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US 2016.0002733A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0002733 A1 Chu (43) Pub. Date: Jan. 7, 2016 (54) ASSESSING RISK FORENCEPHALOPATHY Related U.S. Application Data INDUCED BYS-FLUOROURACL, OR (60) Provisional application No. 61/772,949, filed on Mar. CAPECTABINE 5, 2013. Publication Classification (71) Applicant: THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNOR (51) Int. C. UNIVERSITY, Palo Alto, CA (US) CI2O I/68 (2006.01) (52) U.S. C. (72) Inventor: Gilbert Chu, Stanford, CA (US) CPC ........ CI2O I/6886 (2013.01); C12O 2600/156 (2013.01); C12O 2600/106 (2013.01); C12O (21) Appl. No.: 14/769,961 2600/142 (2013.01) (22) PCT Fled: Feb. 26, 2014 (57) ABSTRACT Methods and systems are provided for determining Suscepti (86) PCT NO.: PCT/US14/18739 bility to 5-fluorouracil (5-FU) or capecitabine toxicity. Meth ods are provided for treating a human Subject based on a S371 (c)(1), determined susceptibility to 5-fluorouracil (5-FU) or capecit (2) Date: Aug. 24, 2015 abine toxicity. Patent Application Publication Jan. 7, 2016 Sheet 1 of 17 US 2016/0002733 A1 Figure 1A urea cycle pyrimidine synthesis -- - - - - - - - - - - - Glin / WPA H al-NAGS NH 3. NH3CPSIDcarbamoyl-P Glu->NAG->|CPS Ca rbamyl-Asp: carbamoyl-P OHO : P. Orotate ornithine citruline s --AlORNT - Y - - - OMPwY Ornithine citruline UDP am UMP as UTP RR urea { UDP in OSuccinat A. 5-FUTP arginine 8 gypsuccina e CUMP i. cycleRECTS-5-FdUMP4-5-FU dTMP Figure IB /a-ketoglutarate pyruvate Asp PD PC 4-acetyl-CoA Glu oxaloacetate malate isocitrate Krebs cycle NH3 fumarate a-ketoglutarate Glu succinate succinyl-CoA methylmalonyl-CoA r a fatty acid proponyi-UOE. X--fattyfatty acid acyl-CoA oxidation ---fatty acyl-CoA4ACAS acetyl-CoAACAD caritine - - - - - - - - - - - - - - - - - - - - - - - - - - - - - site Patent Application Publication Jan. 7, 2016 Sheet 2 of 17 US 2016/0002733 A1 Figure 2A Seen at local ER with delirium Admitted with Confusion, ataxia Capecitabine lactulose - S 160 O E S. N 120 O E 80 E s normal level fl O Days Figure 2B 2 O 1 5 10 5 O O 6 12 18 24 Time (hrs) Patent Application Publication Jan. 7, 2016 Sheet 3 of 17 US 2016/0002733 A1 Figure2C 70 Baseline Midcycle O O O 1 2 3 4 5 -6 8 9 O 11 12 13 14 5 16 17 18 1920 2: 22 23 24 25 26 27 28 29 Patients Patent Application Publication Jan. 7, 2016 Sheet 4 of 17 US 2016/0002733 A1 FIGURE 3 &gge S 744 1083. 