tumor Suppressor Gene in Glioblastoma
`Multiforme. David A. Solomon,Jung-Sik Kim, Sultan Jenkins,
`Hablom Ressom, Michael Huang, Nicholas Coppa, Lauren Mabanta,
`Darell Bigner, Hai Yan, Walter Jean, and Todd Waldmansssssssseresesseee2564
`
`A Requirement for DICER to Maintain Full Promoter CpG Island
`Hypermethylation in Human CancerCells. Angela H.Ting,
`Hiromu Suzuki, Leslie Cope, Kornel E. Schuebel, Byron H.Lee,
`Minoru Toyota, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino,
`and Stephen B. Baylin .sscsssessccsesseccresrensesesscacssssesssersensenersessarserasaseasens2570
`
`BCR/ABLInhibits Mismatch Repair to Protect from Apoptosis
`and Induce Point Mutations. Tomasz Stoklosa, Tomasz Poplawski,
`Mateusz Koptyra, Margaret Nieborowska-Skorska, Grzegorz Basak,
`Artur Slupianek, Marina Rayevskaya, Ilona Seferynska, Larry Herrera,
`Janusz Blasiak, and Tomasz SKOrskis.cccsssscerscrsesessessersescesessssssesseseseoeen2576
`
`Secondary BRCAI Mutations in BRCA1-Mutated Ovarian Carcinomas
`with Platinum Resistance. Elizabeth M. Swisher, Wataru Sakai,
`Beth Y. Karlan, Kaitlyn Wurz, Nicole Urban, and Toshiyasu Taniguchi....2581
`
`Identification of Let-7-Regulated Oncofetal Genes. Benjamin Boyerinas,
`Sun-Mi Park, Noam Shomron, Mads M.Hedegaard,Jeppe Vinther,
`Jens S. Andersen,Christine Feig, Jinbo Xu, Christopher B. Burge,
`NICH IAGUSE ReLelerescssnrsoreensnsnsraracnorstsescncarareciserearcssvestamrrerccacnsestsrencecea 2587
`
`Veeten Biology, Pathobiology, and Genetics
`
`A Role for TAZ in Migration, Invasion, and Tumorigenesis of Breast
`Cancer Cells. Siew Wee Chan, Chun Jye Lim, Ke Guo, Chee Peng Ng,
`lan Lee, Walter Hunziker, Qi Zeng, and Wanjin Hong.esecerssesesserererees2592
`
`Cyclin D1 and CDK4Activity Contribute to the Undifferentiated
`Phenotype in Neuroblastoma.Jan J. Molenaar, Marli E. Ebus,
`Jan Koster, Peter vanSluis, Carel J.M. van Noesel, Rogier Versteeg,
`OGMUIDp NM Carribeeeetnaestenremreetanrss.csetiscscttssorasatsvsnccenscaeneSiceenstenteartsssras2599
`
`The Signatures of Autozygosity amongPatients with Colorectal
`Cancer, Manny D.Bacolod, Gunter S. Schemmann, Shuang Wang,
`Richard Shattock, Sarah F. Giardina, Zhaoshi Zeng,JinruShia,
`Robert F, Stengel, Norman Gerry, Josephine Ho, Tomas Kirchhoff,
`Bert Gold, Michael F, Christman, Kenneth Offit, William L. Gerald,
`Daniel A. Notterman,Jurg Ott, Philip B. Paty, and Francis Barany.......2610
`
`p53 Loss Synergizes with Estrogen and Papillomaviral Oncogenes
`to Induce Cervical and Breast Cancers. Anny Shai, Henry C.Pitot,
`and Paul F, Lambert .scsccscscsesecseseseesssessscescesessescseseneansesseoensoessseeseenseeaees 2622
`
`Bile Acid Exposure Up-regulates Tuberous Sclerosis Complex
`1/Mammalian Target of Rapamycin Pathway in Barrett’s-Associated
`Esophageal Adenocarcinoma.Chia-Jui Yen, Julie G. Izzo, Dung-Fang Lee,
`Sushovan Guha, Yongkun Wei, Tsung-Teh Wu, Chun-Te Chen, Hsu-Ping Kuo,
`Jung-Mao Hsu, Hui-Lung Sun, Chao-Kai Chou, Navtej S. Buttar,
`Kenneth K. Wang, Peng Huang,Jaffer Ajani, and Mien-Chie Hung......2632
`
`Analysis of the Mechanisms Mediating Tumor-Specific Changes
`in Gene Expression in HumanLiver Tumors. Luis G. Acevedo,
`
`MarkBieda, Roland Green, and PeggyJ. Farnhameeescssesereree
`+2641
`
`Broad Overexpression of Ribonucleotide Reductase Genes in Mice
`Specifically Induces Lung Neoplasms. Xia Xu, Jennifer L. Page,
`Jennifer A. Surtees, HouchunLiu, Sarah Lagedrost, Young Lu,
`Roderick Bronson, Eric Alani, Alexander Yu. Nikitin,
`and Robert S. WeiSS ..sscscssecsssssrescsssrssccreseacesneersesesenseneersneceseanesensecesneses2652
`
`Genome-Wide Promoter Analysis Uncovers Portions of the Cancer
`Methylome. Mohammad Obaidul Hoque, Myoung Sook Kim,
