JP6663438B2 - 癌および皮膚病変の治療 - Google Patents
癌および皮膚病変の治療 Download PDFInfo
- Publication number
- JP6663438B2 JP6663438B2 JP2017540976A JP2017540976A JP6663438B2 JP 6663438 B2 JP6663438 B2 JP 6663438B2 JP 2017540976 A JP2017540976 A JP 2017540976A JP 2017540976 A JP2017540976 A JP 2017540976A JP 6663438 B2 JP6663438 B2 JP 6663438B2
- Authority
- JP
- Japan
- Prior art keywords
- hpv
- dose
- vaccine
- patient
- administering
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 206010028980 Neoplasm Diseases 0.000 title claims description 89
- 201000011510 cancer Diseases 0.000 title claims description 33
- 238000011282 treatment Methods 0.000 title claims description 29
- 206010040882 skin lesion Diseases 0.000 title description 8
- 231100000444 skin lesion Toxicity 0.000 title description 8
- 229960002566 papillomavirus vaccine Drugs 0.000 claims description 56
- 230000003902 lesion Effects 0.000 claims description 46
- 229960005486 vaccine Drugs 0.000 claims description 45
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 31
- 210000004027 cell Anatomy 0.000 claims description 29
- 108010008038 Synthetic Vaccines Proteins 0.000 claims description 28
- 229940124551 recombinant vaccine Drugs 0.000 claims description 28
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 23
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 22
- 108090000623 proteins and genes Proteins 0.000 claims description 22
- 102000004169 proteins and genes Human genes 0.000 claims description 22
- 206010004146 Basal cell carcinoma Diseases 0.000 claims description 19
- 201000001441 melanoma Diseases 0.000 claims description 15
- 229920001184 polypeptide Polymers 0.000 claims description 13
- 208000000260 Warts Diseases 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 230000007170 pathology Effects 0.000 claims description 12
- 201000010153 skin papilloma Diseases 0.000 claims description 12
- 206010059313 Anogenital warts Diseases 0.000 claims description 11
- 239000000427 antigen Substances 0.000 claims description 10
- 102000036639 antigens Human genes 0.000 claims description 10
- 108091007433 antigens Proteins 0.000 claims description 10
- 239000002671 adjuvant Substances 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- 230000003612 virological effect Effects 0.000 claims description 7
- 238000003745 diagnosis Methods 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 229940047091 other immunostimulants in atc Drugs 0.000 claims description 5
- 229960001438 immunostimulant agent Drugs 0.000 claims description 4
- 239000003022 immunostimulating agent Substances 0.000 claims description 4
- 230000003308 immunostimulating effect Effects 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 108010067390 Viral Proteins Proteins 0.000 claims 1
- 241000701806 Human papillomavirus Species 0.000 description 83
- 238000000034 method Methods 0.000 description 62
- 208000000453 Skin Neoplasms Diseases 0.000 description 32
- 201000000849 skin cancer Diseases 0.000 description 27
- 208000009608 Papillomavirus Infections Diseases 0.000 description 19
- 229940124897 Gardasil Drugs 0.000 description 13
- 229940021993 prophylactic vaccine Drugs 0.000 description 10
- 238000011200 topical administration Methods 0.000 description 5
- 210000004927 skin cell Anatomy 0.000 description 4
- 208000000907 Condylomata Acuminata Diseases 0.000 description 3
- 241000341655 Human papillomavirus type 16 Species 0.000 description 3
- 208000025009 anogenital human papillomavirus infection Diseases 0.000 description 3
- 201000004201 anogenital venereal wart Diseases 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 230000037451 immune surveillance Effects 0.000 description 3
- 229940021747 therapeutic vaccine Drugs 0.000 description 3
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000011256 aggressive treatment Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 241000282412 Homo Species 0.000 description 1
