Pharming (genetics)

Source: Wikipedia, the free encyclopedia.

Pharming, a

pharmaceutical", refers to the use of genetic engineering to insert genes that code for useful pharmaceuticals into host animals or plants that would otherwise not express those genes, thus creating a genetically modified organism (GMO).[1][2] Pharming is also known as molecular farming, molecular pharming[3] or biopharming.[4]

The products of pharming are recombinant proteins or their metabolic products. Recombinant proteins are most commonly produced using bacteria or yeast in a bioreactor, but pharming offers the advantage to the producer that it does not require expensive infrastructure, and production capacity can be quickly scaled to meet demand, at greatly reduced cost.[5]

History

The first recombinant plant-derived protein (PDP) was human serum albumin, initially produced in 1990 in transgenic tobacco and potato plants.[6] Open field growing trials of these crops began in the United States in 1992 and have taken place every year since. While the United States Department of Agriculture has approved planting of pharma crops in every state, most testing has taken place in Hawaii, Nebraska, Iowa, and Wisconsin.[7]

In the early 2000s, the pharming industry was robust. Proof of concept has been established for the production of many

non-Hodgkin's lymphoma.[9]

However, in late 2002, just as ProdiGene was ramping up production of trypsin for commercial launch

volunteer plants (left over from the prior harvest) of one of their GM corn products were harvested with the conventional soybean crop later planted in that field.[11][unreliable source?] ProdiGene was fined $250,000 and ordered by the USDA to pay over $3 million in cleanup costs. This raised a furor and set the pharming field back, dramatically.[5] Many companies went bankrupt as companies faced difficulties getting permits for field trials and investors fled.[5] In reaction, APHIS introduced more strict regulations for pharming field trials in the US in 2003.[12] In 2005, Anheuser-Busch threatened to boycott rice grown in Missouri because of plans by Ventria Bioscience
to grow pharm rice in the state. A compromise was reached, but Ventria withdrew its permit to plant in Missouri due to unrelated circumstances.

The industry has slowly recovered, by focusing on pharming in simple plants grown in

Newcastle disease, produced in plant cell culture – the first plant-produced vaccine approved in the U.S.[14][15]

In mammals

Historical development

Milk is presently the most mature system to produce recombinant proteins from transgenic organisms. Blood, egg white, seminal plasma, and urine are other theoretically possible systems, but all have drawbacks. Blood, for instance, as of 2012 cannot store high levels of stable recombinant proteins, and biologically active proteins in blood may alter the health of the animals.[16] Expression in the milk of a mammal, such as a cow, sheep, or goat, is a common application, as milk production is plentiful and purification from milk is relatively easy. Hamsters and rabbits have also been used in preliminary studies because of their faster breeding.

One approach to this technology is the creation of a transgenic mammal that can produce the biopharmaceutical in its milk (or blood or urine). Once an animal is produced, typically using the pronuclear microinjection method, it becomes efficacious to use cloning technology to create additional offspring that carry the favorable modified genome.

goats. Marketing permission was granted by the European Medicines Agency in August 2006.[19]

Patentability issues

As indicated above, some mammals typically used for food production (such as goats, sheep, pigs, and cows) have been modified to produce non-food products, a practice sometimes called pharming. Use of genetically modified goats has been approved by the FDA and EMA to produce

biopharmaceuticals
.

The patentability of such biopharmaceuticals and their process of manufacture is uncertain. Probably, the biopharmaceuticals themselves so made are unpatentable, assuming that they are chemically identical to the preexisting drugs that they imitate. Several 19th century

United States Supreme Court decisions hold that a previously known natural product manufactured by artificial means cannot be patented.[21] An argument can be made for the patentability of the process for manufacturing a biopharmaceutical, however, because genetically modifying animals so that they will produce the drug is dissimilar to previous methods of manufacture; moreover, one Supreme Court decision seems to hold open that possibility.[22]

On the other hand, it has been suggested that the recent Supreme Court decision in

Mayo v. Prometheus[23] may create a problem in that, in accordance with the ruling in that case, "it may be said that such and such genes manufacture this protein in the same way they always did in a mammal, they produce the same product, and the genetic modification technology used is conventional, so that the steps of the process 'add nothing to the laws of nature that is not already present.[24]
If the argument prevailed in court, the process would also be ineligible for patent protection. This issue has not yet been decided in the courts.

