A Pilot Pharmacogenomic Study Examining the Influence of Cytotoxic and Metabolising Genetic Polymorphisms on Chemotherapy Toxicity and Outcome in Osteosarcoma

Total Page:16

File Type:pdf, Size:1020Kb

A Pilot Pharmacogenomic Study Examining the Influence of Cytotoxic and Metabolising Genetic Polymorphisms on Chemotherapy Toxicity and Outcome in Osteosarcoma A PILOT PHARMACOGENOMIC STUDY EXAMINING THE INFLUENCE OF CYTOTOXIC AND METABOLISING GENETIC POLYMORPHISMS ON CHEMOTHERAPY TOXICITY AND OUTCOME IN OSTEOSARCOMA DR RACHAEL WINDSOR BSc, MBBS, MRCPCH, MSc UNIVERSITY COLLEGE LONDON FACULTY OF CLINICAL SCIENCES MD(Res) CLINICAL RESEARCH January 2013 MD Res Pharmacogenomics of Osteosarcoma January 2013 1 DECLARATION ‘I, Rachael Windsor confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis.' MD Res Pharmacogenomics of Osteosarcoma January 2013 2 ABSTRACT Background: Osteosarcoma is the most common malignant bone tumour in children and young people. Multi-agent MAP chemotherapy ( Methotrexate, Adriamycin, cis Platin) forms the backbone of standard treatment protocols but approximately 40% patients respond poorly to chemotherapy. It was hypothesized that pharmacogenomic profiling of osteosarcoma patients may facilitate optimisation of treatment with the aim of improved outcomes and decreased burden of late effects. This pilot study aimed to investigate associations of 36 candidate genetic polymorphisms in MAP pathway genes with histological response (HR), survival and grade 3-4 chemotherapy toxicity. A secondary aim was preliminary analysis of genome-wide copy number variation in osteosarcoma. Methods: Blood samples and retrospective chemotherapy toxicity data were obtained from 60 patients who had completed MAP chemotherapy. All patients were manually genotyped for 5 polymorphisms. The remaining 31 polymorphisms were genotyped in 50 patients using the Illumina 610-Quad microarray. Associations between candidate polymorphisms and HR, progression-free survival and toxicity were estimated using Pearson’s χ2 and Fisher’s Exact tests, the Kaplan-Meier method, the log-rank test and Cox proportional hazards model. Copy number analysis was performed using PennCNV. Results: Poor histological response was associated with ABCC2 c.24C>T (p=0.011) and GSTP1 c.313A>G p.Ile 105 Val (p=0.009) whereas MTHFD1 c.1958G>A p.Arg 653 Gln was protective (p=0.03). Methotrexate toxicity was associated with MTHFR c.1298A>C p.Glu 429 Ala (p=0.038), ABCC2 c.3563T>A p.Val 1188 Glu (p=0.028) and ABCB1 c.3435T>C Ile 145 Ile (p=0.027). Variants of GSTP1 c.313A>G p.Ile 105 Val were at increased risk of myelosuppression (p=0.024) and cardiac damage (p=0.008). Eight recurrent copy number variations were identified, none significant. Conclusions: This pilot study explored the pharmacogenomics of osteosarcoma chemotherapy and although limited by small sample size secondary to retrospective recruitment and the rarity of this tumour, it remains the most comprehensive study to MD Res Pharmacogenomics of Osteosarcoma January 2013 3 date. A number of novel polymorphic associations were observed as well as confirming several previously reported findings. Cautious interpretation is required but further prospective investigation is warranted. MD Res Pharmacogenomics of Osteosarcoma January 2013 4 Table of Contents List of abbreviations............................................................................................8 1.0 Introduction .................................................................................................10 1.1 Candidate polymorphism study ...............................................................10 1.2 Genome wide analysis of CNV................................................................12 2.0 Osteosarcoma: background........................................................................13 2.1 Clinical and pathological features............................................................13 2.2 Current therapeutic strategy....................................................................14 Figure 1: MAP chemotherapy schematic ...................................................16 2.3 Osteosarcoma: late effects of chemotherapy ..........................................17 2.3.1 Cardiotoxicity ....................................................................................17 Figure 2: The relationship between cardiac and non-cardiac findings in long-term survivors of childhood malignancy treated with anthracyclines..18 Figure 3: Candidate genes involved in adverse effects of doxorubicin in a cardiomyocyte............................................................................................19 2.3.2 Nephrotoxicity ...................................................................................20 2.3.3 Ototoxicity .........................................................................................20 2.3.4 Fertility ..............................................................................................21 3.0 Pharmacology and pharmacogenomics of MAP chemotherapy..................23 3.1 Pharmacology of MAP chemotherapy .....................................................23 3.1.1 Methotrexate.....................................................................................23 Figure 4: Methotrexate drug pathway ........................................................25 3.1.2 Doxorubicin.......................................................................................26 Figure 5: Doxorubicin drug pathway ..........................................................28 3.1.3 Cisplatin............................................................................................29 Figure 6: Platinum drug pathway ...............................................................31 