- 206010029098 Neoplasm skin Diseases 0.000 description 1
- 206010040844 Skin exfoliation Diseases 0.000 description 1
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000035618 desquamation Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- ZXQYGBMAQZUVMI-GCMPRSNUSA-N gamma-cyhalothrin Chemical compound CC1(C)[C@@H](\C=C(/Cl)C(F)(F)F)[C@H]1C(=O)O[C@H](C#N)C1=CC=CC(OC=2C=CC=CC=2)=C1 ZXQYGBMAQZUVMI-GCMPRSNUSA-N 0.000 description 1
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960005030 other vaccine in atc Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 230000037075 skin appearance Effects 0.000 description 1
- 230000036548 skin texture Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/20011—Papillomaviridae
- C12N2710/20034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/20011—Papillomaviridae
- C12N2710/20071—Demonstrated in vivo effect
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Virology (AREA)
- Microbiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biomedical Technology (AREA)
- Dermatology (AREA)
- Communicable Diseases (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201462068332P | 2014-10-24 | 2014-10-24 | |
| US62/068,332 | 2014-10-24 | ||
| PCT/US2015/057150 WO2016065281A1 (en) | 2014-10-24 | 2015-10-23 | Cancer and skin lesion treatment |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2017531699A JP2017531699A (ja) | 2017-10-26 |
| JP2017531699A5 JP2017531699A5 (OSRAM) | 2018-11-15 |
| JP6663438B2 true JP6663438B2 (ja) | 2020-03-11 |
Family
ID=55761638
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2017540976A Active JP6663438B2 (ja) | 2014-10-24 | 2015-10-23 | 癌および皮膚病変の治療 |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US10238729B2 (OSRAM) |
| EP (1) | EP3209676A4 (OSRAM) |
| JP (1) | JP6663438B2 (OSRAM) |
| KR (1) | KR102285401B1 (OSRAM) |
| CN (1) | CN107001430A (OSRAM) |
| AU (1) | AU2015335652B2 (OSRAM) |
| BR (1) | BR112017008280A2 (OSRAM) |
| CA (1) | CA2965498A1 (OSRAM) |
| CL (1) | CL2017001008A1 (OSRAM) |
| IL (1) | IL251825B2 (OSRAM) |
| MX (1) | MX395186B (OSRAM) |
| MY (1) | MY195018A (OSRAM) |
| PH (1) | PH12017500754A1 (OSRAM) |
| SG (1) | SG11201703262UA (OSRAM) |
| WO (1) | WO2016065281A1 (OSRAM) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2019506435A (ja) * | 2016-02-27 | 2019-03-07 | エイチピーブイヴァックス, リミテッド ライアビリティー カンパニー.Hpvvax, Llc. | ワクチンを使用して癌または皮膚病変を治療するための方法および組成物 |
Family Cites Families (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60126737T2 (de) * | 2001-03-23 | 2007-11-08 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Modifizierte HPV E6- und E7-Gene und -Proteine als Impfstoff |
| GB0110431D0 (en) * | 2001-04-27 | 2001-06-20 | Glaxosmithkline Biolog Sa | Novel compounds |
| US20060222656A1 (en) * | 2005-04-01 | 2006-10-05 | University Of Maryland, Baltimore | MAGE-A3/HPV 16 peptide vaccines for head and neck cancer |
| GB0206359D0 (en) * | 2002-03-18 | 2002-05-01 | Glaxosmithkline Biolog Sa | Viral antigens |
| GB0206360D0 (en) * | 2002-03-18 | 2002-05-01 | Glaxosmithkline Biolog Sa | Viral antigens |
| GB0222953D0 (en) * | 2002-10-03 | 2002-11-13 | Glaxo Group Ltd | Novel Compounds |
| CA2510457C (en) | 2002-12-20 | 2011-12-06 | Glaxosmithkline Biologicals S.A. | Hpv-16 and -18 l1 vlp vaccine |
| PL1758609T3 (pl) * | 2004-06-16 | 2013-02-28 | Glaxosmithkline Biologicals Sa | Szczepionka przeciw HPV16 i HPV18 oraz co najmniej jednemu HPV innego typu wybranemu spośród HPV 31, 45 lub 52 |
| US8399610B2 (en) | 2004-08-05 | 2013-03-19 | University College Cardiff Consultants Limited | HPV vaccine comprising peptides from host cell proteins |
| GB0417430D0 (en) | 2004-08-05 | 2004-09-08 | Uc3 | A novel HPV vaccine comprising peptides from host cell proteins |
| US7709010B2 (en) * | 2007-03-09 | 2010-05-04 | Merck Sharp & Dohme Corp. | Papillomavirus vaccine compositions |
