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TOMATOLOGIAUS009777332B2 DET MAN KANN MAN UNITED (12 ) United States Patent ( 10 ) Patent No. : US 9 , 777 ,332 B2 Campana et al. ( 45 ) Date of Patent : Oct. 3 , 2017 ( 54 ) METHODS AND COMPOSITIONS FOR ( 56 ) References Cited IDENTIFYING MINIMAL RESIDUAL DISEASE IN ACUTE LYMPHOBLASTIC U . S . PATENT DOCUMENTS LEUKEMIA 2006 /0240434 Al 10 /2006 Gabert et al. 2007 / 0020670 A11 / 2007 Loken et al. @( 75 ) Inventors : Dario Campana, Kent Vale (SG ) ; 2012 /0202202 A18 /2012 Wang et al . Elaine Coustan - Smith , Kent Vale (SG ) FOREIGN PATENT DOCUMENTS @( 73 ) Assignee : St. Jude Children ' s Research BR WO 2010140885 A1 * 12 /2010 .. .. GOIN 33/ 5094 Hospital, Memphis , TN (US ) EP 2 259 065 AL 8 / 2010 WO WO 2007 /008759 A2 1 / 2007 ( * ) Notice : Subject to any disclaimer , the term of this WO WO 2010140885 A1 * 12 / 2010 patent is extended or adjusted under 35 U . S . C . 154 (b ) by 233 days . OTHER PUBLICATIONS Campana et al. , Immunophenotyping of Leukemia , Journal of (21 ) Appl. No. : 14 /005 ,921 Immunological Methods, 2000 , 243 , 59 - 74 . * Campana , Minimal Residual Disease in Acute Lymphoblastic Leu (22 ) PCT Filed : Mar . 14 , 2012 kemia , Hematology , 2010 , 7 - 12 . * US Patent and Trademark Office (USPTO ) , Examples , Nature Based Products , Interim Guidance , 2014 , 1 - 17 . * ( 86 ) PCT No .: PCT/ US2012 /028993 Opinion of the United States Court of Appeals for the Federal Circuit, Genetic Technologies Limited v . Merial LLC , 2016 , 1 - 20 . * $ 371 ( c )( 1 ) , Opinion of the United States Court of Appeals for the Federal ( 2 ) , ( 4 ) Date : Oct. 2 , 2013 Circuit, Ariosa Diagnostics , Inc. v . Sequenom , Inc. , 2015 , 1 - 21 . * Stetler - Stevenson et al. , Chapter 3 , Flow Cytometry , Diagnostic (87 ) PCT Pub . No. : WO2012 / 134813 Tehcniques in Hematological Malignancies , W . Erber ed ., 2010 , 51 -63 . * PCT Pub . Date : Oct. 4 , 2012 Coustan - Smith , Elaine , et al. , “ Immunologic minimal residual diease detection in acute lymphoblastic leukemia : A comparative approach to molecular testing, " Best Practice & Research Clinical (65 ) Prior Publication Data Haematology , 2010 , vol. 23 ( 3 ) , pp . 347 - 358 . US 2014 /0148354 A1 May 29, 2014 Kato , K . , et al . , “ Antibody arrays for quantitative immunophenotyp ing, ” Biomaterials, 2007 , vol. 28 ( 6 ) , pp . 1289 - 1297 . Shehata , M ., et al ., “ Partial Characterization and In Vitro Expansion of Putative CLL Precursor/ Stem Cells Which Are Dependent on Related U . S . Application Data Bone Marrow Microenvironment for Survival ,” Blood ( Ash Annual (60 ) Provisional application No . 61/ 470 ,056 , filed on Mar . Meeting Abstracts ) , 2010 , vol . 116 ( 21) , pp . 1 - 2 , Abstract 2433 . 31 , 2011. * cited by examiner Primary Examiner — Amy M Bunker (51 ) Int. Ci. ( 74 ) Attorney , Agent, or Firm — Womble Carlyle C40B 30 /04 ( 2006 . 01 ) Sandridge & Rice LLP C40B 30 / 00 ( 2006 .01 ) C120 1 /68 ( 2006 .01 ) (57 ) ABSTRACT GOIN 33 /574 (2006 .01 ) This invention provides methods and kits for diagnosing , ( 52 ) U . S . CI. ascertaining the clinical course of minimal residual disease CPC .. C12Q 1 / 6886 ( 2013 .01 ) ; GOIN 33/ 57426 associated with acute lymphoblastic leukemia ( ALL ) . Spe (2013 .01 ) ; GOIN 2333 /705 (2013 .01 ) cifically the invention provides methods and kits useful in (58 ) Field of Classification Search the diagnosis and determination of clinical parameters asso CPC . .. .. .. .. .. C12Q 1 /6886 ciated with diseases associated with ALL based on patterns USPC . .. .. .. .. .. .. 