PT2292249E - Conjugados proteicos não citotóxicos - Google Patents
Conjugados proteicos não citotóxicos Download PDFInfo
- Publication number
- PT2292249E PT2292249E PT101841146T PT10184114T PT2292249E PT 2292249 E PT2292249 E PT 2292249E PT 101841146 T PT101841146 T PT 101841146T PT 10184114 T PT10184114 T PT 10184114T PT 2292249 E PT2292249 E PT 2292249E
- Authority
- PT
- Portugal
- Prior art keywords
- protease
- fragment
- sensory afferent
- nociceptive sensory
- site
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
- A61K38/4893—Botulinum neurotoxin (3.4.24.69)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/6415—Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Clostridium (G)
-
- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6489—Metalloendopeptidases (3.4.24)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/24—Metalloendopeptidases (3.4.24)
- C12Y304/24069—Bontoxilysin (3.4.24.69), i.e. botulinum neurotoxin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Zoology (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Wood Science & Technology (AREA)
- General Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Biotechnology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biophysics (AREA)
- Toxicology (AREA)
- Microbiology (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Immunology (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Rheumatology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Enzymes And Modification Thereof (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0426394A GB0426394D0 (en) | 2004-12-01 | 2004-12-01 | Fusion proteins |
GB0504966A GB0504966D0 (en) | 2004-12-01 | 2005-03-10 | Re-targeted toxin conjugates |
GB0504964A GB0504964D0 (en) | 2004-12-01 | 2005-03-10 | Fusion proteins |
Publications (1)
Publication Number | Publication Date |
---|---|
PT2292249E true PT2292249E (pt) | 2015-07-13 |
Family
ID=34043886
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PT101665560T PT2366399E (pt) | 2004-12-01 | 2005-12-01 | Conjugados proteicos não citotóxicos |
PT101841146T PT2292249E (pt) | 2004-12-01 | 2005-12-01 | Conjugados proteicos não citotóxicos |
PT101841500T PT2335718E (pt) | 2004-12-01 | 2005-12-01 | Conjugados proteicos não citotóxicos |
PT05810103T PT1830872E (pt) | 2004-12-01 | 2005-12-01 | Proteínas de fusão |
PT58107111T PT1877073E (pt) | 2004-12-01 | 2005-12-01 | Conjugados proteicos não citotóxicos |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PT101665560T PT2366399E (pt) | 2004-12-01 | 2005-12-01 | Conjugados proteicos não citotóxicos |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PT101841500T PT2335718E (pt) | 2004-12-01 | 2005-12-01 | Conjugados proteicos não citotóxicos |
PT05810103T PT1830872E (pt) | 2004-12-01 | 2005-12-01 | Proteínas de fusão |
PT58107111T PT1877073E (pt) | 2004-12-01 | 2005-12-01 | Conjugados proteicos não citotóxicos |
Country Status (13)
Country | Link |
---|---|
US (5) | US8187834B2 (pt) |
EP (4) | EP2366399B1 (pt) |
JP (7) | JP5174463B2 (pt) |
AT (1) | ATE488245T1 (pt) |
CY (2) | CY1111324T1 (pt) |
DE (1) | DE602005024857D1 (pt) |
DK (6) | DK2366399T3 (pt) |
ES (6) | ES2356179T3 (pt) |
GB (3) | GB0426394D0 (pt) |
HU (2) | HUE025964T2 (pt) |
PL (3) | PL2292249T3 (pt) |
PT (5) | PT2366399E (pt) |
SI (2) | SI1877073T1 (pt) |
Families Citing this family (62)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9617671D0 (en) * | 1996-08-23 | 1996-10-02 | Microbiological Res Authority | Recombinant toxin fragments |
US7192596B2 (en) * | 1996-08-23 | 2007-03-20 | The Health Protection Agency Ipsen Limited | Recombinant toxin fragments |
ES2277854T5 (es) * | 1999-08-25 | 2011-02-04 | Allergan, Inc. | Neurotoxinas recombinantes activables. |
ES2648046T3 (es) | 2002-11-12 | 2017-12-28 | The Brigham And Women's Hospital, Inc. | Vacuna de polisacárido para infecciones estafilocócicas |
US7811584B2 (en) * | 2004-06-30 | 2010-10-12 | Allergan, Inc. | Multivalent clostridial toxins |