`Kimberly Laskie Ostrow, Junwei Liu, G. Bea A. Wisman, Hannah Lui Park,
`Maria Luana Poeta, Carmen Jeronimo, Rui Henrique, Agnes Lendvai,
`Ed Schuuring, Shahnaz Begum, Eli Rosenbaum, Maté Ongenaert,
`Keishi Yamashita, Joseph Califano, William Westra, Ate G.J. van der Zee,
`Wim Van Criekinge, and David Sidransky....escsssssssesseecssersreesererseceeeenes2661
`
`Targeted Deletion of Prkarla Reveals a Role for Protein Kinase A
`in Mesenchymal-to-Epithelial Transition. Kiran S, Nadella,
`Georgette N. Jones,Anthony Trimboli, ConstantineA. Stratakis,
`Gustavo Leone, and LawrenceS. Kirschner...puneseusersteecesestansrceses2671
`
`Androgen Receptor Overexpression in Prostate Cancer Linked to
`Pure Loss from a Novel Repressor Complex. Longgui G. Wang,
`Edward M.Johnson,Yayoi Kinoshita, James S. Babb, Michael T. Buckley,
`LeonardF. Liebes, Jonathan Melamed, Xiao-MeiLiu, Ralf Kurek,
`Liliana Ossowski, and Ara C. Ferrari ..scessssssssevessesssesssessensensesresesneane2678
`
`Novel and Highly Recurrent ChromosomalAlterations in Sézary
`Syndrome. Maarten H. Vermeer, Remco van Doorn, Remco Dijkman,
`Xin Mao, Sean Whittaker, Pieter C. van Voorst Vader,
`Marie-Jeanne P. Gerritsen, Marie-Louise Geerts, Sylke Gellrich,
`Ola Séderberg, Karl-Johan Leuchowius, Ulf Landegren,
`Jacoba J. Out-Luiting, Jeroen Knijnenburg, Marije IJszenga,
`Karoly Szuhai, Rein Willemze, and Cornelis P. Tensen ....s.esessessseee
`
`
`
`Distinct RADS1 Associations with RAD52 and BCCIP in Response
`to DNA DamageandReplication Stress. Justin Wray, JingmeiLiu,
`Jac A. Nickoloff, and Zhiyuan Shen.ssecsssesscscsssssseesssoreenseeceeeeseareeeeseeses2699
`
`MUCI1 Expression Is Regulated by DNA Methylation and Histone H3
`Lysine 9 Modification in Cancer Cells. Norishige Yamada,Yukari Nishida,
`Hideaki Tsutsumida, Tomofumi Hamada, Masamichi Goto, Michiyo Higashi,
`Mitsuharu Nomoto, and Suguru Yonezawa evesesersesesenssecssssssseeseserssssconenes2708
`
`Breast Carcinoma~Associated Fibroblasts and Their Counterparts
`Display Neoplastic-Specific Changes. Nahed M. Hawsawi,
`Hazem Ghebeh,Siti-Faujiah Hendrayani, Asma Tulbah, Maha Al-Eid,
`Taher Al-Tweigeri, Dahish Ajarim, Ayodele Alaiya, Said Dermime,
`and Abdelilah Aboussekhra...ssssscssseserenseensrersensens sasenccusnenarsennvenseurersnesed LZ
`Miltenyi Ex. 1003 Page 2
`
`Miltenyi Ex. 1003 Page 2
`
`

`

`Contents (Continued)
`pNA Methyltransferase 1 and 3B Activate BAG-1 Expression via
`‘pecruitment of CTCFL/BORIS and Modulation of Promoter Histone
`ethylation. Lunching Sun, Lei Huang, Phuongmai Nguyen,
`Kheem S. Bisht, Gil Bar-Sela, Allen S. Ho, C. Matthew Bradbury,
`Wwenqiang Yu, HengmiCui, Sunmin Lee,JaneB. Trepel,
`andrewP. Feinberg, and David Gius..ssssuesssssssssssssssssrrsssssrecsecesscesssnssseeee2720
`
`Cell, Tumor, and Stem Cell Biology
`
`Genistein Induces the p21WAF1/CIP1 and p16INK4a Tumor
`guppressor Genes in Prostate Cancer Cells by Epigenetic Mechanisms
`Involving Active Chromatin Modification, Shahana Majid,
`Nobuyuki Kikuno,Jason Nelles, Emily Noonan, Yuichiro Tanaka,
`Ken Kawamoto,Hiroshi Hirata, Long C. Li, Hong Zhao, Steve T. Okino,
`Robert F. Place, Deepa Pookot, and Rajvir Dahiya wscsssssereceesseosnereeeeeeed1OO
`
`{he Promyelocytic Leukemia Zinc Finger-MicroRNA-221/-222
`pathway Controls MelanomaProgression through Multiple
`_(Qncogenic Mechanisms.Federica Felicetti, M. Cristina Errico,
`_Lisabianea Bottero, Patrizia Segnalini, Antonella Stoppacciaro,
`MauroBiffoni, Nadia Felli, Gianfranco Mattia, Marina Petrini,
`Mario P. Colombo,Cesare Peschle, and Alessandra Care ssessseesssssssseeeene2745
`
`Matrix Metalloproteinase-8 Functions-as a Metastasis Suppressor
`through Modulation of Tumor Cell Adhesion and Invasion.