In plants

Plant-made pharmaceuticals (PMPs), also referred to as pharming, is a sub-sector of the

proteins and associated molecules such as peptides and secondary metabolites. The proteins and molecules can then be harvested and used to produce pharmaceuticals.[25]

potatoes, tobacco, flax or safflower.[26] Tobacco has been a highly popular choice of organism for the expression of transgenes, as it is easily transformed, produces abundant tissues, and survives well in vitro and in greenhouses.[27] The advantage of rice and flax is that they are self-pollinating, and thus gene flow issues (see below) are avoided. However, human error could still result in modified crops entering the food supply. Using a minor crop such as safflower or tobacco avoids the greater political pressures and risk to the food supply involved with using staple crops such as beans or rice. Expression of proteins in plant cell or hairy root cultures also minimizes risk of gene transfer, but at a higher cost of production. Sterile hybrids may also be used for the bioconfinement of transgenic plants, although stable lines cannot be established.[28] Grain crops are sometimes chosen for pharming because protein products targeted to the endosperm of cereals have been shown to have high heat stability. This characteristic makes them an appealing target for the production of edible vaccines, as viral coat proteins stored in grains do not require cold storage the way many vaccines currently do. Maintaining a temperature controlled supply chain of vaccines is often difficult when delivering vaccines to developing countries.[29]

Most commonly, plant transformation is carried out using

CaMV35S), a powerful constitutive promoter for driving expression in plants.[30] Localization signals may be attached to the protein of interest to cause accumulation to occur in a specific sub-cellular location, such as chloroplasts or vacuoles. This is done in order to improve yields, simplify purification, or so that the protein folds properly.[31][32] Recently, the inclusion of antisense genes in expression cassettes has been shown to have potential for improving the plant pharming process. Researchers in Japan transformed rice with an antisense SPK gene, which disrupts starch accumulation in rice seeds, so that products would accumulate in a watery sap that is easier to purify.[33]

Recently, several non-crop plants such as the

bioreactors (as opposed to being grown in fields), secrete the transformed proteins into the growth medium and, thus, substantially reduce the burden of protein purification in preparing recombinant proteins for medical use.[34][35][36] In addition, both species can be engineered to cause secretion of proteins with human patterns of glycosylation, an improvement over conventional plant gene-expression systems.[37][38] Biolex Therapeutics developed a duckweed-based expression platform; it sold the business to Synthon and declared bankruptcy in 2012.[citation needed
]

Additionally, an Israeli company, Protalix, has developed a method to produce therapeutics in cultured transgenic carrot or tobacco cells.[39] Protalix and its partner, Pfizer, received FDA approval to market its drug, taliglucerase alfa (Elelyso), as a treatment for Gaucher's disease, in 2012.[40]

Regulation

Main article:
Regulation of the release of genetic modified organisms

The regulation of genetic engineering concerns the approaches taken by governments to assess and manage the risks associated with the development and release of genetically modified crops. There are differences in the regulation of GM crops – including those used for pharming – between countries, with some of the most marked differences occurring between the USA and Europe. Regulation varies in a given country depending on the intended use of the products of the genetic engineering. For example, a crop not intended for food use is generally not reviewed by authorities responsible for food safety.

Controversy

Main article: Genetically modified food controversies

There are controversies around GMOs generally on several levels, including whether making them is ethical, issues concerning intellectual property and market dynamics; environmental effects of GM crops; and GM crops' role in industrial agricultural more generally. There are also specific controversies around pharming.

