The Possibility of Systematic Research

Total Page:16

File Type:pdf, Size:1020Kb

The Possibility of Systematic Research The Possibility of Systematic Research Fraud Targeting Under-Studied Human Genes: Causes, Consequences, and Potential Solutions Jennifer Byrne, Natalie Grima, Amanda Capes-Davis, Cyril Labbé To cite this version: Jennifer Byrne, Natalie Grima, Amanda Capes-Davis, Cyril Labbé. The Possibility of Systematic Re- search Fraud Targeting Under-Studied Human Genes: Causes, Consequences, and Potential Solutions. Biomarker Insights, 2019, 14, pp.117727191982916. 10.1177/1177271919829162. hal-02057728 HAL Id: hal-02057728 https://hal.archives-ouvertes.fr/hal-02057728 Submitted on 5 Mar 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. BMI0010.1177/1177271919829162Biomarker InsightsByrne et al 829162review-article2019 Biomarker Insights The Possibility of Systematic Research Fraud Targeting Volume 14: 1–12 © The Author(s) 2019 Under-Studied Human Genes: Causes, Consequences, Article reuse guidelines: sagepub.com/journals-permissions and Potential Solutions DOI:https://doi.org/10.1177/1177271919829162 10.1177/1177271919829162 Jennifer A Byrne1,2 , Natalie Grima1 , Amanda Capes-Davis3 and Cyril Labbé4 1Molecular Oncology Laboratory, Children’s Cancer Research Unit, Kids Research, The Children’s Hospital at Westmead, Westmead, NSW, Australia. 2Discipline of Child and Adolescent Health, The University of Sydney and The Children’s Hospital at Westmead, Westmead, NSW, Australia. 3CellBank Australia, Children’s Medical Research Institute and The University of Sydney, Westmead, NSW, Australia. 4Univ Grenoble Alpes, CNRS, Grenoble INP, LIG, Grenoble, France. ABSTRACT: A major reason for biomarker failure is the selection of candidate biomarkers based on inaccurate or incorrect published results. Incorrect research results leading to the selection of unproductive biomarker candidates are largely considered to stem from unintentional research errors. The additional possibility that biomarker research may be actively misdirected by research fraud has been given comparatively little consideration. This review discusses what we believe to be a new threat to biomarker research, namely, the possible systematic production of fraudulent gene knockdown studies that target under-studied human genes. We describe how fraudulent papers may be produced in series by paper mills using what we have described as a ‘theme and variations’ model, which could also be considered a form of salami slicing. We describe features of these single-gene knockdown publications that may allow them to evade detection by journal editors, peer reviewers, and readers. We then propose a number of approaches to facilitate their detection, including improved awareness of the features of publications constructed in series, broader requirements to post submitted manuscripts to preprint servers, and the use of semi-automated literature screening tools. These approaches may collectively improve the detection of fraudulent studies that might otherwise impede future biomarker research. KEYWORDS: Biomarkers, cancer, gene knockdown techniques, research fraud, paper mill, salami publication, under-studied gene RECEIVED: October 10, 2018. ACCEPTED: January 8, 2019. DECLaratiON OF CONFLictiNG INTEREsts: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this TYPE: Review article. FUNDING: The author(s) disclosed receipt of the following financial support for the research, authorship, and/ or publication of this article: This work is supported by the CORRESPONDING AUTHOR: Jennifer A Byrne, Molecular Oncology Laboratory, funding from the Post-Truth Initiative, a University of Sydney Research Excellence Initiative Children’s Cancer Research Unit, Kids Research, The Children’s Hospital at Westmead, (SREI 2020) (to J.A.B.) and from the US Office of Research Integrity Project Grant Locked Bag 4001, Westmead, NSW 2145, Australia. ORIIR180038-01-00 (to J.A.B. and C.L.). This work was supported by donations to the Email: [email protected] Children’s Cancer Research Unit