`Ana Gutiérrez-Ferndndez, Antonio Fueyo, Alicia R. Folgueras,
`Cecilia Garabaya, Caroline J. Pennington, Simon Pilgrim,
`Dylan R. Edwards, Deborah L. Holliday, J. Louise Jones, Paul N. Span,
`Tred C.GJ. Sweep, Xose S. Puente, and Carlos L6pez-Otiti.ssesssscrsseree2755
`
`Epigenetic Inactivation of the Canonical Wnt Antagonist SRY-Box
`‘Containing Gene 17 in Colorectal Cancer. Wei Zhang, Sabine C. Gléckner,
`Mingzhou Guo, Emi Ota Machida, David H. Wang, Hariharan Easwaran,
`leancler Van Neste, James G. Herman, Kornel E. Schuebel, D, Neil Watkins,
`Nita Ahuja, and Stephen B. Baylin...ssessscsscsersssessesesseesSaretesTsTeensaareseceTesen2764
`
`MicroRNAs 221 and 222 Bypass Quiescence and Compromise Cell
`Survival. Ricardo Medina,Sayyed K. Zaidi, Chang-GongLiu,JanetL.Stein,
`Andre J. vanWijnen,Carlo M.Croce, and Gary S.Stein...sseerorereesesroX723
`
`Manganese Superoxide Dismutase Modulates Hypoxia-Inducible
`Factor-1a Induction via Superoxide. Suwimol Kaewpila,
`Sujatha Venkataraman, Garry R. Buettner, and Larry W. Oberley........2781
`Negative Regulation of YAP by LATS1 Underscores Evolutionary
`Conservationof the Drosophila Hippo Pathway. Jianmin Zhang,
`Gromaslaw A. Smolen, and Daniel A. Haber...pesreceenenenspasesesearesesss2789
`
`Down-regulation of Caspase-2 by Rottlerin via Protein Kinase
`C-6-Independent Pathway, AlakanandaBasu, Brett Adkins,
`
`and Chandreyi Basu sesssesenecessesensseveacaneasgneonensrusosesorsSeseneeesnnsaserseeee79D
`Targeting CD24 for Treatmentof Colorectal and Pancreatic Cancer
`by Monoclonal Antibodies or Small Interfering RNA.Eyal Sagiv,
`Alex Starr, Uri Rozovski, Rami Khosravi, Peter Altevogt, Timothy Wang,
`PANE: Nadir Arber csssssisiseissssesssecseensssnnesarssesascensosusanossaseetseenscedisessstoursesass 2803
`The Mitochondrial Uncoupling Protein-2 Promotes Chemoresistance
`in CancerCells. Zoltan Derdak, Nicholas M. Mark, GuidoBeldi,
`Simon C. Robson, Jack'R. Wands, and GyOrgy Bay.sssscssesceeeeesseroreeee2813
`
`
`
`
`
`
`
`
`
`Experimental Therapeutics, Molecular Targets,
`and Chemical Biology
`‘Targeting Endoplasmic Reticulum Stress and Akt with OSU-03012
`4ndGefitinib or Erlotinib to Overcome Resistance to Epidermal
`‘Growth Factor Receptor Inhibitors. Yu-Chieh Wang, Samuel K.Kulp,
`Dasheng Wang, Chih-ChengYang, Aaron M.Sargeant, Jui-Hsiang Hung,
`Yoko Kashida, Mamoru Yamaguchi, Geen-Dong Chang,
`And Ching-Shih Chen ssvssesseseersseseeconseseaessscasroneneceneeserrscsnessssseseveee2820
`
`Synthetic Lethality by Lentiviral Short Hairpin RNA Silencing of
`Thymidylate Kinase and Doxorubicin in Colon Cancer Cells
`Regardless of the p53 Status. Chun-Mei Hu and Zee-Fen Chang......2831
`Coordinated Epidermal Growth Factor Receptor Pathway Gene
`Overexpression Predicts Epidermal Growth Factor Receptor Inhibitor
`Sensitivity in Pancreatic Cancer. Antonio Jimeno, Aik Choon ‘Tan,
`Jordy Coffa, N.V. Rajeshkumar, Peter Kulesza, Belen Rubio-Viqueira,
`Jenna Wheelhouse, Begofia Diosdado, Wells A. Messersmith,
`Christine Iacobuzio-Donahue, Anirban Maitra, Marileila Varella-Garcia,
`Fred R. Hirsch, Gerrit A. Meijer, and Manuel Hidalgo .ssssesssssssseesseese1002841
`NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against
`Xenograft Tumor Growth, Angiogenesis, and Metastasis.