Advantages

pharmacologically active proteins, there are no proteins in plants that are similar to human proteins. On the other hand, plants are still sufficiently closely related to animals and humans that they are able to correctly process and configure both animal and human proteins. Their seeds and fruits also provide sterile packaging containers for the valuable therapeutics and guarantee a certain storage life.[41]

protein synthesis.[6][41] These proteins are currently being produced in animal cell cultures, but the resulting product is often prohibitively expensive for many patients. For these reasons, science has been exploring other options for producing proteins of therapeutic value.[2][8][15]

These pharmaceutical crops could become extremely beneficial in developing countries. The World Health Organization estimates that nearly 3 million people die each year from vaccine preventable disease, mostly in Africa. Diseases such as measles and hepatitis lead to deaths in countries where the people cannot afford the high costs of vaccines, but pharm crops could help solve this problem.[42]

Disadvantages

While molecular farming is one application of

drought resistance or pesticide resistance, are not believed to affect the food itself. Other GM foods in development, such as fruits designed to ripen faster or grow larger, are believed not to affect humans any differently from non-GM varieties.[2][15][41][43]

In contrast, molecular farming is not intended for crops destined for the food chain. It produces plants that contain physiologically active compounds that accumulate in the plant’s tissues. Considerable attention is focused, therefore, on the restraint and caution necessary to protect both consumer health and environmental biodiversity.[2]

The fact that the plants are used to produce drugs alarms

GMO corn accidentally ended up in commercial food products. Activists also are concerned about the power of business. According to the Canadian Food Inspection Agency, in a recent report, says that U.S. demand alone for biotech pharmaceuticals is expanding at 13 percent annually and to reach a market value of $28.6 billion in 2004.[43] Pharming is expected to be worth $100 billion globally by 2020.[44]

List of originators (companies and universities), research projects and products

Please note that this list is by no means exhaustive.

  • USDA Center for Veterinary Biologics[45] Dow never intended to market the vaccine.[46] "'Dow Agrosciences used the animal vaccine as an example to completely run through the process. A new platform needs to be approved, which can be difficult when authorities get in contact with it for the first time', explains the plant physiologist Stefan Schillberg, head of the Molecular Biology Division at the Fraunhofer Institute for Molecular Biology and Applied Ecology Aachen."[47]
  • Fraunhofer Institute for Molecular Biology and Applied Ecology, with sites in Germany, the US, and Chile[48] is the lead institute of the Pharma Planta consortium of 33 partner organizations from 12 European countries and South Africa, funded by the European Commission.[49] Pharma Planta is developing systems for plant production of proteins in greenhouses in the European regulatory framework.[50] It is collaborating on biosimilars with Plantform and PharmaPraxis (see below).[51]
  • antithrombin III
    in goat milk
  • GTC Biotherapeutics – ATryn (recombinant human antithrombin) in goat milk[52]
  • Icon Genetics produces therapeutics in transiently infected Nicotiana benthamiana (relative of tobacco) plants in greenhouses in Halle, Germany
    non-Hodgkin's lymphoma.[54]
  • Iowa State University – immunogenic protein from E. coli bacteria in pollen-free corn as a potential vaccine against E. coli for animals and humans[55][56][57]
  • Kentucky Bioprocessing took over Large Scale Biology's facilities in Owensboro, Kentucky, and offers contract biomanufacturing services in tobacco plants, grown in greenhouses or in open fields.[58]
  • COVID-19 virus,[60] initiating a Phase I clinical trial in July 2020.[61][62]
  • PharmaPraxis – Developing biosimilars in collaboration with PlantForm (see below) and Fraunhofer.[51]
  • Pharming –
    C1 inhibitor, human collagen 1, fibrinogen (with American Red Cross), and lactoferrin in cow milk[63] The intellectual property behind the fibrinogen project was acquired from PPL Therapeutics when PPL went bankrupt in 2004.[64]
  • Phyton Biotech uses plant cell culture systems to manufacture
    taxanes, including paclitaxel and docetaxel[65]
  • Planet Biotechnology –
    antibodies against Streptococcus mutans, antibodies against doxorubicin, and ICAM 1 receptor in tobacco[66]
  • PlantForm Corporation – biosimilar trastuzumab in tobacco[67] – It is developing biosimilars in collaboration with PharmaPraxis (see above) and Fraunhofer.[51]
  • ProdiGene – was developing several proteins, including aprotinin, trypsin and a veterinary TGE vaccine in corn. Was in process of launching trypsin product in 2002[10] when later that year its field test crops contaminated conventional crops.[11] Unable to pay the $3 million cost of the cleanup, it was purchased by International Oilseed Distributors in 2003[68][69] International Oilseed Distributors is controlled by Harry H. Stine,[70] who owns one of the biggest soybeans genetics companies in the US.[71] ProdiGene's maize-produced trypsin, with the trademark TrypZean[72] is currently sold by Sigma-Aldritch as a research reagent.[73][74][75]
  • Beta carotene in rice (this is "Golden rice 2"), which Syngenta has donated to the Golden Rice Project[76]
  • Arizona State University – Hepatitis C vaccine in potatoes[77][78]
  • Ventria Bioscience – lactoferrin and lysozyme in rice
  • Washington State University – lactoferrin and lysozyme in barley[79][80]
  • European COST Action on Molecular Farming – COST Action FA0804 on Molecular Farming provides a pan-European coordination centre, connecting academic and government institutions and companies from 23 countries.[81] The aim of the Action is to advance the field by encouraging scientific interactions, providing expert opinion and encouraging commercial development of new products. The COST Action also provides grants allowing young scientists to visit participating laboratories across Europe for scientific training.
  • Ebola virus disease. Two Americans who had been infected in Liberia were reported to be improving with the drug. ZMapp was made using antibodies produced by GM tobacco plants.[82][83]

