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Methods and Compositions for the Treatment of Non-Small Cell Lung Cancer

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(19) TZZ_¥_T (11) EP 1 743 947 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12Q 1/68 (2006.01) C12N 15/12 (2006.01) 11.01.2012 Bulletin 2012/02 G01N 33/50 (2006.01) C12N 15/11 (2006.01) A61P 35/00 (2006.01) A61K 39/00 (2006.01) (21) Application number: 06022167.8 (22) Date of filing: 22.09.2003 (54) Methods and compositions for the treatment of non-small cell lung cancer Verfahren und Zusammensetzungen zur Behandlung von nichtkleinzelligem Lungenkrebs Méthodes et compositions pour le traitement du cancer du poumon "non à petites cellules" (84) Designated Contracting States: (60) Divisional application: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 10010306.8 / 2 264 185 HU IE IT LI LU MC NL PT RO SE SI SK TR 10010307.6 / 2 264 186 10010308.4 / 2 264 187 (30) Priority: 30.09.2002 US 414673 P 10010309.2 / 2 264 190 28.02.2003 US 451374 P 10010310.0 / 2 264 457 28.04.2003 US 466100 P 10010311.8 / 2 278 028 10010312.6 / 2 270 498 (43) Date of publication of application: 10010313.4 / 2 270 499 17.01.2007 Bulletin 2007/03 10010314.2 / 2 270 500 10010315.9 / 2 270 501 10010316.7 / 2 270 502 10010317.5 / 2 270 503 10010318.3 / 2 270 210 10010319.1 / 2 270 211 10010320.9 / 2 270 212 10010321.7 / 2 270 213 10010322.5 / 2 270 214 10010323.3 / 2 270 215 10010324.1 / 2 270 216 10010325.8 / 2 270 217 10010326.6 / 2 270 218 10010327.4 / 2 270 219 10010328.2 / 2 270 220 10010329.0 / 2 270 221 10010330.8 / 2 270 222 10010331.6 / 2 270 223 10010332.4 / 2 270 224 10010333.2 / 2 270 225 (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 03753941.8 / 1 551 998 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 743 947 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 743 947 B1 (73) Proprietor: Oncotherapy Science, Inc. • VIRTANEN C ET AL: "Integrated classification of Kawasaki-shi lung tumors and cell lines by expression Kanagawa 213-0012 (JP) profiling" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL (72) Inventors: ACADEMY OF SCIENCE, WASHINGTON, DC, US, • Nakamura, Yusuke vol. 99, no. 19, 17 September 2002 (2002-09-17), Yokohama-shi, pages 12357-12362, XP002904255 ISSN: Kanagawa 225-0011 (JP) 0027-8424 • Daigo, Yataro • COJOCARU GADY ET AL: "Transcriptional Yokohama-shi, profiling of non-small cell lung cancer using Kanagawa 222-0031 (JP) oligonucleotide microarrays." CHEST. MAR • Nakatsuru, Shuichi 2002, vol. 121, no. 3 Suppl, March 2002 (2002-03), Saitama-shi, page 44S, XP002349234 ISSN: 0012-3692 Saitama 338-0002 (JP) • IGNEY FREDERIK H ET AL: "Immune escape of tumors: Apoptosis resistance and tumor (74) Representative: Vossius & Partner counterattack", JOURNAL OF LEUKOCYTE Siebertstrasse 4 BIOLOGY, vol. 71, no. 6, June 2002 (2002-06), 81675 München (DE) pages 907-920, ISSN: 0741-5400 • YOSHITAKE YOSHIHIRO ET AL: "Proliferation (56) References cited: potential-related protein, an ideal esophageal WO-A-01/72775 WO-A2-2006/090810 cancer antigen for immunotherapy, identified using complementary DNA microarray • WANG T ET AL: "IDENTIFICATION OF GENES analysis.", CLINICAL CANCER RESEARCH : AN DIFFERENTIALLY OVER-EXPRESSED IN LUNG OFFICIAL JOURNAL OF THE AMERICAN SQUAMOUS CELL CARCINOMA USING ASSOCIATION FOR CANCER RESEARCH 1 OCT COMBINATION OF CDNA SUBTRACTION AND 2004, vol. 10, no. 19, 1 October 2004 (2004-10-01), MICROARRAY ANALYSIS" ONCOGENE, pages 6437-6448, ISSN: 1078-0432 BASINGSTOKE, HANTS, GB, vol. 19, no. 12, 16 • ISHIKAWA N ET AL: "Characterization of SEZ6L2 March 2000 (2000-03-16), pages 1519-1528, cell-surface protein as a novel prognostic marker XP000951444 ISSN: 0950-9232 for lung cancer", CANCER SCIENCE, JAPANESE • YANIV K ET AL: "The involvement of a conserved CANCER ASSOCIATION, TOKYO, JP LNKD- DOI: family of RNA binding proteins in embryonic 10.1111/J.1349-7006.2006.00258.X, vol. 97, no. 8, development and carcinogenesis" GENE: AN 1 August 2006 (2006-08-01) , pages 737-745, INTERNATIONAL JOURNAL ON GENES AND XP002460091, ISSN: 1347-9032 GENOMES, ELSEVIER, AMSTERDAM, NL, vol. • GABRILOVICH DMITRY ET AL: "Tumor escape 287, no. 1-2, 3 April 2002 (2002-04-03), pages from immune response: mechanisms and targets 49-54, XP002271204 ISSN: 0378-1119 of activity", CURRENT DRUG TARGETS, • FUJII TAKESHI ET AL: "A preliminary BENTHAM SCIENCE PUBLISHER, US, vol. 4, no. transcriptome map of non-small cell lung 7, 1 October 2003 (2003-10-01) , pages 525-536, cancer." CANCER RESEARCH. 