`Suzanne A, Eccles, Andy Massey, Florence I. Raynaud, Swee Y. Sharp,
`Gary Box, Melanie Valenti, Lisa Patterson, Alexis de Haven Brandon,
`Sharon Gowan,Frances Boxall, Wynne Aherne, Martin Rowlands,
`Angela Hayes, Vanessa Martins, Frederique Urban, Kathy Boxall,
`Chrisostomos Prodromou, Laurence Pearl, Karen James,
`Thomas P. Matthews, Kwai-Ming Cheung, Andrew Kalusa,Keith Jones,
`Edward McDonald,Xavier Barril, Paul A. Brough,Julie E. Cansfield,
`Brian Dymock, Martin J. Drysdale, Harry Finch, Rob Howes,
`Roderick E. Hubbard, Alan Surgenor, Paul Webb, Mike Wood,
`Lisa Wright, and Paul Workmanws. ssoenees eax esenesaipsniestners siiennteabeseaiie 2850
`
`Bone Marrow X Kinase-Mediated Signal Transductionin Irradiated
`Vascular Endothelium. Tianxiang Tu, Dinesh Thotala, Ling Geng,
`Dennis E. Hallahan, and ChristopherD. Willey ...essssssseessseestseseeareersseeZOOL
`NOV-002, a Glutathione Disulfide Mimetic, as a Modulatorof Cellular
`Redox Balance. Danyelle M. Townsend,Lin He, Steven Hutchens,
`Tracy E. Garrett, ChristopherJ. Pazoles, and Kenneth D, Tew «ssesesersses2870
`
`Imaging TransgeneActivity In vivo. Terence PF. Gade,
`Jason A. Koutcher, William M.Spees, Bradley J. Beattie,
`Vladimir Ponomarey, Michael Doubrovin, Ian M. Buchanan,
`Tatiana Beresten, Kristen L. Zakian, H. Carl Le, William P. Tong,
`Philipp Mayer-Kuckuk, Ronald G. Blasberg, and Juri G. Gelovani........2878
`
`Targeting a Tumor-Specific Laminin Domain Critical for Human
`Carcinogenesis. Mark Tran,Patricia Rousselle, Pasi Nokelainen,
`Sruthi Tallapragada, Ngon T. Nguyen, Edgar F. Fincher,
`and M.Peter Marinkovich......soteeneosaracnensesenscanenseesescenseneveneseterorerenesvereeeDOOD
`
`Soft Tissue SarcomaCells Are Highly Sensitive to AKT Blockade:
`A Role for p53-Independent Up-regulation of GADD45a.
`Quan-Sheng Zhu, WenhongRen,Borys Korchin, Guy Lahat, Adam Dicker,
`Yiling Lu, Gordon Mills, Raphael E.Pollock, and Dina Lev ws...sooner2895
`
`New Derivatives of Vitamin B12 Show Preferential Targeting of
`Tumors. Robert Waibel, Hansjérg Treichler, Niklaus G. Schaefer,
`Dave R. van Staveren, Stefan Mundwiler, Susanne Kunze, Martin Kiienzi,
`Roger Alberto, Jakob Ntiesch, Alexander Knuth, Holger Moch,
`
`Roger Schibli, and Pius August Schubiger........esevees
`scsescerseense+00002904
`
`PeroxisomeProliferator-Activated Receptor y-Mediated Up-regulation
`of Syndecan-1 by n-3 Fatty Acids Promotes Apoptosis of HumanBreast
`CancerCells, Haiguo Sun,Isabelle M. Berquin, Rick T. Owens,
`Joseph T. O'Flaherty, and Iris J. Edwards ..sssessessssseessouoaensmunsasantaasysarecoreeee2912
`
`Triterpenoid CDDO-Methy] Ester Inhibits the Janus-Activated
`Kinase-1 (JAK1)Signal TransducerandActivator of Transcription-3
`(STAT3) Pathway by Direct Inhibition ofJAK1 and STAT3.
`Rehan Ahmad, Deepak Raina, Colin Meyer, and Donald Kufe.....ssssse02920
`
`Apoptotic Activity and Mechanism of 2-Cyano-3,12-Dioxoolean-1,
`9-Dien-28-Oic-Acid and Related Synthetic Triterpenoids in Prostate
`Cancer. Marc L. Hyer, Ranxin Shi, Maryla Krajewska, Colin Meyer,
`Irina V. Lebedeva, Paul B.Fisher, and John C. Reed ...s.s00See2927
`
`A New Pharmacologic Action of CCI-779 Involves FKBP12-Independent
`Inhibition of mTOR KinaseActivity and Profound Repression of Global
`Protein Synthesis. Boris Shor, Wei-Guo Zhang, Lourdes Toral-Barza,
`Jessica Lucas, Robert T. Abraham,James J. Gibbons, and Ker Yu .ssess0002934
`Miltenyi Ex. 1003 Page 3
`
`Miltenyi Ex. 1003 Page 3
`
`

`

`
`
`Contents (Continued)
`pus Mimetic ABT-737 Potentiates TRAIL-Mediated Apoptotic
`gignaling by Unsequestering Bim and Bak in Human Pancreatic
`cancer Cells. Shengbing Huang and Prank A. SimiCrOp@sessssseseeesee2944
`
`containment of Tumor-Colonizing Bacteria by Host Neutrophils.