of the Children’s Hospital at Westmead. Introduction where it is becoming increasingly apparent that molecular driv- Biomarkers in human health research ers may not always be obvious from the cancer phenotype. Biomarkers can predict patient survival,1,2 and responses to Biomarkers represent a type of Holy Grail in research. The con- treatment,1–3 with a subset of biomarkers representing so-called cept that single or groups of analytes can illuminate and inform companion diagnostics used to assign patients to molecularly complex biological and disease processes continues to inspire 2 targeted treatments. Biomarkers can also enable disease moni- countless researchers and their supporting institutions and inves- 1,2 toring, allowing disease progression to be detected earlier and tors. Biomarkers that can be measured reliably at low cost in therefore treated more effectively. accessible biospecimens have played significant roles in improv- ing human health.1 Many biomarkers now guide routine medi- Challenges in cancer biomarker research cal diagnoses through standardised testing processes that can continue to be refined and improved through ongoing research. Quality biomarker research relies on several key factors, includ- New biomarkers continue to be sought, particularly in the ing the selection of plausible candidate biomarkers, the availa- field of cancer.1–3 The increasing molecular complexity of cancer bility of appropriate reagents and techniques with which to sub-types, the costs of treatments and the periods of time during investigate these candidate biomarkers, and appropriate cohorts which patients can undergo treatment, and post-treatment mon- of fit-for-purpose biospecimens from informative and relevant itoring, all provide numerous opportunities for reliable biomark- populations in which to test these biomarkers.1-4 The search ers to improve patient outcomes and/or reduce treatment cost for cancer biomarkers has, however, been plagued by problems and complexity.1–3 Because of the cost of cancer treatments and that have meant that outcomes from this field have not always the long periods during which patients may be treated, different met their expected promise.1,3-6 Some reasons for biomarker types of biomarkers are required.1–3 Biomarkers can enable dis- failure lie in the nature of cancer biology itself. Cancer is rarely ease diagnosis,1,2 particularly in the era of personalised medicine the result of a single gene, protein, or cellular pathway, but Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Biomarker Insights Figure 1. Five phases of biomarker development, shown as the biomarker research pipeline, adapted from Pepe et al.9 The number of biomarker candidates within the pipeline (shown above the phase diagram) progressively reduces as candidate biomarkers are sequentially analysed, and a proportion of candidates are discarded. At the same time, the resources required to advance each candidate progressively increase (shown below the phase diagram). The selection of unproductive candidates at phase 1 may prevent more productive candidates from entering the pipeline. instead involves many potential driver genes working in con- researchers may integrate the results of high-throughput stud- cert to produce complex, interwoven, and sometimes unstable ies with results from targeted analyses of the function of the phenotypes.2,7 As such, it may be difficult to identify single or gene or protein in question (Figure 2). These targeted studies small numbers of analytes whose measurement accurately may have examined the effects of overexpressing the gene and/ reflects very complex composite phenotypes.7 It can be even or of knocking down or inhibiting its function in cancer cell more difficult for single biomarkers to outperform existing lines and/or non-transformed control cell types. Multiple stud- gold standard descriptors such as tumour stage and grade, ies commonly suggesting that a candidate gene drives cancer which represent the combined action of many individual bio- phenotypes, either in a single cancer type or in different cancer logical factors that have been operating over time periods rang- types, could increase the priority of such a biomarker candidate ing from weeks to decades. (Figure 2). This may favour the selection of candidates sup- ported by multiple lines of experimental evidence for further Selection of new candidate cancer biomarkers analysis to the possible exclusion of other candidates lacking such experimental evidence (Figure 2). A fundamental component of precision medicine and bio- marker research is the selection of plausible