15 JUN 2002, vol. XP008135851, ISSN: 1389-4501 62, no. 12, 15 June 2002 (2002-06-15), pages 3340-3346, XP002349233 ISSN: 0008-5472 • WIGLE DENNIS A ET AL: "Molecular profiling of non-small cell lung cancer and correlation with disease-free survival" CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, BALTIMORE, MD, US, vol. 62, no. 11, 1 June 2002 (2002-06-01), pages 3005-3008, XP002271233 ISSN: 0008-5472 2 EP 1 743 947 B1 Description [0001] The present application is related to USSN 60/414,673, filed September 30, 2002, USSN 60/451,3 74, filed February 28, 2003, and USSN 60/466,100, filed April 28,2003. 5 Technical Field [0002] The present invention relates to the field of biological science, more specifically to the field of cancer research. In particular, the invention discloses methods of diagnosing non-small cell lung cancers and genes with elevated or 10 decreased expression in such cancerous cells. Background Art [0003] Lung cancer is one of the most commonly fatal humans tumors. Many genetic alterations associated with the 15 development and progression of lung cancer has been reported. Although genetic changes can aid prognostic efforts and predictions of metastatic risk or response to certain treatments, information about a single or a limited number of molecular markers generally fails to provide satisfactory results for clinical diagnosis of non-small cell lung cancer (NSCLC)(Mitsudomi et al., Clin Cancer Res 6: 4055-63 (2000); Niklinski et aL, Lung Cancer. 34 Suppl 2: S53-8 (200 1); Watine, Brnj 320: 379-80 (2000)). Non-small cell lung cancer (NSCLC) is by far the most common form, accounting 20 for nearly 80% of lung tumors (Society, A. C. Cancer Facts and Figures 2001, 2001.). The overall 10-year survival rate remains as low as 10% despite recent advances in multi-modality therapy, because the majority of NSCLCs are not diagnosed until advanced stages (Fry, W. A, Philips, J. L., and Menck, H. R. Ten year survey of lung cancer treatment and survival in hospitals in the United Stated a national cancer data base report, Cancer. 86: 1867-76., 1999.). Although chemotherapy regimens based on platinum are considered the reference standards for treatment of NSCLC, those 25 drugs are able to extend survival of patients with advanced NSCLC only about six weeks (Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group, Bmj. 311: 899-909., 1995.). Numerous targeted therapies are being investigated for this disease, including tyrosine kinase inhibitors, but so far promising results have been achieved in only a limited number of patients and some recipients suffer severe adverse reactions (Kris M, N. R., Herbst RS A phase II trial of 30 ZD1839 (’Iressa’) in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum and docetaxel- based regimens (IDEAL 2)., Proc Am Soc Clin Oncol. 21: 292a(A1166), 2002). [0004] cDNA microarray technologies have enabled to obtain comprehensive profiles of gene expression in normal and malignant cells, and compare the gene expression in malignant and corresponding normal cells (Okabe et al., Cancer Res 61:2129-37 (2001); Kitahara et al., Cancer Res 61: 3544-9 (2001); Lin et al., Oncogene 21:4120-8 (2002); 35 Hasegawa et al., Cancer Res 62:7012-7 (2002)). This approach enables to disclose the complex nature of cancer cells, and helps to understand the mechanism of carcinogenesis. Identification of genes that are deregulated in tumors can lead to more precise and accurate diagnosis of individual cancers, and to develop novel therapeutic targets (Bienz and Clevers, Cell 103:311-20 (2000)). To disclose mechanisms underlying tumors from a genome-wide point of view, and discover target molecules for diagnosis and development of novel therapeutic drugs, the present inventors have been 40 analyzing the expression profiles of tumor cells using a cDNA microarray of 23040 genes (Okabe et al., Cancer Res 61: 2129-37 (2001); Kitahara et al., Cancer Res 61:3544-9 (2001); Lin et al., Oncogene 21:4120-8 (2002); Hasegawa et al., Cancer Res 62:7012-7 (2002)). [0005] Studies designed to reveal mechanisms of carcinogenesis have already facilitated identification of molecular targets for anti-tumor agents. For example, inhibitors of farnexyltransferase (FTIs) which were originally developed to 45 inhibit the growth-signaling pathway related to Ras, whose activation depends on posttranslational famesylation, has been effective in treating Ras-dependent tumors in animal models (He et al., Cell 99:335-45 (1999)). Clinical trials on human using a combination or anti-cancer drugs and anti-HER2 monoclonal antibody, trastuzumab, have been conducted to antagonize the proto-oncogene receptor HER2/neu; and have been achieving improved clinical response and overall survival of breast-cancer patients (Lin et al., Cancer Res 61:6345-9 (2001)).