`Kathrin Westphal, Sara Leschner, Jadwiga Jablonska, Holger Loessner,
`and Siegfried WEISS .ssssssssssvesrsseessnesseneesssessseneensaneccsnecctnecennseessnecsesearenacse2952
`pedirecting Specificity of T-Cell Populations For CD19 Using the
`sleeping Beauty System. Harjeet Singh, Pallavi R. Manuri, SimonOlivares,
`Navid Dara, Margaret J. Dawson, Helen Huls, Perry B. Hackett,
`Donald B. Kohn,ElizabethJ. Shpall, Richard E. Champlin,
`and Laurence J.N. COOpeLssssssssssesresesereeessseacececesessssssseeseassersesessseasanneses 2961
`
`|
`
`Jnterleukin-15/Interleukin-15Ra Complexes Promote Destruction of
`Established Tumors by Reviving Tumor-Resident CD8* T Cells.
`Mathieu Epardaud, Kutlu G, Elpek, Mark P. Rubinstein, Ai-ris Yonekura,
`Angelique Bellemare-Pelletier, Roderick Bronson, Jessica A. Hamerman,
`Ananda W. Goldrath, and ShannonJ. Turleyssssssssssessscscsessssessesesessanaes2972
`
`Modeling the CD8* T Effector to Memory Transition in Adoptive
`1-Cell Antitumor Immunotherapy. Cleo E.Rolle, Roberto Carrio,
`and Thomas R. Malek...csssssssssoroserserssccecesseversvessensesseceseesscssesceecoeereesnens2984
`
`Loss of CTL Function among High-Avidity Tumor-Specitic
`CD8* T Cells following TumorInfiltration. Claire N. Janicki,
`$, RhiannonJenkinson, Neil A. Williams, and David J. Morgan .....-002993
`
`Clinical Research
`
`Gender-Related Survival Differences Associated with EGFR
`
`Polymorphisms in Metastatic Colon Cancer. Oliver A. Press, Wu Zhang,
`Michael A. Gordon, Dongyun Yang, Georg Lurje, SymaIqbal,
`Anthony El-Khoueiry, and Heinz-Josef Lenz....sssscossssserserssssesssessesesoes3037
`
`Soreoleh
`Genetic Variation in the Inhibin Pathway and Risk of Testicular
`Germ Cel] Tumors. Mark P. Purdue, Barry I. Graubard,
`Stephen J. Chanock, Mark V. Rubertone, Ralph L. Erickson,
`and Katherine A. MCGIYIN «.esssccsesercereerssreersonsntercesstaccsesnrsneesesees3043
`
`Double-Strand Break Damageand Associated DNA Repair Genes
`Predispose Smokers to Gene Methylation. Shuguang Leng,
`Christine A. Stidley, Randy Willink, Amanda Bernauer, Kieu Do,
`Maria A. Picchi, Xin Sheng, Melissa A. Frasco, David Van Den Berg,
`FrankD,Gilliland, Christopher Zima, Richard E. Crowell,
`and Steven A. Belinsky....sssscssecsoesereesessssssseescccnesersensesessnessecsersensereseaes3049
`
`uel
`Enhancement of UVB-Induced Apoptosis by Apigenin in Human
`Keratinocytes and Organotypic Keratinocyte Cultures.
`Adnan O, Abu-Yousif, Kimberly A. Smith, Spiro Getsios, KathleenJ. Green,
`
`Rukiyah T. Van Dross, andJill C. Pelling....sccssserererersessersreseseessessesensoees3057
`
`The Regulatory T Cell-Associated Transcription Factor FoxP3Is
`Expressed by TumorCells. Lisa M. Ebert, Bee Shin Tan, Judy Browning,
`Suzanne Svobodova, Sarah E. Russell, Naomi Kirkpatrick, Craig Gedye,
`Denis Moss, Sweet Ping Ng, Duncan MacGregor,IanD. Davis,
`Jonathan Cebon,and Weisan Chen sescssscsseresreccrsssseersesrencscsessessecsesesenees3001
`
`Effect of Low-Fat Diet on Development of Prostate Cancer and Akt
`Phosphorylation in the Hi-Myc Transgenic Mouse Model.
`Naoko Kobayashi, R. James Barnard, Jonathan Said, Jenny Hong-Gonzalez,
`Dan M. Corman, Melvin Ku, Ngan Bao Doan, Dorina Gui, David Elashoff,
`Pinchas Cohen, and William J. ArOnsOn...s.csssssceccerescereensenrecsnrnassentnsess3066
`
`Synthetic CD4* T Cell-Targeted Antigen-Presenting Cells Elicit
`Protective Antitumor Responses.Stefano Caserta, Patrizia Alessi,
`Jlenia Guarnerio, Veronica Basso, and Anna Mondino.essscesessercsreesees3010
`
`Interleukin 21 Enhances Antibody-Mediated TumorRejection.