Recommended publications
  • Tpd52l2 (NM 025482) Mouse Tagged ORF Clone – MR202509
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for MR202509 Tpd52l2 (NM_025482) Mouse Tagged ORF Clone Product data: Product Type: Expression Plasmids Product Name: Tpd52l2 (NM_025482) Mouse Tagged ORF Clone Tag: Myc-DDK Symbol: Tpd52l2 Synonyms: 2810411G23Rik; AU016537; C86069; D54 Vector: pCMV6-Entry (PS100001) E. coli Selection: Kanamycin (25 ug/mL) Cell Selection: Neomycin ORF Nucleotide >MR202509 ORF sequence Sequence: Red=Cloning site Blue=ORF Green=Tags(s) TTTTGTAATACGACTCACTATAGGGCGGCCGGGAATTCGTCGACTGGATCCGGTACCGAGGAGATCTGCC GCCGCGATCGCC ATGGACTCTGCTAGCCAAGATATCAACCTGAATTCTCCTAACAAAGGTGTGCTGTCTGACTTTATGACTG ACGTCCCTGTTGACCCAGGTGTGGTCCACCGGACTCCAGTTGTAGAAGGCCTGACAGAGGGGGAGGAAGA AGAGCTTCGGGCTGAGCTTGCTAAGGTGGAAGAAGAAATTGTCACTCTGCGCCAGGTGCTGGCAGCCAAA GAGAGGCACTGTGGAGAGCTGAAAAGGAGGCTGGGCCTCTCCACATTAGGGGAGCTGAAGCAGAACCTGT CTAGGAGCTGGCATGATGTGCAGGTCTCTACTGCCTATGTGAAAACGTCTGAGAAACTTGGAGAGTGGAA TGAGAAAGTGACGCAGTCTGACCTCTACAAGAAGACTCAAGAAACTCTTTCACAGGCTGGACAGAAAACA TCAGCTGCCCTGTCCACCATGGGCTCTGCCATCAGCAGGAAGCTTGGAGACATGAGCAGCTACTCCATCC GCCACTCGATAAGTATGCCTGTCATGAGGAACTCAGCCACCTTCAAGTCATTTGAAGACCGAGTGGGGAC CATAAAGTCTAAGGTTGTGGGTGGCAGAGAGAATGGCAGCGATAACCTCCCTCCCTCTCCTGGAAGTGGT GACCAGACATTGCCGGATCATGCGCCTTTC ACGCGTACGCGGCCGCTCGAGCAGAAACTCATCTCAGAAGAGGATCTGGCAGCAAATGATATCCTGGATT ACAAGGATGACGACGATAAGGTTTAA This product is to be used for laboratory only. Not for diagnostic or therapeutic use.
    [Show full text]
  • Identification of Tumor-Associated Cassette Exons in Human Cancer
    Valletti et al. Molecular Cancer 2010, 9:230 http://www.molecular-cancer.com/content/9/1/230 RESEARCH Open Access Identification of tumor-associated cassette exons in human cancer through EST-based computational prediction and experimental validation Alessio Valletti1†, Anna Anselmo2†, Marina Mangiulli1, Ilenia Boria1, Flavio Mignone3, Giuseppe Merla4, Vincenzo D’Angelo5, Apollonia Tullo6, Elisabetta Sbisà6, Anna Maria D’Erchia1, Graziano Pesole1,7* Abstract Background: Many evidences report that alternative splicing, the mechanism which produces mRNAs and proteins with different structures and functions from the same gene, is altered in cancer cells. Thus, the identification and characterization of cancer-specific splice variants may give large impulse to the discovery of novel diagnostic and prognostic tumour biomarkers, as well as of new targets for more selective and effective therapies. Results: We present here a genome-wide analysis of the alternative splicing pattern of human genes through a computational analysis of normal and cancer-specific ESTs from seventeen anatomical groups, using data available in AspicDB, a database resource for the analysis of alternative splicing in human. By using a statistical methodology, normal and cancer-specific genes, splice sites and cassette exons were predicted in silico. The condition association of some of the novel normal/tumoral cassette exons was experimentally verified by RT-qPCR assays in the same anatomical system where they were predicted. Remarkably, the presence in vivo of the predicted alternative transcripts, specific for the nervous system, was confirmed in patients affected by glioblastoma. Conclusion: This study presents a novel computational methodology for the identification of tumor-associated transcript variants to be used as cancer molecular biomarkers, provides its experimental validation, and reports specific biomarkers for glioblastoma.