Projects known to be abandoned

  • Agragen, in collaboration with University of Alberta – docosahexaenoic acid and human serum albumin in flax[84][85][86]
  • Chlorogen, Inc. –
    chloroplasts. Went out of business in 2007.[87]
  • Dow Chemical Company made a deal with Sunol Molecular in 2003 to develop antibodies against tissue factor in plants and in mammalian cell culture and to compare them.[88] In 2005 Sunol sold all its tissue factor antagonists to Tanox,[89][90] which in turn was bought by Genentech in 2003. Genentech licensed the tissue factor program to Altor in 2008[91] Altor is itself a spinout from Sunol.[92] The product under development, ALT-836, formerly known as TNX-832 and Sunol-cH36,[93] is not the plant-produced antibody, but rather is a mammalian antibody, more specifically, a chimeric antibody produced in a hybridoma.[94]
  • Epicyte – spermicidal antibodies in corn[95] Epicyte was purchased by Biolex in 2004 at which time Epicyte's portfolio was described as "focused on the discovery and development of human monoclonal antibody products as treatments for a wide range of infectious and inflammatory diseases."[96]
  • Large Scale Biology Corporation (LSBC) (bankrupt)
    G-CSF, and Hepatitis B vaccine antigens in tobacco. In 2004, LSBC announced an agreement with Sigma-Aldritch under which LSB would produce recombinant aprotinin in plants of the tobacco family and Sigma-Aldrich would commercially distribute LSBC's recombinant product to its customers in the R&D, cell culture and manufacturing markets.[98] As of October 2012 SIgma still has the protein in stock.[99]
  • Meristem Therapeutics –
    protease inhibitors in tobacco. Liquidated in 2008.[100]
  • Novoplant GmgH – therapeutic proteins in tobacco and feed peas.[101] Conducted field trials in US of feed peas for pigs that produced anti-bacterial antibodies.[102] Former CSO is now with another company;[103] appears that Novoplant is out of business.
  • Monsanto Company
    – abandoned development of pharmaceutical producing corn
  • PPL Therapeutics –
    sheep milk. This is the company that created Dolly the Sheep, the first cloned animal. Went bankrupt in 2004. Assets were acquired by Pharming[64] and an investment group including University of Pittsburgh Medical Center.[104]
  • SemBioSys – insulin in safflower. In May 2012, SemBioSys terminated its operations.[105]