506 / 9 of surface marker expression unique to ALL . See application file for complete search history . 10 Claims, 6 Drawing Sheets U . S . Patent Oct . 3 , 2017 Sheet 1 of 6 US 9 , 777, 332 B2 P < 0 . 0001 P < 0 .001 1000 - - ofthe OCEAN $ Setelage ww. oBogdog MFI 800$oso 8Settelee o. portog oesteja- G20 ! wwwww 080130 ): Como roagopaAbreu 88$ NL NL NLz 898$z8 NL NL NL NL BCL2 HSPB1 CD304 CD164 CD73 CD300A CD 200 P < 0 . 01 P = 0 . 03 MITTE1000 , - - - - oSelo 8 - oobstante - - - G www - - - - • MFI - - - ogbago - 300%488ozo - ( ) tog * OUI eofoota wwwwww Bog -Bolooz N ? N 1 N 1 zo309N L NL NL CD72 CD130 zoCD37 CD86 CD976 CD123 FIGURE 1 U . S . Patent Oct. 3 , 2017 Sheet 2 of 6 US 9 ,777 ,332 B2 * - - 100007 - - - - - - 1000 - ofte - - + www + + + MFI - ww -wwwwwwwww . w Bebo ö z8$80 ote 88001936.888 zoof81880 - ! - www -Bebeklerog! . i ö-Books80 i - O -BOSSSSS N N 1 N 1 1 N zooloN 1 N 7 CD99 CD102 CD44 CD24 082IGB7 CD1C CTNNA1 CD79b w 8 - - - 10001 w - w - - w - * - ranwww - - * - - g - - - - - - + - - - - - - - * - ww4H+ - MFI - 5 - 48°08 - - wwwwww- 0 - - - - 0 -w - - - } - co o - olo tome awesome anima generaciones la demand glo b e N N1N1 N1 N1 N1 N1 N1 N1 7 CD49f PBX1 EPOR CD69 CD132 CD83 CD120 IL13RA CD62L FIGURE 2 U . S . Patent Oct. 3 , 2017 Sheet 3 of 6 US 9 ,777 ,332 B2 n = 0 n = 35 , -- PCR(%) ? OOOOOoode n = 63 n = 3 0 .01 0 . 1 1 10 Flow Cytometry ( % ) FIGURE 3 U , S , Patent Oct. 3 , 2017 Sheet 4 0f 6 _ US 9 ,777 ,332 B2 Pf. 1 Pf. 2 o BoL2 D HSPB1 ? D HSPB1 ? CD200 A CD86 CD123 8 ? CD200 : é?? CD97 MFI_ CD102 CD99 ???? 0 1942 _ 01 6 1942 Days from diagnosis Days from diagnosis Pt. 3 Pf. 4 3007 CD123 CD123 9 cb300A CD97 ? MFI é#& 8 0 1942 0 1942 Days from diagnosis Days from diagnosis FIGURE4 U . S . Patent Oct. 3 , 2017 Sheet 5 of 6 US 9 ,777 ,332 B2 CD44(u) CD24(u) CD44 BCL2 CD73 CD123 CD72 CD86 CD200 CD79b CD164 CD97 CD99 Hyperdiploid HSPB1 CD304 ETV6 - RUNX1 TCF3 -PBX1 BCR -ABL1 MLL Other . Ó 20 15140 60 80 100 % of cases with differential expression FIGURE 5 U . S . Patent Oct. 3 , 2017 Sheet 6 of 6 US 9 ,777 ,332 B2 MRD = 0 .01 % CD19 CD19 CD19 www CD868 CD38 CD97° CD38 CD97 CD38 E23MRD = 0 . 001 % CD19 CD19 CD8Q TICD38 CD97 º CD38° || CD97 CD38 FIGURE 6 US 9 ,777 ,332 B2 METHODS AND COMPOSITIONS FOR Blood . 115 : 3206 -3214 ; Stow et al. (2010 ) Blood . 115 : 4657 IDENTIFYING MINIMAL RESIDUAL 4663 ) . There is strong evidence supporting its prognostic DISEASE IN ACUTE LYMPHOBLASTIC significance in adult ALL (Krampera et al. ( 2003 ) Br J LEUKEMIA Haematol. 120 :74 - 79 ; Vidriales , et al. ( 2003 ) Blood . 101 : 5 4695 - 4700 ; Raff et al. (2007 ) Blood . 109 : 910 - 915 ; Holow CROSS - REFERENCE TO RELATED iecki et al. ( 2008 ) Br. J . Haematol. 142 : 227 -237 ; Bassan et APPLICATIONS al. ( 2009 ) Blood . 113 :4153 - 4162) . Thus , MRD monitoring has been introduced into many This application is a 35 U . S . C . 8273 U . S . National Stage contemporary treatment protocols for risk assignment and of International Application PCT /US2012 /028993 filed Mar . 