`MarkJ. Smyth, Michele WL. Teng, Janelle Sharkey, Jennifer A. Westwood,
`Nicole M. Haynes, Hideo Yagita, Kazuyoshi Takeda, Pallavur V. Sivakumar,
`and Michael H. Kershaw. .ssssscesercsssssrsaseesessessecnssesesenenrserssarneneasenneseasess3019
`
`Letters to the Editor
`
`A Statistical Reappraisal of the Findings of an Esophageal
`Cancer Genome-WideAssociation Study. Alexander Statnikov
`ATLCUCEHUMP Lianeceatentesenettateeaettaaesteesecetaccumtntetteteertanetsertenttssncccvesccsosces3074
`
`Endocrinology
`
`Correction: T-cadherin Regulates Angiogenesis ........ssssssssesserseres3076
`
`The Helix-Loop-Helix Protein Id1 Requires Cyclin D1 to Promote the
`Proliferation of MammaryEpithelial Cell Acini. C. Elizabeth Caldon,
`Alexander Swarbrick, Christine S.L. Lee, Robert L. Sutherland,
`and Elizabeth A. MUSZTOVC vsssscscsestsresssesesseecerssasesssessassessessseseesetescenees3026
`
`Correction: Cosmic Mutation in Cancer ...ssscssersoseroreceesecssersesseseveeee3076
`
`Correction: Human Topoisomerase 20 Conjugates
`With SUMO-2...cccscsssessssvevssssescessscsesseseacacneseensseararsessanoeesesenssassanenseesconnee3076
`
`Miltenyi Ex. 1003 Page 4
`
`Miltenyi Ex. 1003 Page 4
`
`

`

`Researc
`A Journal of the American Association for Cance
` r Researep,
` AACR Officers
`
`
`Publishing Information
`Raymond N. DuBois, President
`Tyler E. Jacks, President-Elect
`(860) 350-0041; Fax: (860) 350-0039;
`Bayard D, Clarkson, Treasurer
`or E-mail: tarpinNA@turpin-
`Margaret Foti,
`distribution,com]; or (UK Main
`Chief Executive Officer and
`Office), Pegasus Drive, Stratton
`Managing Editor
`Business Park, Biggleswade,
`Bedfordshire SG18 8TQ, United
`Kingdom [Phone: (44) 0-1767-604-
`957; Pax: (44) 0-1767-601-640; or
`F-mail: custserv@turpin-
`distribution.com]. In Japan, send
`orders and inquiries to: USACO
`Corporation, usaco@usaco,co.|p;
`Swets Japan, info@jp.swets.com;
`EBSCO Japan, Japan@ebsco.com.
`Individuals who are not AACR
`members may subscribe to Volume
`68 (2008) of Cancer Researchat the
`rate of $760 U.S./$900 foreign.
`Cancer Research is only available
`to institutions as a combined
`subscription with Clinical Cancer
`Research. (Foreign subscription cost
`includes cost of surface mail, For
`faster delivery, expedited mailing rates
`are available by contacting the AACR
`Publications department.) Canadian
`subscribers should add 7% GST.
`Changesof addressnotification
`should be sent 60 days in advance
`and include both old and new
`addresses. Membersubscribers should
`send address changes to: AACR
`MemberServices, 615 Chestnut St.,
`17th Floor, Philadelphia, PA 19106-
`4404. Nonmembersubscribers should
`send changes of address to: AACR
`Subscriptionoffice (aforementioned
`address), Copies of the journal which
`are undeliverable because of address
`changeswill be destroyed.
`
`
`
`
`
`
`
`
`issue in which the advettisemen,
`isto be published. Inquiries about
`advertising should be directed toe
`M. J. Mrvica Associates, Inc., 9 We
`Taunton Avenue, Berlin, Nj 08009:
`Phone: (856) 768-9360; Fax: (856)
`753-0064,
`ia
`
`Copyright and Permissions
`All authors who wishto publish
`in Cancer Research must formally
`transfer copyright to the AACR,
`Inc., using the release form available.
`al www.aacrsmartsubmit.org,It js
`understood bythis transfer that
`the authors relinquishall exclusive
`rights of copyright ownership,
`including the rights of reproduction,
`detivation distribution,sale,
`and display.
`
`Authors who preparedtheirarticles
`as part oftheirofficial duties as
`employees of the U.S. Federal
`governmentare not requiredto
`transfer copyright to the AACR,Inc,
`since these articles are considered to
`be in the public domain. However, it.
`is necessary for these authors to sign
`the appropriate sectionof the transfer
`form.In the case ofarticles supported)
`by federal grants or contracts,
`copyright transfer to AACR,Ine., is
`required. The federal government
`may retain a nonexclusivelicense to
`publish or republish such material.
`
`Cancer
`
`Cancer Research [ISSN 0008-5472
`¢ CNREA8] is published twice a
`month, one volumeperyear, by the
`AACR,Inc. Periodicals postage paid
`at Philadelphia, PA, and additional
`mailing offices. POSTMASTER: Send
`address changes to: AACR, 615
`Chestnut St,, 17th Floor, Philadelphia,
`PA 19106-4404, Printed on acid-free
`paper in the United States of America.
`
`Submission of Manuscripts
`Online submission of new
`manuscripts is available at http://can.
`msubmit.net. Complete submission
`instructions and further information
`on the journal's scope and
`publication policies are available in
`the Information for Authors at
`http://cancerres.aacrjournals.org,
`and authors are strongly encouraged
`to review this information prior
`to submission.