See also

References

  1. World Wide Words
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  2. ^ a b c d Norris, Sonya (4 July 2005). "Molecular pharming". Library of Parliament. Parliament of Canada. PRB 05-09E. Archived from the original on May 7, 2010. Retrieved 2008-09-11.
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  10. ^ a b "ProdiGene Launches First Large Scale-Up Manufacturing of Recombinant Protein From Plant System" (Press release). ProdiGene. February 13, 2002. Retrieved March 8, 2013.
  11. ^ a b News of contamination
  12. ^ Biotechnology Regulatory Services Factsheet [Internet]: US Department of Agriculture; c2006. Available from: http://www.aphis.usda.gov/publications/biotechnology/content/printable_version/BRS_FS_pharmaceutical_02-06.pdf Archived 2012-07-03 at the Wayback Machine
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  18. ^ Staff (2008) FDA Approves First Human Biologic Produced by GE Animals US Food and Drug Administration, from the FDA Veterinarian Newsletter 2008 Volume XXIII, No VI, Retrieved 10 December 2012
  19. ^ "Go-ahead for 'pharmed' goat drug". BBC News. June 2, 2006. Retrieved 2006-10-25.
  20. ^ Andre Pollack for The New York Times. February 6, 2009 F.D.A. Approves Drug From Gene-Altered Goats
  21. ^ Richard H. Stern. Mayo v Prometheus: No Patents on Conventional Implementations of Natural Principles and Fundamental Truths, [2012] Eur. Intell. Prop. Rev. 502, 517. See Cochrane v. Badische Anili11 & Soda Fabrik, 111 U.S. 293, 311 (1884) (holding invalid claim to artificially made plant dye; "the product itself could not be patented, even though it was a product made artificially for the first time"); American Wood-Paper Co. v. Fibre Disintegrating Co., 90 U.S. 566, 596 (1874) (holding invalid claim to artificially manufactured paper-pulp because "whatever may be said of their process for obtaining it, the product was in no sense new").
  22. ^ The American Wood-Paper case invalidated the product patent but left open the patentability of the process, saying "whatever may be said of their process for obtaining it...." 90 U.S. at 596.
  23. ^ Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. __, 132 S. Ct. 1289 (2012).
  24. Alice v. CLS Bank
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  39. ^ Protalix website – technology platform Archived October 27, 2012, at the Wayback Machine
  40. ^ Gali Weinreb and Koby Yeshayahou for Globes May 2, 2012. FDA approves Protalix Gaucher treatment Archived May 29, 2013, at the Wayback Machine
  41. ^ a b c "Molecular Farming – Plant Bioreactors". BioPro. Archived from the original on 2011-07-18. Retrieved 2008-09-13.
  42. ISBN 9780801473685.[page needed
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  43. ^ a b c Mandel, Charles (2001-11-06). "Molecular Farming Under Fire". wired. Retrieved 2008-09-13.
  44. ^ "Protein Products for Future Global Good". molecularfarming.com. Retrieved 2008-09-11.
  45. ^ Retrieved on 15 May 2007
  46. ^ Margret Engelhard, Kristin Hagen, Felix Thiele (eds). (2007) Pharming A New Branch of Biotechnology [1]
  47. ^ Farming for Pharma
  48. ^ Fraunhofer website
  49. ^ Pharma Planta website
  50. ^ FAQ page
  51. ^ a b c Brennan, Zachary. Brazilian JV looks to tap plant-based manufacturing system for biosimilars. BioPharma-Reporter.com, 23-Jul-2014.
  52. ^ GTC website
  53. ^ Press release on opening Halle facility
  54. ^ a b Icon press release on clinical trial launch
  55. ^ Iowa State Ag School 2006 Newsletter
  56. ^ APHIS approval
  57. ^ "Iowa State plant scientists tweak their biopharmaceutical corn research project". Archived from the original on 2015-06-02. Retrieved 2012-10-06.
  58. ^ Kentucky Bioprocessing website
  59. ^ Vezina, Louis-P.; D'Aoust, Marc Andre; Landry, Nathalie; Couture, Manon M.J.; Charland, Nathalie; Barbeau, Brigitte; Sheldon, Andrew J. (2011). "Plants As an Innovative and Accelerated Vaccine-Manufacturing Solution". BioPharm International Supplements. 24 (5): s27–30.