3.2 Pharmacogenomics of MAP chemotherapy ............................................32 Table 1: Functional and clinical effects of candidate polymorphisms.........33 3.2.1 The folate pathway (MTX).................................................................38 3.2.2 ATP-Binding Cassette Transporters (MTX, DOX, cisplatin)..............40 3.2.3 Glutathione S-transferases (cisplatin, DOX) .....................................42 3.2.4 Nucleotide excision repair (cisplatin, DOX).......................................44 3.2.5 Carbonyl reductases, NAD(P)H oxidase (DOX)................................46 4.0 Copy number variation................................................................................48 4.1 CNV in osteosarcoma .............................................................................49 Figure 7: Proposed model for CNVs in tumourigenesis .............................50 5.0 Materials and Methods (i): Candidate polymorphism study ........................53 5.1 Study population......................................................................................53 5.1.1 Patient identification..........................................................................53 5.1.2 Ethics................................................................................................53 5.2 Data collection.........................................................................................53 5.2.1 Demographic data ............................................................................53 5.2.2 Chemotherapy toxicity ......................................................................54 Table 2: CTCAE grades for cardiac, renal and ototoxicity .........................55 5.3 Selection of candidate polymorphisms ....................................................56 5.4 Preparation of DNA .................................................................................56 5.4.1 Extraction of genomic DNA from whole blood...................................56 5.4.2 Quantification....................................................................................56 5.5 SNP microarray analysis .........................................................................56 5.5.1 Illumina 610-Quad SNP array ...........................................................57 Figure 8: Illumina 610-Quad microarray ....................................................57 MD Res Pharmacogenomics of Osteosarcoma January 2013 5 5.5.2 Infinium HD whole-genome genotyping single base extension assay (WGG-SBE)...............................................................................................57 Figure 9: Infinium HD WGG-SBE assay ....................................................58 5.6 Polymerase chain reaction (PCR) ...........................................................59 5.6.1 Standard PCR...................................................................................59 5.6.1.1 TS VNTR final amplification ...........................................................60 5.6.1.2 DHFR in/del ...................................................................................60 Table 3: PCR Primer sequences and fragment size ..................................60 Table 4: TS VNTR optimisation steps........................................................61 5.6.1.3 RFLP analysis: TS VNTR G/C SNP...............................................61 Figure 10: Hae III restriction sites ..............................................................62 5.7 Multiplex PCR: GSTT1 and GSTM1 null alleles ......................................62 5.7.1 Gel electrophoresis...........................................................................62 Image 1: TS VNTR gel electrophoresis .....................................................63 Image 2: TS Triple repeat G/C SNP ..........................................................63 Image 3: DHFR electrophoresis.................................................................63 Image 4: GSTT1/GSTM1 electrophoresis..................................................64
Recommended publications
  • OR2AJ1 (P-13): Sc-104521
    SAN TA C RUZ BI OTEC HNOL OG Y, INC . OR2AJ1 (P-13): sc-104521 BACKGROUND APPLICATIONS Olfactory receptors are G protein-coupled receptors that localize to the cilia OR2AJ1 (P-13) is recommended for detection of OR2AJ1 of human origin of olfactory sensory neurons where they display affinity for and bind to a by Western Blotting (starting dilution 1:200, dilution range 1:100-1:1000), variety of odor molecules. The genes encoding olfactory receptors comprise immunofluorescence (starting dilution 1:50, dilution range 1:50-1:500) and the largest family in the human genome. The binding of olfactory receptor solid phase ELISA (starting dilution 1:30, dilution range 1:30-1:3000); may proteins to odor molecules triggers a signal transduction that propagates cross-react with OR2T27. nerve impulses throughout the body, ultimately leading to transmission of the OR2AJ1 (P-13) is also recommended for detection of OR2AJ1 in additional signal to the brain and the subsequent perception of smell. OR2AJ1 (olfac - species, including equine, canine, bovine and porcine. tory receptor 2AJ1) is a 328 amino acid protein. The gene encoding OR2AJ1 maps to human chromosome 1. RECOMMENDED SECONDARY REAGENTS REFERENCES To ensure optimal results, the following support (secondary) reagents are recommended: 1) Western Blotting: use donkey anti-goat IgG-HRP: sc-2020 1. Malnic, B., Hirono, J., Sato, T. and Buck, L.B. 1999. Combinatorial receptor (dilution range: 1:2000-1:100,000) or Cruz Marker™ compatible donkey codes for odors. Cell 96: 713-723. anti- goat IgG-HRP: sc-2033 (dilution range: 1:2000-1:5000), Cruz Marker™ 2.