`
`Manuscript Processing Fee
`Journal policy requires that a
`manuscript fee of $75 be assessed
`for each paperto defray the expenses
`incurred in the editorial review
`process. This fee is nonrefundable
`andis levied regardless of the decision
`rendered onthe paper. Upon
`completion of the online submission
`process, authorswill be directed
`to a secure site for remitting payment
`via credit card. Authors who are
`unable to pay by credit card at the
`time of submission must contact
`Ms. Jeri Williams of the AACR Finance
`office at jeri.williams@aact.org to
`make other arrangements, Manuscripts
`will not enter the review process until
`the submission fee has beenpaid.
`
`Page Charges
`Accepted manuscripts will be
`published with the understanding
`that the author(s) will pay a charge
`of $85 perprinted page for articles
`oneto six pages in length; $115 per
`additional page.
`
`Claims for missing issues made
`within 90 days of the issue date
`will be honored while supplies
`last. Institutions and nonmember
`individuals, contact AACR
`Subscriptionoffice at the
`aforementioned address. AACR
`members, contact AACR Member
`Services department. Phone: (215)
`440-9300; Pax: (215) 440-9412;
`E-mail: membership @aact.org,
`
`Publications Committee
`Michael A. Caligiuri, Chairperson
`Ann P. Chambers
`Yves A. De Clerck
`Glen Dranoff
`Raymond N. DuBois
`D. Gary Gilliland
`Joe W. Gray
`Susan Band Horwitz
`David J. Hunter
`V, Craig Jordan
`Kenneth W, Kinzler
`Michelle M. Le Beau
`Leroy Fong Liu
`Luis F. Parada
`Ramon Parsons
`Louis M. Staudt
`Chery! L. Willman
`George D: Yancopoulos
`Bayard D. Clarkson, ex officio
`David R. Parkinson, ex officio
`
`Publishing and Editorial
`Staff, Cancer Research
`Publisher: Kathleen Case
`Editorial Director:
`J. Heather Cullen
`Asst. Director, Editorial Systems
`& Journal Manager:
`Kelly A. Hadsell
`Production Manager:
`Morgan M. Robinson
`Production Editors:
`Kristin D. Murray
`Jeremy Rosenberg
`Staff Assistant:
`Shira Carroll
`Editorial Associates:
`Crystal Cheepudom
`Mike Williams
`Editorial Assistants:
`Kathleen Jasion
`Kyle A, Overturf
`Naima D, Stone
`
`Special Issues Editor:
`Diane M. Marinelli
`Associate Director,
`Electronic Publishing:
`Michael Beveridge
`Electronic Publishing Specialist:
`Mary Beth Cunney
`Graphics Director:
`Paul Driscoll
`Advertising Production:
`Susan Moore
`
`Marketing Director:
`Jeremy Thompson
`Circulation: Karola Rac
`
`‘Yo read the complete version
`of AACR’s Copyright and
`Permissions Policy, please visit
`hitp://www.aacr.org/home/
`scientists/publications-of-the-aaci/
`copyright-and-permissions-policy.
`aspx. This policy includes further
`information on authots' rightsof
`usage, permission requests from third:
`parties, free access to AACR journals;
`funding agency requirements, and the
`National Institutes of Health Public
`Access Policy.
`
`Cancer Reseatch is abstracted01 indexed)
`in Biological Abstracts, Biochemistty &
`Biophysics Citation Index, Busic BIOSIS)
`BIOSIS Previews (R) Database, Chemie!)
`Abstracts, Index Medicis, MRDLINE,
`Current Contents/Clinical Medicine
`Reference Update, and Science Citatiol
`Index (expanded).
`|
`Noresponsibility is accepted by the:
`Uditors or by AACR, Inc, forthe
`opinions expressed by contributols of
`for the content of the advertisement
`Copyright 2008 by the American
`a
`.
`ne.
`Association for Cancer Research, |
`
`a
`
`Subscription Information
`Subscriptions include online access.
`Except for members of the AACR,all
`subscriptions are payable in advance
`to AACR Subscriptionoffice, The
`address to which all business
`communication, remittances (in
`United States currency orits
`equivalent), and subscription orders
`should be sent: Turpin Distribution,
`(North American Office), ‘The
`Bleachery’, 143 West Street,
`New Milford, CT 06776 [Phone:
`
`Single issues copies and copies of
`back stock of the journal may be
`ordered from the AACR Subscription
`office (see “Subscription
`Information”). Prices are available
`uponrequest.