    [Show full text]
  • Supplementary Materials
    Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2009/0297536A1 Chin Et Al
    US 20090297536A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0297536A1 Chin et al. (43) Pub. Date: Dec. 3, 2009 (54) COMPOSITIONS, KITS, AND METHODS FOR Related U.S. Application Data IDENTIFICATION, ASSESSMENT, (60) Provisional application No. 60/575,795, filed on May PREVENTION AND THERAPY OF CANCER 28, 2004, provisional application No. 60/580,337, filed on Jun. 15, 2004. (75) Inventors: Lynda Chin, Brookline, MA (US); Publication Classification Cameron W. Brennan, New York, NY (US); Ronald A. DePinho, (51) Int. Cl. Brookline, MA (US); Andrew J. A 6LX 39/395 (2006.01) Aguirre, Boston, MA (US) CI2O I/68 (2006.01) C40B 30/00 (2006.01) AOIK 67/00 (2006.01) Correspondence Address: A 6LX 3L/7052 (2006.01) FOLEY HOAG, LLP A638/02 (2006.01) PATENT GROUP, WORLD TRADE CENTER A638/16 (2006.01) WEST C07K I4/00 (2006.01) 155 SEAPORT BLVD C7H 2L/00 (2006.01) BOSTON, MA 02110 (US) C07K 6/00 (2006.01) A6IP35/00 (2006.01) (73) Assignee: Dana-Farber Cancer Institute, (52) U.S. Cl. ................ 424/172.1; 435/6:506/7; 800/10: Inc., Boston, MA (US) 424/183.1; 424/178.1: 514/44 A: 514/2: 514/12: 530/350:536/23.1; 530/389.1 (21) Appl. No.: 11/597,825 (57) ABSTRACT The invention relates to compositions, kits, and methods for (22) PCT Filed: May 27, 2005 detecting, characterizing, preventing, and treating human cancer. A variety of chromosomal regions (MCRs) and mark (86). PCT No.: PCT/US05/18850 ers corresponding thereto, are provided, wherein alterations in the copy number of one or more of the MCRs and/or S371 (c)(1), alterations in the amount, structure, and/or activity of one or (2), (4) Date: Jun.
    [Show full text]
  • The DNA Sequence and Comparative Analysis of Human Chromosome 20
    articles The DNA sequence and comparative analysis of human chromosome 20 P. Deloukas, L. H. Matthews, J. Ashurst, J. Burton, J. G. R. Gilbert, M. Jones, G. Stavrides, J. P. Almeida, A. K. Babbage, C. L. Bagguley, J. Bailey, K. F. Barlow, K. N. Bates, L. M. Beard, D. M. Beare, O. P. Beasley, C. P. Bird, S. E. Blakey, A. M. Bridgeman, A. J. Brown, D. Buck, W. Burrill, A. P. Butler, C. Carder, N. P. Carter, J. C. Chapman, M. Clamp, G. Clark, L. N. Clark, S. Y. Clark, C. M. Clee, S. Clegg, V. E. Cobley, R. E. Collier, R. Connor, N. R. Corby, A. Coulson, G. J. Coville, R. Deadman, P. Dhami, M. Dunn, A. G. Ellington, J. A. Frankland, A. Fraser, L. French, P. Garner, D. V. Grafham, C. Grif®ths, M. N. D. Grif®ths, R. Gwilliam, R. E. Hall, S. Hammond, J. L. Harley, P. D. Heath, S. Ho, J. L. Holden, P. J. Howden, E. Huckle, A. R. Hunt, S. E. Hunt, K. Jekosch, C. M. Johnson, D. Johnson, M. P. Kay, A. M. Kimberley, A. King, A. Knights, G. K. Laird, S. Lawlor, M. H. Lehvaslaiho, M. Leversha, C. Lloyd, D. M. Lloyd, J. D. Lovell, V. L. Marsh, S. L. Martin, L. J. McConnachie, K. McLay, A. A. McMurray, S. Milne, D. Mistry, M. J. F. Moore, J. C. Mullikin, T. Nickerson, K. Oliver, A. Parker, R. Patel, T. A. V. Pearce, A. I. Peck, B. J. C. T. Phillimore, S. R. Prathalingam, R. W. Plumb, H. Ramsay, C. M.