    [Show full text]
  • An Evolutionary Based Strategy for Predicting Rational Mutations in G Protein-Coupled Receptors
    Ecology and Evolutionary Biology 2021; 6(3): 53-77 http://www.sciencepublishinggroup.com/j/eeb doi: 10.11648/j.eeb.20210603.11 ISSN: 2575-3789 (Print); ISSN: 2575-3762 (Online) An Evolutionary Based Strategy for Predicting Rational Mutations in G Protein-Coupled Receptors Miguel Angel Fuertes*, Carlos Alonso Department of Microbiology, Centre for Molecular Biology “Severo Ochoa”, Spanish National Research Council and Autonomous University, Madrid, Spain Email address: *Corresponding author To cite this article: Miguel Angel Fuertes, Carlos Alonso. An Evolutionary Based Strategy for Predicting Rational Mutations in G Protein-Coupled Receptors. Ecology and Evolutionary Biology. Vol. 6, No. 3, 2021, pp. 53-77. doi: 10.11648/j.eeb.20210603.11 Received: April 24, 2021; Accepted: May 11, 2021; Published: July 13, 2021 Abstract: Capturing conserved patterns in genes and proteins is important for inferring phenotype prediction and evolutionary analysis. The study is focused on the conserved patterns of the G protein-coupled receptors, an important superfamily of receptors. Olfactory receptors represent more than 2% of our genome and constitute the largest family of G protein-coupled receptors, a key class of drug targets. As no crystallographic structures are available, mechanistic studies rely on the use of molecular dynamic modelling combined with site-directed mutagenesis data. In this paper, we hypothesized that human-mouse orthologs coding for G protein-coupled receptors maintain, at speciation events, shared compositional structures independent, to some extent, of their percent identity as reveals a method based in the categorization of nucleotide triplets by their gross composition. The data support the consistency of the hypothesis, showing in ortholog G protein-coupled receptors the presence of emergent shared compositional structures preserved at speciation events.
    [Show full text]
  • Gnomad Lof Supplement
    1 gnomAD supplement gnomAD supplement 1 Data processing 4 Alignment and read processing 4 Variant Calling 4 Coverage information 5 Data processing 5 Sample QC 7 Hard filters 7 Supplementary Table 1 | Sample counts before and after hard and release filters 8 Supplementary Table 2 | Counts by data type and hard filter 9 Platform imputation for exomes 9 Supplementary Table 3 | Exome platform assignments 10 Supplementary Table 4 | Confusion matrix for exome samples with Known platform labels 11 Relatedness filters 11 Supplementary Table 5 | Pair counts by degree of relatedness 12 Supplementary Table 6 | Sample counts by relatedness status 13 Population and subpopulation inference 13 Supplementary Figure 1 | Continental ancestry principal components. 14 Supplementary Table 7 | Population and subpopulation counts 16 Population- and platform-specific filters 16 Supplementary Table 8 | Summary of outliers per population and platform grouping 17 Finalizing samples in the gnomAD v2.1 release 18 Supplementary Table 9 | Sample counts by filtering stage 18 Supplementary Table 10 | Sample counts for genomes and exomes in gnomAD subsets 19 Variant QC 20 Hard filters 20 Random Forest model 20 Features 21 Supplementary Table 11 | Features used in final random forest model 21 Training 22 Supplementary Table 12 | Random forest training examples 22 Evaluation and threshold selection 22 Final variant counts 24 Supplementary Table 13 | Variant counts by filtering status 25 Comparison of whole-exome and whole-genome coverage in coding regions 25 Variant annotation 30 Frequency and context annotation 30 2 Functional annotation 31 Supplementary Table 14 | Variants observed by category in 125,748 exomes 32 Supplementary Figure 5 | Percent observed by methylation.