1245 500 1OOO 15OO 2000 SNP position Patent Application Publication Jan. 7, 2016 Sheet 5 of 17 US 2016/0002733 A1 FIGURE 4 y - 0.254.6x - 0.2526 R at O.3943 'O. O 2 3O 40 5 SO Mean baseline ammonia (mol/L) Patent Application Publication Jan. 7, 2016 Sheet 7 of 17 US 2016/0002733 A1 Figure 6 Plasma amino acids Plasma armonia was 81 pirging on day of test FaSia Jewef Ref. range Artific acid frong alarine 77-583 B-alanine 0-2 g-amingadipig acid O-S g-amingbutyric acid S-41 3-aringisobutyric acid arginine 15-128 asparagine 35-4 aspartic acid C-53 citruline 12-55 gyStathignine -3 Systine 5-82 ethalarie -153 glutamic acid 1-13 glutamine 25-5S glycine 151-49 giggySSS. hydroxyproline 1-25 isoleucine 30-18 leucine 72-21 lysine 11S-23S histidine F2-124 ethicine 1-42 Ornithine 48-195 phenylalanine 35-85 proline 97-32S Saggsins Serine 58-18 taurine 54-21 threnie S0-225 tryptophan 1-14 tyrosine 34-12 Waline 19-3S Patent Application Publication Jan. 7, 2016 Sheet 8 of 17 US 2016/0002733 A1 Figure 7 Plasma urine organic acids in Patient 1 Urine organic acids Plasma ammonia was 83 microngll on day of test Purine/pyrimidine rifle eye Ref. range creatinine) creatinine) hypoxanthine 5. Crotic acid thymine normal uracil 4 uric acid not measured Xanthine S Patent Application Publication Jan. 7, 2016 Sheet 9 of 17 US 2016/0002733 A1 {}}}| \ffff s ) to e a Patent Application Publication Jan. 7, 2016 Sheet 10 of 17 US 2016/0002733 A1 Figure 9A Lifar phosphodiestsease PDE4DIP p.R785* 4D interacting ap's cAMPPDE4D to protein CN2 p.Q5G9" 12 {6i E. peptidase N CartOxypeptidase Na-dependent eitfala.a. Ygg" solute carrier family transpaste, ..Y: 6 mites 8 fole is irrinoglycinuria & Yewcilitia -. zinc firger protein possible transcriptional FSCN3 R423 fascis-3 p.S474 lipoprotei Eipase triglyceridig hydrolysis LESSR Wact a sitein WSSB. sortifg-assoc vesicle-fi ediated trains. Of Toti i38 interfeof psilon NE CSS interie? of C-termina-binding crepresses taigeting CBP2 p.Q445 Grotis 2 t3nSctitional registOS R p R192" | 20 (145) to recept. ofactory receptor ROX 47 i8 story recept of ofactory receptor factory recept ORSO s i actory Receptor story recept of factory receptor a. OR.EXE p.Y273" | 108 (71) x aiiatory seceptor (C3 toyeep offactory receptor 45 ifactory recepto: ofactory feceptor 2. 5. factory recepto: ORECS CES actory seceptor olfactory recepto: REAR SR isitory Captor story receptor aifactory feceptor S C2AO 22solute gig carrier fi family organic aris transporter Patent Application Publication Jan. 7, 2016 Sheet 11 of 17 US 2016/0002733 A1 Figure 9B Sara if digits Frg FFFF NKG2-type 1 R p. W74 integral riter fare receptos on MK cells fotai hase-binding for S fre H pG 4.7" roteis }of Wiscers acyl-CoA synthetase ACSR2A p. Rii.5" redi Ein chain family medium chain fatty fiber 2A acid:OA ligase tra Smalbraie 4. tetrasparini protein, call TSFS i.S.S." 5 family embles Rosiferatio dual specificity MAP corponent of the MAP kinase kinase 3 kinase CaScade tuitingti-aSSOC proteis isoform 3 asSociates with untingtin cell division cycle anaphase profiloting protein 27 Oriolog Carex corporteri Serpin peptidase SERENE ifti, clade E is St. inhibits lysine-specific f teases organization of actii RN rhopiin-2 