    [Show full text]
  • Genotype–Phenotype Correlations to Aid in the Prognosis Of
    European Journal of Human Genetics (2007) 15, 446–452 & 2007 Nature Publishing Group All rights reserved 1018-4813/07 $30.00 www.nature.com/ejhg ARTICLE Genotype–phenotype correlations to aid in the prognosis of individuals with uncommon 20q13.33 subtelomere deletions: a collaborative study on behalf of the ‘association des Cytoge´ne´ticiens de langue Franc¸aise’ Myle`ne Be´ri-Deixheimer1, Marie-Jose´ Gregoire1, Annick Toutain2, Kare`ne Brochet1, Sylvain Briault2, Jean-Luc Schaff3, Bruno Leheup4 and Philippe Jonveaux*,1 1Laboratoire de Ge´ne´tique, EA 4002, CHU, Nancy-University, France; 2Service de Ge´ne´tique, Hoˆpital Bretonneau, Tours, France; 3Service de neurologie, CHU, Nancy-Univeristy, France; 4Service de me´decine infantile et ge´ne´tique clinique, CHU, Nancy-Univeristy, France The identification of subtelomeric rearrangements as a cause of mental retardation has made a considerable contribution to diagnosing patients with mental retardation. It is remarkable that for certain subtelomeric regions, deletions have hardly ever been reported so far. All the laboratories from the ‘Association des Cytoge´ne´ticiens de Langue Franc¸aise’ were surveyed for cases where an abnormality of the subtelomere FISH analysis had been ascertained. Among 1511 cases referred owing to unexplained mental retardation, 115 (7.6%) patients showed a clinically significant subtelomeric abnormality. We report the clinical features and the molecular cytogenetic delineation of isolated de novo deletions on 20q13.33 in two cases. Detailed mapping was performed by micro-array CGH in one patient and confirmed by FISH in the two patients. We compare our data with the only three patients reported in the literature.
    [Show full text]
  • D Isease Models & Mechanisms DMM a Ccepted Manuscript
    © 2014. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 Full title: 2 Histopathology Reveals Correlative and Unique Phenotypes in a High Throughput Mouse Phenotyping 3 Screen 4 Short title: 5 Histopathology Adds Value to a High Throughput Mouse Phenotyping Screen 6 Authors: 1,2,4* 3 3 3 3 7 Hibret A. Adissu , Jeanne Estabel , David Sunter , Elizabeth Tuck , Yvette Hooks , Damian M 3 3 3 3 1,2,4 8 Carragher , Kay Clarke , Natasha A. Karp , Sanger Mouse Genetics Project , Susan Newbigging , 1 1,2 3‡ 1,2,4‡ 9 Nora Jones , Lily Morikawa , Jacqui K. White , Colin McKerlie 10 Affiliations: Accepted manuscript Accepted 1 11 Centre for Modeling Human Disease, Toronto Centre for Phenogenomics, 25 Orde Street, Toronto, 12 ON, Canada, M5T 3H7 DMM 2 13 Physiology & Experimental Medicine Research Program, The Hospital for Sick Children, 555 University 14 Avenue, Toronto, ON, Canada, M5G 1X8 3 15 Mouse Genetics Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, 16 Cambridge, CB10 1SA, UK 4 17 Department of Laboratory Medicine & Pathobiology, Faculty of Medicine, University of Toronto, 18 Toronto, ON, Canada, M5S 1A8 19 *Correspondence to Hibret A. Adissu, Centre for Modeling Human Disease, Toronto Centre for Disease Models & Mechanisms 20 21 Phenogenomics, 25 Orde Street, Toronto, ON, Canada, M5T 3H7; [email protected] ‡ 22 Authors contributed equally 23 24 Keywords: 25 Histopathology, High Throughput Phenotyping, Mouse, Pathology 26 1 DMM Advance Online Articles.