    [Show full text]
  • Amino Acid Sequences Directed Against Cxcr4 And
    (19) TZZ ¥¥_T (11) EP 2 285 833 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07K 16/28 (2006.01) A61K 39/395 (2006.01) 17.12.2014 Bulletin 2014/51 A61P 31/18 (2006.01) A61P 35/00 (2006.01) (21) Application number: 09745851.7 (86) International application number: PCT/EP2009/056026 (22) Date of filing: 18.05.2009 (87) International publication number: WO 2009/138519 (19.11.2009 Gazette 2009/47) (54) AMINO ACID SEQUENCES DIRECTED AGAINST CXCR4 AND OTHER GPCRs AND COMPOUNDS COMPRISING THE SAME GEGEN CXCR4 UND ANDERE GPCR GERICHTETE AMINOSÄURESEQUENZEN SOWIE VERBINDUNGEN DAMIT SÉQUENCES D’ACIDES AMINÉS DIRIGÉES CONTRE CXCR4 ET AUTRES GPCR ET COMPOSÉS RENFERMANT CES DERNIÈRES (84) Designated Contracting States: (74) Representative: Hoffmann Eitle AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Patent- und Rechtsanwälte PartmbB HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL Arabellastraße 30 PT RO SE SI SK TR 81925 München (DE) (30) Priority: 16.05.2008 US 53847 P (56) References cited: 02.10.2008 US 102142 P EP-A- 1 316 801 WO-A-99/50461 WO-A-03/050531 WO-A-03/066830 (43) Date of publication of application: WO-A-2006/089141 WO-A-2007/051063 23.02.2011 Bulletin 2011/08 • VADAY GAYLE G ET AL: "CXCR4 and CXCL12 (73) Proprietor: Ablynx N.V. (SDF-1) in prostate cancer: inhibitory effects of 9052 Ghent-Zwijnaarde (BE) human single chain Fv antibodies" CLINICAL CANCER RESEARCH, THE AMERICAN (72) Inventors: ASSOCIATION FOR CANCER RESEARCH, US, • BLANCHETOT, Christophe vol.10, no.
    [Show full text]
  • University of Copenhagen, Grønnegårdsvej 7, 1870 Frederiksberg, Denmark Cesses Covered Were Related to Each Other
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Copenhagen University Research Information System Copy number variations and genome-wide associations reveal putative genes and metabolic pathways involved with feed conversion ratio in beef cattle Satana, Miguel Henrique de Almedia ; Junior, Gerson Antônio Oliveira ; Cesar, Aline Silva Mello; Freua, Mateus Castelani; Gomes, Rodrigo da Costra ; Silva, Saulo da Luz e ; Leme, Paulo Roberto; Fukumasu, Heidge; Carvalho, Minos Esperandio; Ventura, Ricardo Vierira; Coutinho, Luiz Lehmann; Kadarmideen, Haja; Ferraz, José Bento Sterman Published in: Journal of Applied Genetics DOI: 10.1007/s13353-016-0344-7 Publication date: 2016 Document license: Other Citation for published version (APA): Satana, M. H. D. A., Junior, G. A. O., Cesar, A. S. M., Freua, M. C., Gomes, R. D. C., Silva, S. D. L. E., ... Ferraz, J. B. S. (2016). Copy number variations and genome-wide associations reveal putative genes and metabolic pathways involved with feed conversion ratio in beef cattle. Journal of Applied Genetics, 57(4), 495- 504. https://doi.org/10.1007/s13353-016-0344-7 Download date: 08. apr.. 2020 J Appl Genetics DOI 10.1007/s13353-016-0344-7 ANIMAL GENETICS • ORIGINAL PAPER Copy number variations and genome-wide associations reveal putative genes and metabolic pathways involved with the feed conversion ratio in beef cattle Miguel Henrique de Almeida Santana1,2 & Gerson Antônio Oliveira Junior3 & Aline Silva Mello Cesar3 & Mateus Castelani Freua2 & Rodrigo da Costa Gomes4 & Saulo da Luz e Silva2 & Paulo Roberto Leme2 & Heidge Fukumasu2 & Minos Esperândio Carvalho2 & Ricardo Vieira Ventura2,5 & Luiz Lehmann Coutinho6 & Haja N.