10 selection of therapeutic regimens ( Pui et al. ( 2009) N Engl 14 , 2012 , which designates the U . S . and was published by J Med . 360 :2730 - 2741; Gokbuget and Hoelzer. ( 2009 ) the International Bureau in English on Oct. 4 , 2012 , and Semin . Hematol. 46 :64 -75 ; and Faderl et al. ( 2010 ) Cancer. which claims the benefit of U . S . Provisional Application No . 116 : 1165 - 1176 ) . MRD measurements are also clinically 61/ 470 ,056 , filed Mar . 31 , 2011, both of which are hereby useful in patients with relapsed ALL who achieve a second incorporated by reference in their entirety . 15 remission (Coustan - Smith et al. ( 2004 ) Leukemia 18 :499 504 ; Paganin et al . ( 2008 ) Leukemia . 22 :2193 - 2200 ; Raetz et STATEMENT REGARDING FEDERALLY al. (2008 ) J Clin . Oncol. 26 : 3971 - 3978 ) , can help optimize SPONSORED RESEARCH OR DEVELOPMENT the timing of hematopoietic stem cell transplantation (Bader et al . ( 2009 ) J Clin Oncol. 27 : 377 - 384 ) , and guide decisions This invention was made with support under United 20 about donor lymphocyte infusion post - transplant ( Lankester States Government Grant CA60419 awarded by the National et al . ( 2010 ) Leukemia . 24 : 1462 - 1469 ) . Institutes of Health . The United States Government has Among methods for detecting MRD in ALL , PCR ampli certain rights in this invention . fication of antigen - receptor genes has proven to be valuable and has been extensively standardized ( Bruggemann , M . , et REFERENCE TO SEQUENCE LISTING 25 al. ( 2010 ) Leukemia . 24 :521 -535 ) but the technical expertise SUBMITTED ELECTRONICALLY and instrumentation required limit its application to special ized centers . PCR amplification of fusion transcripts may The official copy of the sequence listing is submitted also provide useful clinical information but its applicability electronically via EFS -Web as an ASCII formatted sequence in ALL is restricted by the fact that molecular targets listing with a file named 415313SEQLIST. txt, created on 30 currently adaptable to routine MRD studies are present in Mar . 6 , 2012 , and having a size of 225, 858 bytes and is filed only a minority of patients . Id . Flow cytometric detection of concurrently with the specification . The sequence listing leukemia - specific markers has been shown to predict out contained in this ASCII formatted document is part of the come in numerous clinical correlative studies ( Coustan specification and is herein incorporated by reference in its Smith et al. (1998 ) Lancet. 351 : 550 -554 ; Coustan - Smith et entirety . 35 al. (2000 ) Blood . 96 : 2691 - 2696 ; Dworzak et al . ( 2002 ) Blood . 99 : 1952 - 1958 ; Borowitz , et al . ( 2008 ) Blood . 111 : FIELD OF THE INVENTION 5477 - 5485 ; Basso et al. (2009 ) J Clin Oncol . 27 : 5168 -5174 ; Krampera et al. ( 2003 ) Br J Haematol 120 : 74 -79 ; Vidriales This invention relates generally to the detection of mini et al . (2003 ) Blood 101: 4695 - 4700 ; Holowiecki et al . (2008 ) mal residual disease in patients with acute lymphoblastic 40 Br. J . Haematol . 142 : 227 - 237 ) . The method holds potential leukemia ( ALL ) and , more specifically , to a method to for wider applicability than molecular techniques because improve minimal residual disease monitoring for risk flow cytometric methods for leukemia diagnosis are already assignment and selection of therapeutic regimens .