wioskeleto Equitin Gabxy de-biqirating CJB) JSP p.Ygi 3" | 129 terminal hydrolase Elzy Rig A fif-distridg FC8 p.R5" Gare it protein 8 protease inhibito: putative big-COrjug 9% identical to JB2M, UBENE p. 89." enzyrie E2 N-like role E. DNA repair and it lease Wii NE p.R325* like DNA glycosylass in BER 2-activaigdigail d gated on chaire Zn finger CCCH FC33 S di-Containing protein 3 fielaii Offia SAGEE2 . associated aftiger 2 fielano Ta MAGEB 6 p. R272 3.SSOciated artiger BE CStag p.R72" hypothetical protein 32 Patent Application Publication Jan. 7, 2016 Sheet 12 of 17 US 2016/0002733 A1 Figure 9C Gare ific. F. FFR as Fir Fif proteinhomolog EC-93 A isoform 2 protein CC2D2E isofori, 2 PRAME family RAE is jet 2 rips bindefki, (EKLC activat-e 2 is for Spetmatogethesis SAA8 p.R84." asSociated fiti 8 putatively-proteir Tp p. R21 phosphatase TPTE hypothetical protein C2F p.R37 Ca98.3 W. Wigan: NASB factor A dail containing serine hydroiase-Sike SERH prote 2 ferritin: heavy - Lif .E148 Oystid-like F Patent Application Publication Jan. 7, 2016 Sheet 13 of 17 US 2016/0002733 A1 Patent Application Publication Jan. 7, 2016 Sheet 14 of 17 US 2016/0002733 A1 N N Patent Application Publication Jan. 7, 2016 Sheet 15 of 17 US 2016/0002733 A1 Patent Application Publication Jan. 7, 2016 Sheet 16 of 17 US 2016/0002733 A1 Figure 13 Gere Cf. SNP Position aaf aa2 allele freg fax affeig fre ACAW SE3968 s G . OC55 A BA SW 80 5. NA A 8A: FS874,828 56 G NA ARG 6 SE 488 F9 NA CPS FS795,254 SS C S NA X CPS S525 6. N NA CPS S59398 8. G C NA C2 SEES 85 C O. O. CP2 S88 588 S. C 0.002 DEY i FSSF38F98 s O3 DPYD SSS) 733 W NA DPYD S3883 53. NA DPY) S858 53. S. N DRY SE9595 SS O. O.S EFA S S8 SS T O.O. 46 EPE 9 S35908 S. O.O3 EFE S3338. P , OF HA)-A S. C3 S W O O.O AA FSF58 5S C G NA HAHB 2 S35F3BS O N OO13 O.3 NCCC 3. FSF135OO 59 C NA CCC S35683 48 A. G O. 5 WLYC S fS35.955 43 C O. O).3 AA 4. Sail S7 i O.O.3 O)3 AAE FSSC i. S. A. M 8 S288 9 Y C O.O. OO CC X SS BOOBS 27. R OF O. PC S2229.745 873 N E NA, PC SW63.5 99 A. A. PC SFOA55 FS NP, .33 C FS355S-89 84 W .5 5 SLCA s FS 583 355 R C O.O25 O) SLCFA SR552, 38. t O.O2 SCA S5.583 SS R C CECS SLCAS 5. S388 35 R O.S O.O.5. SLC22A5 S5585. 49 Y D O.S S C22A5 fSSO3FS824 46 S. C O3 FM S8483,928 3 G S O.O.S O5 Patent Application Publication Jan. 7, 2016 Sheet 17 of 17 US 2016/0002733 A1 Figure 14 Frequency of Deleterious SNPs in the Population Max allele Sun of naX P(O) fred, X allele freq P(>1) P(>2) P(>3) O.O. O.39 O.726 0.273 O.O4 O.O4 O.005 0.344 0.79 0.29 0.047 0.05 O.CO O.369 O.69 O.309 O.O54. OOO6 O.O20 O.49 O.657 0.343 OO67 O.OO9 US 2016/0002733 A1 Jan. 7, 2016 ASSESSING RISK FORENCEPHALOPATHY provides methods for treating a human Subject based on a INDUCED BYS-FLUOROURACL, OR predicted susceptibility to 5-fluorouracil (5-FU) or capecit CAPECITABINE abine toxicity.