    [Show full text]
  • Striking Similarities Between Publications from China Describing Single Gene Knockdown Experiments in Human Cancer Cell Lines
    Scientometrics DOI 10.1007/s11192-016-2209-6 Striking similarities between publications from China describing single gene knockdown experiments in human cancer cell lines Jennifer A. Byrne1,2 Cyril Labbé3 [email protected] [email protected] Abstract Comparing 5 publications from China that described knockdowns of the human TPD52L2 gene in human cancer cell lines identified unexpected similarities between these publications, flaws in experimental design, and mismatches between some described experiments and the reported results. Following communications with journal editors, two of these TPD52L2 publications have been retracted. One retraction notice stated that while the authors claimed that the data were original, the experiments had been out-sourced to a biotechnology company. Using search engine queries, automatic text-analysis, different similarity measures, and further visual inspection, we identified 48 examples of highly similar papers describing single gene knockdowns in 1–2 human cancer cell lines that were all published by investigators from China. The incorrect use of a particular TPD52L2 shRNA sequence as a negative or non-targeting control was identified in 30/48 (63%) of these publications, using a combination of Google Scholar searches and visual inspection. Overall, these results suggest that some publications describing the effects of single gene knockdowns in human cancer cell lines may include the results of experiments that were not performed by the authors. This has serious implications for the validity
    [Show full text]
  • W O 2019/079360 a L 25 April 2019 (25.04.2019) W 1P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date W O 2019/079360 A l 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: (72) Inventors; and G01N 33/48 (2006.01) G01N 33/53 (2006.01) (71) Applicants: KEAN, Leslie [US/US]; c/o 818 Stewart St, Suite 603, Seattle, Washington 98101 (US). COLONNA, (21) International Application Number: Lucrezia [US/US]; c/o 818 Stewart St, Suite 603, Seattle, PCT/US2018/056166 Washington 98101 (US). CARROLL, Shaina [US/US]; (22) International Filing Date: c/o 77 Massachusetts Avenue, Cambridge, Massachusetts 16 October 2018 (16. 10.2018) 02139 (US). (25) Filing Language: English (72) Inventors: SHALEK, Alexander K.; c/o 77 Massachu¬ setts Avenue, Cambridge, Massachusetts 02139 (US). ZIE- (26) Publication Language: English GLER, Carly; c/o 77 Massachusetts Avenue, Cambridge, (30) Priority Data: Massachusetts 02139 (US). 62/573,015 16 October 2017 (16. 10.2017) US (74) Agent: SCHER, Michael B. et al.; Johnson, Marcou & (71) Applicants: MASSACHUSETTS INSTITUTE OF Isaacs, LLC, P.O. Bo 691, Hoschton, Georgia 30548 (US). TECHNOLOGY [US/US]; 77 Massachusetts Av¬ (81) Designated States (unless otherwise indicated, for every enue, Cambridge, Massachusetts 02139 (US). SEAT¬ kind of national protection available): AE, AG, AL, AM, TLE CHILDREN'S HOSPITAL DBA SEATTLE AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CHILDREN'S RESEARCH INSTITUTE [US/US]; 818 CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, Stewart St, Suite 603, Seattle, Washington 98101 (US).
    [Show full text]
  • Delayed Recruiting of TPD52 to Lipid Droplets
    www.nature.com/scientificreports OPEN Delayed recruiting of TPD52 to lipid droplets – evidence for a “second wave” of lipid droplet-associated Received: 10 November 2018 Accepted: 18 June 2019 proteins that respond to altered Published: xx xx xxxx lipid storage induced by Brefeldin A treatment Yuyan Chen 1,2, Sarah Frost1,2, Matloob Khushi3,4, Laurence C. Cantrill2,5, Hong Yu6, Jonathan W. Arthur3, Robert K. Bright7, Guy E. Groblewski8 & Jennifer A. Byrne 1,2 Tumor protein D52 (TPD52) is amplifed and overexpressed in breast and prostate cancers which are frequently characterised by dysregulated lipid storage and metabolism. TPD52 expression increases lipid storage in mouse 3T3 fbroblasts, and co-distributes with the Golgi marker GM130 and lipid droplets (LDs). We examined the efects of Brefeldin A (BFA), a fungal metabolite known to disrupt the Golgi structure, in TPD52-expressing 3T3 cells, and in human AU565 and HMC-1-8 breast cancer cells that endogenously express TPD52. Five-hour BFA treatment reduced median LD numbers, but increased LD sizes. TPD52 knockdown decreased both LD sizes and numbers, and blunted BFA’s efects on LD numbers. Following BFA treatment for 1–3 hours, TPD52 co-localised with the trans-Golgi network protein syntaxin 6, but after 5 hours BFA treatment, TPD52 showed increased co-localisation with LDs, which was disrupted by microtubule depolymerising agent nocodazole. BFA treatment also increased perilipin (PLIN) family protein PLIN3 but reduced PLIN2 detection at LDs in TPD52-expressing 3T3 cells, with PLIN3 recruitment to LDs preceding that of TPD52. An N-terminally deleted HA-TPD52 mutant (residues 40–184) almost exclusively targeted to LDs in both vehicle and BFA treated cells.