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    Hanna Joleen 2018 Thesis.Pdf

    Validation of an In Vitro Mutagenicity Assay Based on Pulmonary Epithelial Cells from the Transgenic MutaMouse: Intra-Laboratory Variability and Metabolic Competence By: Joleen Hanna, B.Sc. A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science In Biology Specializing in Chemical and Environmental Toxicology Supervisor: Dr. Paul White (University of Ottawa) Thesis Advisory Committee: Dr. Frances Pick (University of Ottawa) Dr. Iain Lambert (Carleton University) University of Ottawa Ontario, Canada March 2018 © Joleen Hanna, Ottawa, Canada, 2018 Abstract: Genetic toxicity tests used for regulatory screening must be rigorously validated to ensure accuracy, reliability and relevance. Hence, prior to establishment of an internationally- accepted test guideline, a new assay must undergo multi-stage validation. An in vitro transgene mutagenicity assay based on an immortalized cell line derived from MutaMouse lung (i.e., FE1 cells) is currently undergoing formal validation. FE1 cells retain a lacZ transgene in a λgt10 shuttle vector that can be retrieved for scoring of chemically-induced mutations. This work contributes to validation of the in vitro transgene (lacZ) mutagenicity assay in MutaMouse FE1 cells. More specifically, the work includes an intra-laboratory variability study, and a follow-up study to assess the endogenous metabolic capacity of FE1 cells. The former is essential to determine assay reliability, the latter to define the range of chemicals that can be reliably screened without an exogenous metabolic activation mixture (i.e., rat liver S9). The intra- laboratory variability assessment revealed minimal variability; thus, assay reproducibility can be deemed acceptable. Assessment of metabolic capacity involved exposure of FE1 cells to 5 known mutagens, and subsequent assessment of changes in the expression of genes involved in xenobiotic metabolism; induced transgene mutant frequency (±S9) was assessed in parallel.
  • Bioinformatics Analysis of Potential Key Genes and Mechanisms in Type 2 Diabetes Mellitus Basavaraj Vastrad1, Chanabasayya Vastrad*2

    Bioinformatics Analysis of Potential Key Genes and Mechanisms in Type 2 Diabetes Mellitus Basavaraj Vastrad1, Chanabasayya Vastrad*2

    bioRxiv preprint doi: https://doi.org/10.1101/2021.03.28.437386; this version posted March 29, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus Basavaraj Vastrad1, Chanabasayya Vastrad*2 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karnataka, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2021.03.28.437386; this version posted March 29, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Type 2 diabetes mellitus (T2DM) is etiologically related to metabolic disorder. The aim of our study was to screen out candidate genes of T2DM and to elucidate the underlying molecular mechanisms by bioinformatics methods. Expression profiling by high throughput sequencing data of GSE154126 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between T2DM and normal control were identified. And then, functional enrichment analyses of gene ontology (GO) and REACTOME pathway analysis was performed. Protein–protein interaction (PPI) network and module analyses were performed based on the DEGs. Additionally, potential miRNAs of hub genes were predicted by miRNet database . Transcription factors (TFs) of hub genes were detected by NetworkAnalyst database. Further, validations were performed by receiver operating characteristic curve (ROC) analysis and real-time polymerase chain reaction (RT-PCR).