    [Show full text]
  • Explorations in Olfactory Receptor Structure and Function by Jianghai
    Explorations in Olfactory Receptor Structure and Function by Jianghai Ho Department of Neurobiology Duke University Date:_______________________ Approved: ___________________________ Hiroaki Matsunami, Supervisor ___________________________ Jorg Grandl, Chair ___________________________ Marc Caron ___________________________ Sid Simon ___________________________ [Committee Member Name] Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Neurobiology in the Graduate School of Duke University 2014 ABSTRACT Explorations in Olfactory Receptor Structure and Function by Jianghai Ho Department of Neurobiology Duke University Date:_______________________ Approved: ___________________________ Hiroaki Matsunami, Supervisor ___________________________ Jorg Grandl, Chair ___________________________ Marc Caron ___________________________ Sid Simon ___________________________ [Committee Member Name] An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Neurobiology in the Graduate School of Duke University 2014 Copyright by Jianghai Ho 2014 Abstract Olfaction is one of the most primitive of our senses, and the olfactory receptors that mediate this very important chemical sense comprise the largest family of genes in the mammalian genome. It is therefore surprising that we understand so little of how olfactory receptors work. In particular we have a poor idea of what chemicals are detected by most of the olfactory receptors in the genome, and for those receptors which we have paired with ligands, we know relatively little about how the structure of these ligands can either activate or inhibit the activation of these receptors. Furthermore the large repertoire of olfactory receptors, which belong to the G protein coupled receptor (GPCR) superfamily, can serve as a model to contribute to our broader understanding of GPCR-ligand binding, especially since GPCRs are important pharmaceutical targets.
    [Show full text]
  • CNV Detection and Association Studies in the Brown Swiss Cattle Breed
    University of Milan Department of Veterinary Medicine Ph.D. Course in Veterinary and Animal Sciences Class 29 CNV detection and association studies in the Brown Swiss cattle breed Raphaëlle T.M.M. Prinsen R10464 – R35 Tutor: Prof. Alessandro Bagnato Ph.D. Coordinator: Prof. Fulvio Gandolfi Academic Year: 2016 Academic year: 2016 CNV detection and association studies in the Brown Swiss cattle breed Raphaëlle T.M.M. Prinsen 2 To Andrea, my beloved husband, who gave me endless love, support, encouragement and endurance to complete this hard work. … and to our little baby: you are the most beautiful gift I could ever imagine. 3 Contents Sintesi – Italiano ............................................................................... 7 Capitolo 1 ................................................................................................................................ 7 Capitolo 2 ................................................................................................................................ 8 Capitolo 3 ................................................................................................................................ 9 Abstract – English ........................................................................... 10 Chapter 1 .............................................................................................................................. 10 Chapter 2 .............................................................................................................................. 11 Chapter 3 .............................................................................................................................
    [Show full text]
  • Supplementary Methods
    doi: 10.1038/nature06162 SUPPLEMENTARY INFORMATION Supplementary Methods Cloning of human odorant receptors 423 human odorant receptors were cloned with sequence information from The Olfactory Receptor Database (http://senselab.med.yale.edu/senselab/ORDB/default.asp). Of these, 335 were predicted to encode functional receptors, 45 were predicted to encode pseudogenes, 29 were putative variant pairs of the same genes, and 14 were duplicates. We adopted the nomenclature proposed by Doron Lancet 1. OR7D4 and the six intact odorant receptor genes in the OR7D4 gene cluster (OR1M1, OR7G2, OR7G1, OR7G3, OR7D2, and OR7E24) were used for functional analyses. SNPs in these odorant receptors were identified from the NCBI dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP) or through genotyping. OR7D4 single nucleotide variants were generated by cloning the reference sequence from a subject or by inducing polymorphic SNPs by site-directed mutagenesis using overlap extension PCR. Single nucleotide and frameshift variants for the six intact odorant receptors in the same gene cluster as OR7D4 were generated by cloning the respective genes from the genomic DNA of each subject. The chimpanzee OR7D4 orthologue was amplified from chimpanzee genomic DNA (Coriell Cell Repositories). Odorant receptors that contain the first 20 amino acids of human rhodopsin tag 2 in pCI (Promega) were expressed in the Hana3A cell line along with a short form of mRTP1 called RTP1S, (M37 to the C-terminal end), which enhances functional expression of the odorant receptors 3. For experiments with untagged odorant receptors, OR7D4 RT and S84N variants without the Rho tag were cloned into pCI.