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  • Identification of Differentially Expressed Genes in Human Bladder Cancer Through Genome-Wide Gene Expression Profiling

    Identification of Differentially Expressed Genes in Human Bladder Cancer Through Genome-Wide Gene Expression Profiling

    521-531 24/7/06 18:28 Page 521 ONCOLOGY REPORTS 16: 521-531, 2006 521 Identification of differentially expressed genes in human bladder cancer through genome-wide gene expression profiling KAZUMORI KAWAKAMI1,3, HIDEKI ENOKIDA1, TOKUSHI TACHIWADA1, TAKENARI GOTANDA1, KENGO TSUNEYOSHI1, HIROYUKI KUBO1, KENRYU NISHIYAMA1, MASAKI TAKIGUCHI2, MASAYUKI NAKAGAWA1 and NAOHIKO SEKI3 1Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520; Departments of 2Biochemistry and Genetics, and 3Functional Genomics, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan Received February 15, 2006; Accepted April 27, 2006 Abstract. Large-scale gene expression profiling is an effective CKS2 gene not only as a potential biomarker for diagnosing, strategy for understanding the progression of bladder cancer but also for staging human BC. This is the first report (BC). The aim of this study was to identify genes that are demonstrating that CKS2 expression is strongly correlated expressed differently in the course of BC progression and to with the progression of human BC. establish new biomarkers for BC. Specimens from 21 patients with pathologically confirmed superficial (n=10) or Introduction invasive (n=11) BC and 4 normal bladder samples were studied; samples from 14 of the 21 BC samples were subjected Bladder cancer (BC) is among the 5 most common to microarray analysis. The validity of the microarray results malignancies worldwide, and the 2nd most common tumor of was verified by real-time RT-PCR. Of the 136 up-regulated the genitourinary tract and the 2nd most common cause of genes we detected, 21 were present in all 14 BCs examined death in patients with cancer of the urinary tract (1-7).
  • Identification of Isobutyryl-Coa Dehydrogenase and Its Deficiency

    Identification of Isobutyryl-Coa Dehydrogenase and Its Deficiency

    Molecular Genetics and Metabolism 77 (2002) 68–79 www.academicpress.com Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans Tien V. Nguyen,a Brage S. Andresen,b,c Thomas J. Corydon,b Sandro Ghisla,d Nasser Abd-El Razik,d Al-Walid A. Mohsen,a Stephen D. Cederbaum,e Diane S. Roe,f Charles R. Roe,f Nicolas J. Lench,g and Jerry Vockleya,* a Department of Medical Genetics, Mayo Clinic, Rochester, MN 55905, USA b Institute for Human Genetics, Aarhus University, Aarhus, Denmark c Research Unit for Molecular Medicine, Skejby Sygehus and Aarhus University, Aarhus, Denmark d Faculty of Biology, University of Konstanz, Konstanz, Germany e Department of Pediatrics, UCLA Medical Center, Los Angeles, CA, USA f Institute of Metabolic Disease, Baylor University, Dallas, TX, USA g Molecular Medicine Unit, University of Leeds, St. JamesÕ University Hospital, Leeds, UK Received 19 July 2002; received in revised form 31 July 2002; accepted 1 August 2002 Abstract The acyl-CoA dehydrogenases (ACDs) are a family of related enzymes that catalyze the a,b-dehydrogenation of acyl-CoA esters. Two homologues active in branched chain amino acid metabolism have previously been identified. We have used expression in Escherichia coli to produce a previously uncharacterized ACD-like sequence (ACAD8) and define its substrate specificity. Purified À1 À1 recombinant enzyme had a kcat=Km of 0.8, 0.23, and 0.04 (lM s ) with isobutyryl-CoA, (S) 2-methylbutyryl-CoA, and n-propionyl- CoA, respectively, as substrates. Thus, this enzyme is an isobutyryl-CoA dehydrogenase. A single patient has previously been described whose fibroblasts exhibit a specific deficit in the oxidation of valine.