  60. ^ St. Philip, Elizabeth; Favaro, Avis; MacLeod, Meredith (2020-07-14). "The hunt for a vaccine: Canadian company begins human testing of COVID-19 candidate". CTV News. Retrieved 2020-07-14.
  61. ^ Vishwadha Chander (2020-07-14). "Canada's Medicago begins human trials of plant-based COVID-19 vaccine". National Post. Reuters. Retrieved 2020-07-14.
  62. ^ "Safety, Tolerability and Immunogenicity of a Coronavirus-Like Particle COVID-19 Vaccine in Adults Aged 18-55 Years". ClinicalTrials.gov. Retrieved 14 July 2020.
  63. ^ Company website
  64. ^ a b Press on Pharming Purchase of PPL assets
  65. ^ Phyton Biotech Official Website
  66. ^ Company website
  67. ^ Company website
  68. ^ Press release from internet archive
  69. ^ Bloomberg BusinessWeek Profile
  70. ^ "Stocks". 2 November 2023.[dead link]
  71. ^ Stine Seeds Website
  72. ^ Trademark listing
  73. ^ SIgma Info Sheet
  74. ^ Ray, Kevin; Jalili, Pegah R. (2011). "Characterization of TrypZean: a Plant-Based Alternative to Bovine-Derived Trypsin (Peer-Reviewed)". BioPharm International. 24 (10): 44–8.
  75. ^ Sigma Catalog
  76. ^ FAQ page
  77. ^ "Charles Arntzen | School of Life Sciences".
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  79. ^ "NEPA Decision Summary for Permit #10-047-102r" (PDF). Animal and Plant Health Inspection Service. March 10, 2010.
  80. ^ Wettstein lab webpage
  81. ^ COST Action FA0804 Official Website
  82. ^ Ward, Andrew (8 August 2014) Biotech groups face ethical dilemmas in race for Ebola Cure, Financial Times, Page 4, Internet article retrieved 8 August 2014
  83. ^ Langreth, Robert, et al (5 August 2014) Ebola Drug Made From Tobacco Plant Saves U.S. Aid Workers Bloomberg News, Retrieved 8 August 2014
  84. ^ Published PCT Application
  85. ^ CEO Sam Huttenbauer testified before Congress in 2005 about their GM flax efforts Testimony
  86. ^ Web search on October 6, 2012, found no website for this company and found that executives are all with other companies.
  87. ^ Bloomberg BusinessWeek Profile
  88. ^ Plant production for cancer protein Sept 22, 2003
  89. ^ Press Release
  90. ^ Purchase contract
  91. ^ Press Release
  92. ^ Altor website
  93. ^ Clinical trial number NCT00879606 for "Anti-TF Antibody (ALT-836) to Treat Septic Patients With Acute Lung Injury or Acute Respiratory Distress Syndrome" at ClinicalTrials.gov
  94. PMID 20062929
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  95. ^ "GM corn set to stop man spreading his seed". The Guardian. 2001-09-09. Archived from the original on 2023-06-03.
  96. ^ Trelys press release
  97. Sacramento Business Journal
    . Retrieved 2007-05-10.
  98. ^ Biomanufacturing Press Release
  99. ^ Sigma catalog Aprotinin
  100. ^ History of bankrupt biotech companies
  101. ^ Cordis entry on Novoplant
  102. ^ APHIS approval
  103. ^ Kiprijanov biography
  104. ^ UPMC buys PPL assets
  105. ^ Press release May 15, 2012: SemBioSys Announces First Quarter Results and Provides Update on Activities

Further reading

  • Biotech firm puts off rice crop here But company says it plans to sow next year. St. Louis Post-Dispatch. April 29, 2005. Pg. A3.
  • Biotech potato provides hepatitis vaccine. The Atlanta Journal-Constitution. February 15, 2005. Pg. 3A.
  • Biotechnology Venture Hits Unexpected Snags. The New York Times. November 23, 2001. Pg. 5.
  • Canadian scientists make insulin from plants: 'Bio-pharming' poised to meet huge diabetes demand at less cost. The Ottawa Citizen. February 27, 2005. Pg. A1.
  • GM corn set to stop man spreading his seed. The Observer. September 9, 2001. Pg. 1.
  • Pharming plans transgenic first. Financial Times. May 3, 2005. Pg. 18.
  • USDA says bio-crop safeguards are tighter ProdiGene is back in Nebraska with test plot. Omaha World Herald. June 2, 2004 Pg. 01D
  • Release Permits for Pharmaceuticals, Industrials, Value Added Proteins for Human Consumption, or for Phytoremediation Granted or Pending by APHIS as of March 29, 2006. [2]

External links

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