| CN101530612A (zh) * | 2008-03-10 | 2009-09-16 | 北京康乐卫士生物技术有限公司 | 16型重组人乳头瘤病毒疫苗 |
| CN101530614A (zh) * | 2008-03-10 | 2009-09-16 | 北京康乐卫士生物技术有限公司 | 五价重组人乳头瘤病毒疫苗 |
| WO2009127988A1 (en) | 2008-04-16 | 2009-10-22 | Universite De Lausanne | Method and vaccine for optimizing the specific immune responses |
| CN107080833A (zh) * | 2009-04-10 | 2017-08-22 | 约翰·霍普金斯大学 | 作为广谱人类乳头状瘤病毒（hpv）疫苗的乳头状瘤病毒样颗粒（vlp） |
| US9724404B2 (en) * | 2009-04-13 | 2017-08-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | HPV particles and uses thereof |
| CN101890160B (zh) * | 2009-04-28 | 2014-06-18 | 北京康乐卫士生物技术有限公司 | 多价重组人乳头瘤病毒疫苗及其应用 |
| JP5758385B2 (ja) | 2009-06-19 | 2015-08-05 | アイジェン インコーポレーテッド | 子宮頸がんワクチン |
| US20120087937A1 (en) * | 2009-06-25 | 2012-04-12 | Brigitte Desiree Alberte Colau | Novel compositions |
| AR074485A1 (es) * | 2009-12-04 | 2011-01-19 | Consejo Nac Invest Cient Tec | Vacuna contra lesiones neoplasicas o cancerosas causadas por el virus del papiloma humano (vph), procedimientos, usos y metodos |
| US8809562B2 (en) * | 2011-06-06 | 2014-08-19 | Chevron Phillips Chemical Company Lp | Use of metallocene compounds for cancer treatment |
| US20130064849A1 (en) * | 2011-07-14 | 2013-03-14 | The Board Of Regents Of The University Of Texas | Methods to treat and prevent cardiovascular disease using human papillomavirus vaccines |
| US20150110824A1 (en) * | 2012-03-18 | 2015-04-23 | Glaxosmithkline Biologicals, Sa | Method of vaccination against human papillomavirus |
| US20150086587A1 (en) * | 2012-03-28 | 2015-03-26 | Kansas State University Research Foundation | Vaccine adjuvant |
| US20140275082A1 (en) * | 2013-03-14 | 2014-09-18 | Abbvie Inc. | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
| US9974849B2 (en) | 2013-10-13 | 2018-05-22 | Bioventures, Llc | Human Papilloma virus therapeutic vaccine |
-
2015
- 2015-10-23 CN CN201580064634.6A patent/CN107001430A/zh active Pending
- 2015-10-23 SG SG11201703262UA patent/SG11201703262UA/en unknown
- 2015-10-23 MX MX2017005418A patent/MX395186B/es unknown
- 2015-10-23 WO PCT/US2015/057150 patent/WO2016065281A1/en not_active Ceased
- 2015-10-23 BR BR112017008280-2A patent/BR112017008280A2/pt not_active Application Discontinuation
- 2015-10-23 CA CA2965498A patent/CA2965498A1/en active Pending
- 2015-10-23 MY MYPI2017000594A patent/MY195018A/en unknown
- 2015-10-23 IL IL251825A patent/IL251825B2/en unknown
- 2015-10-23 AU AU2015335652A patent/AU2015335652B2/en active Active
- 2015-10-23 JP JP2017540976A patent/JP6663438B2/ja active Active
- 2015-10-23 US US14/921,648 patent/US10238729B2/en active Active
- 2015-10-23 EP EP15853497.4A patent/EP3209676A4/en not_active Ceased
- 2015-10-23 KR KR1020177013441A patent/KR102285401B1/ko active Active
-
2017
- 2017-04-24 CL CL2017001008A patent/CL2017001008A1/es unknown
- 2017-04-24 PH PH12017500754A patent/PH12017500754A1/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2019506435A (ja) * | 2016-02-27 | 2019-03-07 | エイチピーブイヴァックス, リミテッド ライアビリティー カンパニー.Hpvvax, Llc. | ワクチンを使用して癌または皮膚病変を治療するための方法および組成物 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR102285401B1 (ko) | 2021-08-02 |
| US10238729B2 (en) | 2019-03-26 |
| MY195018A (en) | 2023-01-03 |
| IL251825A0 (en) | 2017-06-29 |
| PH12017500754A1 (en) | 2017-10-30 |
| MX2017005418A (es) | 2017-11-30 |
| IL251825B2 (en) | 2023-09-01 |
| CA2965498A1 (en) | 2016-04-28 |
| BR112017008280A2 (pt) | 2018-01-02 |
| CL2017001008A1 (es) | 2017-11-24 |
| KR20170072279A (ko) | 2017-06-26 |
| AU2015335652A1 (en) | 2017-05-25 |
| JP2017531699A (ja) | 2017-10-26 |
| AU2015335652B2 (en) | 2020-07-02 |
| US20160114023A1 (en) | 2016-04-28 |
| IL251825B1 (en) | 2023-05-01 |
| MX395186B (es) | 2025-03-21 |
| CN107001430A (zh) | 2017-08-01 |
| EP3209676A4 (en) | 2018-03-28 |
| WO2016065281A1 (en) | 2016-04-28 |
| EP3209676A1 (en) | 2017-08-30 |
| SG11201703262UA (en) | 2017-05-30 |
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