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  • (P -Value&lt;0.05, Fold Change≥1.4), 4 Vs. 0 Gy Irradiation

    (P -Value<0.05, Fold Change≥1.4), 4 Vs. 0 Gy Irradiation

    Table S1: Significant differentially expressed genes (P -Value<0.05, Fold Change≥1.4), 4 vs. 0 Gy irradiation Genbank Fold Change P -Value Gene Symbol Description Accession Q9F8M7_CARHY (Q9F8M7) DTDP-glucose 4,6-dehydratase (Fragment), partial (9%) 6.70 0.017399678 THC2699065 [THC2719287] 5.53 0.003379195 BC013657 BC013657 Homo sapiens cDNA clone IMAGE:4152983, partial cds. [BC013657] 5.10 0.024641735 THC2750781 Ciliary dynein heavy chain 5 (Axonemal beta dynein heavy chain 5) (HL1). 4.07 0.04353262 DNAH5 [Source:Uniprot/SWISSPROT;Acc:Q8TE73] [ENST00000382416] 3.81 0.002855909 NM_145263 SPATA18 Homo sapiens spermatogenesis associated 18 homolog (rat) (SPATA18), mRNA [NM_145263] AA418814 zw01a02.s1 Soares_NhHMPu_S1 Homo sapiens cDNA clone IMAGE:767978 3', 3.69 0.03203913 AA418814 AA418814 mRNA sequence [AA418814] AL356953 leucine-rich repeat-containing G protein-coupled receptor 6 {Homo sapiens} (exp=0; 3.63 0.0277936 THC2705989 wgp=1; cg=0), partial (4%) [THC2752981] AA484677 ne64a07.s1 NCI_CGAP_Alv1 Homo sapiens cDNA clone IMAGE:909012, mRNA 3.63 0.027098073 AA484677 AA484677 sequence [AA484677] oe06h09.s1 NCI_CGAP_Ov2 Homo sapiens cDNA clone IMAGE:1385153, mRNA sequence 3.48 0.04468495 AA837799 AA837799 [AA837799] Homo sapiens hypothetical protein LOC340109, mRNA (cDNA clone IMAGE:5578073), partial 3.27 0.031178378 BC039509 LOC643401 cds. [BC039509] Homo sapiens Fas (TNF receptor superfamily, member 6) (FAS), transcript variant 1, mRNA 3.24 0.022156298 NM_000043 FAS [NM_000043] 3.20 0.021043295 A_32_P125056 BF803942 CM2-CI0135-021100-477-g08 CI0135 Homo sapiens cDNA, mRNA sequence 3.04 0.043389246 BF803942 BF803942 [BF803942] 3.03 0.002430239 NM_015920 RPS27L Homo sapiens ribosomal protein S27-like (RPS27L), mRNA [NM_015920] Homo sapiens tumor necrosis factor receptor superfamily, member 10c, decoy without an 2.98 0.021202829 NM_003841 TNFRSF10C intracellular domain (TNFRSF10C), mRNA [NM_003841] 2.97 0.03243901 AB002384 C6orf32 Homo sapiens mRNA for KIAA0386 gene, partial cds.
  • Figure S1. HAEC ROS Production and ML090 NOX5-Inhibition

    Figure S1. HAEC ROS Production and ML090 NOX5-Inhibition

    Figure S1. HAEC ROS production and ML090 NOX5-inhibition. (a) Extracellular H2O2 production in HAEC treated with ML090 at different concentrations and 24 h after being infected with GFP and NOX5-β adenoviruses (MOI 100). **p< 0.01, and ****p< 0.0001 vs control NOX5-β-infected cells (ML090, 0 nM). Results expressed as mean ± SEM. Fold increase vs GFP-infected cells with 0 nM of ML090. n= 6. (b) NOX5-β overexpression and DHE oxidation in HAEC. Representative images from three experiments are shown. Intracellular superoxide anion production of HAEC 24 h after infection with GFP and NOX5-β adenoviruses at different MOIs treated or not with ML090 (10 nM). MOI: Multiplicity of infection. Figure S2. Ontology analysis of HAEC infected with NOX5-β. Ontology analysis shows that the response to unfolded protein is the most relevant. Figure S3. UPR mRNA expression in heart of infarcted transgenic mice. n= 12-13. Results expressed as mean ± SEM. Table S1: Altered gene expression due to NOX5-β expression at 12 h (bold, highlighted in yellow). N12hvsG12h N18hvsG18h N24hvsG24h GeneName GeneDescription TranscriptID logFC p-value logFC p-value logFC p-value family with sequence similarity NM_052966 1.45 1.20E-17 2.44 3.27E-19 2.96 6.24E-21 FAM129A 129. member A DnaJ (Hsp40) homolog. NM_001130182 2.19 9.83E-20 2.94 2.90E-19 3.01 1.68E-19 DNAJA4 subfamily A. member 4 phorbol-12-myristate-13-acetate- NM_021127 0.93 1.84E-12 2.41 1.32E-17 2.69 1.43E-18 PMAIP1 induced protein 1 E2F7 E2F transcription factor 7 NM_203394 0.71 8.35E-11 2.20 2.21E-17 2.48 1.84E-18 DnaJ (Hsp40) homolog.