    [Show full text]
  • Supplementary Materials
    Web Extra Materials Tissue Core 3 µM Section Tissue Microarray Slide Supplementary Figure S1. Process of tissue microarray construction. Representative areas of the tumor were identified by a pathologist on H&E stained sections. Reference histological slides with the specific area marked by the pathologist were aligned with the respective donor block. The corresponding areas were marked on paraffin blocks and three parallel tissue cores were obtained per tumor to account for intratumoral heterogeneity. Tissue arrays were constructed by placing 1 mm diameter cores in recipient paraffin blocks using a tissue arrayer (Galileo TMA CK3500 Tissue Micro arrayer; ISETMA Software, Integrated System Engineering, Milan, Italy), and limited to 72 cores per recipient block. Then, consecutive sections (with a thickness of 3 μm) were cut from each TMA block, and mounted on microscope slides. Finally, the unstained slides were deparaffinized and rehydratedand using standard methods, and immunohistochemically assayed. 1 cancer Breast cancer Cervical cancer Colorectal cancer Endometrial Glioma cancer neck and Head cancer Liver cancer Lung Melanoma cancer Ovarian cancer Pancreatic cancer Prostate cancer Renal cancer Stomach cancer Testis cancer Thyroid cancer Urothelial ABCB1 0.6 0.3 4.6 0.6 2.7 0.2 7.8 0.3 0.2 0.2 2.3 1.5 7.1 0.9 0.5 0.8 0.3 ANO7 0.3 0.3 0.8 0.6 0.3 0.2 0.4 0.4 0.4 0.1 0.6 27 0.5 0.8 0.5 0.4 0.3 AQP5 0.4 1.9 0.1 53.8 2.4 0.2 0 1.7 0.3 21.3 20.8 0.2 0 3.9 1.8 4.5 0.1 ATP2B2 0 0 0 0.4 3.2 0 6.7 0 0 0.9 0 0 0.8 0 0 0 0 CD19 0.2 0.3 0.3 0.4
    [Show full text]
  • Application No. AU 2009212543 B2 (19) AUSTRALIAN PATENT OFFICE
    (12) STANDARD PATENT (11) Application No. AU 2009212543 B2 (19) AUSTRALIAN PATENT OFFICE (54) Title Use of microvesicles in diagnosis, prognosis and treatment of medical diseases and conditions (51) International Patent Classification(s) C12Q 1/68 (2006.01) (21) Application No: 2009212543 (22) Date of Filing: 2009.02.02 (87) WIPONo: WO09/100029 (30) Priority Data (31) Number (32) Date (33) Country 61/100,293 2008.09.26 US 61/025,536 2008.02.01 US (43) Publication Date: 2009.08.13 (44) Accepted Journal Date: 2015.07.09 (71) Applicant(s) The General Hospital Corporation (72) Inventor(s) Russo, Leileata M.;Brown, Dennis;Skog, Johan Karl Olov;Miranda, Kevin C.;Breakefield, Xandra O. (74) Agent / Attorney Pizzeys, PO Box 291, WODEN, ACT, 2606 (56) Related Art WO 2003/076603 A2 (ANOSYS INC.) 18 September 2003 US 2007/0104738 A1 (TATISCHEFF, I., et al.) 10 May 2007 US 2006/0116321 A1 (ROBBINS, P. D., et al.) 01 June 2006 WO 2007/103572 A2 (AETHLON MEDICAL, INC.) 13 September 2007 WO 2009/015357 A1 (UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION, INC.) 29 January 2009 # Baj-Krzyworzeka, M., et al. 2006. Cancer Immunology, Immunotherapy, vol. 55, pages 808-818. WO 2009/021322 A1 (THE ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING/MCGILL UNIVERSITY) 19 February 2009 WO 2009/036236 A1 (THE OHIO STATE UNIVERSITY RESEARCH FOUNDATION) 19 March 2009 WO 2005/121369 A2 (SOURCEPHARM, INC.) 22 December 2005 WO 2001/036601 A1 (CHIRON S.P.A.) 25 May 2001 WO 1994/022018 A1 (NYCOMED PHARMA A/S) 29 September 1994 CA 2543198 A1 (MIN, W-P and ICHIM, T.