    [Show full text]
  • High-Density Array Comparative Genomic Hybridization Detects Novel Copy Number Alterations in Gastric Adenocarcinoma
    ANTICANCER RESEARCH 34: 6405-6416 (2014) High-density Array Comparative Genomic Hybridization Detects Novel Copy Number Alterations in Gastric Adenocarcinoma ALINE DAMASCENO SEABRA1,2*, TAÍSSA MAÍRA THOMAZ ARAÚJO1,2*, FERNANDO AUGUSTO RODRIGUES MELLO JUNIOR1,2, DIEGO DI FELIPE ÁVILA ALCÂNTARA1,2, AMANDA PAIVA DE BARROS1,2, PAULO PIMENTEL DE ASSUMPÇÃO2, RAQUEL CARVALHO MONTENEGRO1,2, ADRIANA COSTA GUIMARÃES1,2, SAMIA DEMACHKI2, ROMMEL MARIO RODRÍGUEZ BURBANO1,2 and ANDRÉ SALIM KHAYAT1,2 1Human Cytogenetics Laboratory and 2Oncology Research Center, Federal University of Pará, Belém Pará, Brazil Abstract. Aim: To investigate frequent quantitative alterations gastric cancer is the second most frequent cancer in men and of intestinal-type gastric adenocarcinoma. Materials and the third in women (4). The state of Pará has a high Methods: We analyzed genome-wide DNA copy numbers of 22 incidence of gastric adenocarcinoma and this disease is a samples and using CytoScan® HD Array. Results: We identified public health problem, since mortality rates are above the 22 gene alterations that to the best of our knowledge have not Brazilian average (5). been described for gastric cancer, including of v-erb-b2 avian This tumor can be classified into two histological types, erythroblastic leukemia viral oncogene homolog 4 (ERBB4), intestinal and diffuse, according to Laurén (4, 6, 7). The SRY (sex determining region Y)-box 6 (SOX6), regulator of intestinal type predominates in high-risk areas, such as telomere elongation helicase 1 (RTEL1) and UDP- Brazil, and arises from precursor lesions, whereas the diffuse Gal:betaGlcNAc beta 1,4- galactosyltransferase, polypeptide 5 type has a similar distribution in high- and low-risk areas and (B4GALT5).
    [Show full text]
  • Inbred Mouse Strains Expression in Primary Immunocytes Across
    Downloaded from http://www.jimmunol.org/ by guest on September 28, 2021 Daphne is online at: average * The Journal of Immunology published online 29 September 2014 from submission to initial decision 4 weeks from acceptance to publication Sara Mostafavi, Adriana Ortiz-Lopez, Molly A. Bogue, Kimie Hattori, Cristina Pop, Daphne Koller, Diane Mathis, Christophe Benoist, The Immunological Genome Consortium, David A. Blair, Michael L. Dustin, Susan A. Shinton, Richard R. Hardy, Tal Shay, Aviv Regev, Nadia Cohen, Patrick Brennan, Michael Brenner, Francis Kim, Tata Nageswara Rao, Amy Wagers, Tracy Heng, Jeffrey Ericson, Katherine Rothamel, Adriana Ortiz-Lopez, Diane Mathis, Christophe Benoist, Taras Kreslavsky, Anne Fletcher, Kutlu Elpek, Angelique Bellemare-Pelletier, Deepali Malhotra, Shannon Turley, Jennifer Miller, Brian Brown, Miriam Merad, Emmanuel L. Gautier, Claudia Jakubzick, Gwendalyn J. Randolph, Paul Monach, Adam J. Best, Jamie Knell, Ananda Goldrath, Vladimir Jojic, J Immunol http://www.jimmunol.org/content/early/2014/09/28/jimmun ol.1401280 Koller, David Laidlaw, Jim Collins, Roi Gazit, Derrick J. Rossi, Nidhi Malhotra, Katelyn Sylvia, Joonsoo Kang, Natalie A. Bezman, Joseph C. Sun, Gundula Min-Oo, Charlie C. Kim and Lewis L. Lanier Variation and Genetic Control of Gene Expression in Primary Immunocytes across Inbred Mouse Strains Submit online. Every submission reviewed by practicing scientists ? is published twice each month by http://jimmunol.org/subscription http://www.jimmunol.org/content/suppl/2014/09/28/jimmunol.140128 0.DCSupplemental Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc.
    [Show full text]