`
`Advertisements in
`Cancer Research
`
`Advertisement insertion orders and
`copy must be received approximately
`five weeks prior to the date of the
`
`Miltenyi Ex. 1003 Page 5
`
`Miltenyi Ex. 1003 Page 5
`
`

`

`
` This material may be protected by Copyright law (Title 17 U.S. Code)
` eeite Article
`Redirecting Specificity of T-Cell Populations For CD19 Using the
`Sleeping Beauty System
`
`Harjeet Singh, Pallavi R. Manuri, Simon Olivares, Navid Dara,’ MargaretJ. Dawson,
`Helen Huls,’ Perry B. Hackett, Donald B. Kohn,’ Elizabeth J. Shpall,”
`Richard E. Champlin, and LaurenceJ.N. Cooper’
`
`Divisions of 'Pediatrics and “Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas; ‘Department of
`Genelics, Cell Biology and Development, Universily of Minnesota, St. Paul, Minnesota; and ‘Division of Research Immunology/Bone
`Marrow ‘Transplantation, Children’s Hospital Los Angeles, Los Angeles, California
`
`Abstract
`Genetic modification of clinical-grade T cells is undertaken to
`augment function, including redirecting specificity for desired
`antigen. We and others have introduced a chimeric antigen
`receptor (CAR) to enable T cells to recognize lineage-specific
`tumor antigen, such as CD19, and early-phase humantrials
`are currently assessing safety and feasibility. However, a sig-
`nificant barrier to next-generation clinical studies is devel-
`oping a suitable CAR expression vector capable of genetically
`modifying a broad population of T cells. Transduction of
`T cells is relatively efficient but
`it requires specialized
`manufacture of expensive clinical grade recombinant virus.
`Electrotransfer of naked DNA plasmid offers a cost-effective
`alternative approach, but
`the inefficiency of transgene
`integration mandates ex vivo selection under cytocidal
`concentrations of drug to enforce expression of selection
`genes to achieve clinically meaningful numbers of CAR*
`T cells. We report a new approach to efficiently generating
`T cells with redirected specificity, introducing DNA plasmids
`from the Sleeping Beauty transposon/transposase system
`to directly express a CD19-specific CAR in memory and
`effector T cells without drug selection. When coupled with
`numerical expansion on CD19° artificial antigen-presenting
`cells, this gene transfer method results in rapid outgrowth
`of CD4* and CD8" T cells expressing CAR to redirect specificity
`for CD19* tumorcells. [Cancer Res 2008;68(8):2961-71]
`
`Introduction
`
`The most robust example of successful T-cell therapy occurs
`following allogeneic hematopoietic stem-cell transplantation where
`the engrafted donor-derived T cells recognize recipient
`tumor-
`associated antigens in the context of MHC. However, the graft-
`versus-tumor effect after allogeneic-hematopoietic stem cell
`transplantation is incomplete, resulting in relapse as the major
`Cause of mortality. To augment the graft-versus-tumor effect for
`B-lineage neoplasms, we have previously shown that genetically
`modified peripheral blood- and umbilical cord blood-derived
`T cells can be rendered specific for CD19, a molecule constitutively
`expressed on B-cell malignancies (1, 2). The redirected specificity
`was achieved by electrotransfer of a linearized DNA plasmid
`Coding for a first-generation chimeric antigen receptor (CAR),
`
`
`Requests for reprints: Laurence J.N. Cooper, University of Texas M. D. Anderson
`‘heer Center, Pediatrivs-Research, Unit 907, 1515 Toleombe Boulevard, Houston, TX
`F030. Phone: 713-568 “S208; Fax: 713-792-9832; E-mail: Ijneooperd@mdandersanarg.
`©2008 American Association for Cancer Research.
`doi:10.1158/0008-5472.CAN-07-5600
`
`————_——
`Www.aacrjournals.org
`
`designated CD19R, which recognizes CD19 via the scFv of a murine
`CD19-specific monoclonal antibody (mAb)
`fused to a chimeric
`CD3-¢-derived activation endodomain.A phaseI trial (BB-IND1141,
`clinicalTrials.gov identifier: NCT00182650;
`ref. 3)
`is currently
`evaluating the safety and feasibility of infusing autologous T cells
`electroporated to coexpress CD19R CAR and the hygromycin
`phosphotransferase (Hy) and herpes simplex virus-1 thymidine
`kinase selection/suicide fusion transgene (4).
`Weanticipated that the therapeuticefficacy of adoptive transfer of
`CD19-specific T cells would be improved by developing a CAR with a
`fully competent activation signal and introducing the CAR into
`central memory (CM)T cells. As a result, a second-generation CAR,
`designated CD19RCD28, has been developed that provides CD19-
`dependentsignaling through chimeric CD3-¢ and CD28,resulting in
`improved in vivo persistence and antitumoreffect, compared with
`CD19R*T cells (5). To furtheroptimize the clinical potential of CAR'
`T cells, while taking advantageof the cost-efficiency of nonviral gene
`transfer, we desired a clinically feasible approach to the efficient
`propagation of CAR* T-cell populations,
`including Tey,
`in the
`absence of expression immunogenic drug selection genes, such as
`Hy. We reasonedthat genetically modified T cells could be selectively
`propagated, upon activating T cells for sustained proliferation,
`through the introduced second-generation CAR. To maximize
`transgene expression, we codon-optimized (CoOp) the CAR as
`reports have shown that codon optimization of genes toward human
`consensus codon usage increases protein expression (6, 7).
`The focus on developing nonviral gene transfer technologies is
`justified based on the cost and time savings compared with
`developing recombinantclinical-grade viral supernatant, which are
`subject to rigorous regulatory oversight and rely on specialized
`manufacturing experience of a limited number of production
`facilities. Although the transfection efficiency of nonvira