    [Show full text]
  • High-Resolution Copy-Number Variation Map Reflects Human Olfactory Receptor Diversity and Evolution
    High-Resolution Copy-Number Variation Map Reflects Human Olfactory Receptor Diversity and Evolution Yehudit Hasin1., Tsviya Olender1., Miriam Khen1, Claudia Gonzaga-Jauregui1,2, Philip M. Kim3, Alexander Eckehart Urban4, Michael Snyder3,4, Mark B. Gerstein3,5,6, Doron Lancet1, Jan O. Korbel3,7* 1 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel, 2 Centro de Ciencias Geno´micas, Universidad Nacional Auto´noma de Me´xico, Cuernavaca, Morelos, Me´xico, 3 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America, 4 Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut, United States of America, 5 Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America, 6 Department of Computer Science, Yale University, New Haven, Connecticut, United States of America, 7 Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany Abstract Olfactory receptors (ORs), which are involved in odorant recognition, form the largest mammalian protein superfamily. The genomic content of OR genes is considerably reduced in humans, as reflected by the relatively small repertoire size and the high fraction (,55%) of human pseudogenes. Since several recent low-resolution surveys suggested that OR genomic loci are frequently affected by copy-number variants (CNVs), we hypothesized that CNVs may play an important role in the evolution of the human olfactory repertoire. We used high-resolution oligonucleotide tiling microarrays to detect CNVs across 851 OR gene and pseudogene loci. Examining genomic DNA from 25 individuals with ancestry from three populations, we identified 93 OR gene loci and 151 pseudogene loci affected by CNVs, generating a mosaic of OR dosages across persons.
    [Show full text]
  • University of Copenhagen, Grønnegårdsvej 7, 1870 Frederiksberg, Denmark Cesses Covered Were Related to Each Other
    Copy number variations and genome-wide associations reveal putative genes and metabolic pathways involved with feed conversion ratio in beef cattle Satana, Miguel Henrique de Almedia ; Junior, Gerson Antônio Oliveira ; Cesar, Aline Silva Mello; Freua, Mateus Castelani; Gomes, Rodrigo da Costra ; Silva, Saulo da Luz e ; Leme, Paulo Roberto; Fukumasu, Heidge; Carvalho, Minos Esperandio; Ventura, Ricardo Vierira; Coutinho, Luiz Lehmann; Kadarmideen, Haja; Ferraz, José Bento Sterman Published in: Journal of Applied Genetics DOI: 10.1007/s13353-016-0344-7 Publication date: 2016 Document license: Other Citation for published version (APA): Satana, M. H. D. A., Junior, G. A. O., Cesar, A. S. M., Freua, M. C., Gomes, R. D. C., Silva, S. D. L. E., Leme, P. R., Fukumasu, H., Carvalho, M. E., Ventura, R. V., Coutinho, L. L., Kadarmideen, H., & Ferraz, J. B. S. (2016). Copy number variations and genome-wide associations reveal putative genes and metabolic pathways involved with feed conversion ratio in beef cattle. Journal of Applied Genetics, 57(4), 495-504. https://doi.org/10.1007/s13353-016-0344-7 Download date: 25. Sep. 2021 J Appl Genetics DOI 10.1007/s13353-016-0344-7 ANIMAL GENETICS • ORIGINAL PAPER Copy number variations and genome-wide associations reveal putative genes and metabolic pathways involved with the feed conversion ratio in beef cattle Miguel Henrique de Almeida Santana1,2 & Gerson Antônio Oliveira Junior3 & Aline Silva Mello Cesar3 & Mateus Castelani Freua2 & Rodrigo da Costa Gomes4 & Saulo da Luz e Silva2 & Paulo Roberto Leme2 & Heidge Fukumasu2 & Minos Esperândio Carvalho2 & Ricardo Vieira Ventura2,5 & Luiz Lehmann Coutinho6 & Haja N. Kadarmideen1 & José Bento Sterman Ferraz2 Received: 29 September 2015 /Revised: 20 January 2016 /Accepted: 2 March 2016 # Institute of Plant Genetics, Polish Academy of Sciences, Poznan 2016 Abstract The use of genome-wide association results com- explained by each window.
    [Show full text]