EP1824971B1 (en) * | 2004-11-22 | 2016-01-13 | New York University | Genetically engineered clostridial genes, proteins encoded by the engineered genes, and uses thereof |
US8399400B2 (en) * | 2004-12-01 | 2013-03-19 | Syntaxin, Ltd. | Fusion proteins |
US8603779B2 (en) | 2004-12-01 | 2013-12-10 | Syntaxin, Ltd. | Non-cytotoxic protein conjugates |
US8778634B2 (en) | 2004-12-01 | 2014-07-15 | Syntaxin, Ltd. | Non-cytotoxic protein conjugates |
GB0426394D0 (en) * | 2004-12-01 | 2005-01-05 | Health Prot Agency | Fusion proteins |
US8512984B2 (en) * | 2004-12-01 | 2013-08-20 | Syntaxin, Ltd. | Non-cytotoxic protein conjugates |
US8168206B1 (en) | 2005-10-06 | 2012-05-01 | Allergan, Inc. | Animal protein-free pharmaceutical compositions |
AR060188A1 (es) * | 2006-03-30 | 2008-05-28 | Glaxosmithkline Biolog Sa | Procedimiento de conjugacion |
GB0610867D0 (en) | 2006-06-01 | 2006-07-12 | Syntaxin Ltd | Treatment of pain |
US10792344B2 (en) | 2006-06-29 | 2020-10-06 | Merz Pharma Gmbh & Co. Kgaa | High frequency application of botulinum toxin therapy |
AR061669A1 (es) * | 2006-06-29 | 2008-09-10 | Merz Pharma Gmbh & Co Kgaa | Aplicacion de alta frecuencia de terapia con toxina botulinica |
AU2009223161B2 (en) | 2008-03-14 | 2014-10-30 | Allergan, Inc. | Immuno-based botulinum toxin serotype A activity assays |
KR101604515B1 (ko) * | 2008-03-14 | 2016-03-17 | 알러간, 인코포레이티드 | 면역-기반 보툴리눔 독소 세로타입 a 활성 검정 |
EP2310029B1 (en) | 2008-06-12 | 2019-04-03 | Ipsen Bioinnovation Limited | Fusion proteins for use in the treatment of cancer |
CN102112145B (zh) * | 2008-06-12 | 2014-07-30 | 辛它可辛有限公司 | 神经内分泌病的抑制 |
CN105085349B (zh) * | 2008-07-21 | 2018-02-09 | 布赖汉姆妇女医院 | 与合成的β‑1,6 葡糖胺寡糖相关的方法和组合物 |
GB0820970D0 (en) * | 2008-11-17 | 2008-12-24 | Syntaxin Ltd | Suppression of cancer |
EP2373294B1 (en) | 2008-12-10 | 2016-04-20 | Allergan, Inc. | Clostridial toxin pharmaceutical compositions |
DK3281953T3 (da) | 2009-03-13 | 2020-01-20 | Allergan Inc | Immun-baserede omdirigerede endopeptidase-aktivitetsassays |
US8198229B2 (en) * | 2009-05-29 | 2012-06-12 | Allergan, Inc. | Methods of treating urogenital-neurological disorders using galanin retargeted endopepidases |
MX2012006985A (es) | 2009-12-16 | 2012-09-12 | Allergan Inc | Toxinas clostridium modificadas que comprenden un dominio de enlace al sitio de escision de la proteasa integrado. |
MX2012008650A (es) | 2010-01-25 | 2012-11-23 | Allergan Inc | Metodos de conversion intracelular de proteinas monocatenarias en su formula bicatenaria. |
WO2011091419A2 (en) * | 2010-01-25 | 2011-07-28 | New York Universiy | Recombinant derivatives of botulinum neurotoxins engineered for trafficking studies and neuronal delivery |
EP2650003B1 (en) | 2010-05-20 | 2016-07-27 | Allergan, Inc. | Degradable clostridial toxins |
EP3173095A1 (en) | 2010-10-14 | 2017-05-31 | Allergan, Inc. | Targeted delivery of targeted exocytosis modulators to the sphenopalatine ganglion for treatment of headache disorders |
WO2012112420A1 (en) | 2011-02-14 | 2012-08-23 | Allergan, Inc. | Treatments using psma ligand endopeptidases |
US20120244188A1 (en) | 2011-03-25 | 2012-09-27 | Allergan, Inc. | Treatment of Sensory Disturbance Disorders |
US20120251573A1 (en) | 2011-03-28 | 2012-10-04 | Allergan, Inc. | Endopeptidase Treatment of Neuroendocrine Disorders |
US20120251575A1 (en) | 2011-03-28 | 2012-10-04 | Allergan, Inc. | Endopeptidase Treatment of Involuntary Movement Disorders |
US20120251574A1 (en) | 2011-03-28 | 2012-10-04 | Allergan, Inc. | Endopeptidase and Neurotoxin Combination Treatment of Multiple Medical Conditions |
US20120251519A1 (en) | 2011-03-29 | 2012-10-04 | Allergan, Inc. | Endopeptidase Treatment of Smooth Muscle Disorders |
US20120258132A1 (en) | 2011-03-29 | 2012-10-11 | Allergan, Inc. | Vagal Nerve-Based Disorders |
US20120251518A1 (en) | 2011-03-29 | 2012-10-04 | Allergan, Inc. | Endopeptidase Treatment of Sexual Dysfunction Disorders |
US20120251515A1 (en) | 2011-03-29 | 2012-10-04 | Allergan, Inc. | Endopeptidase Treatment of Cosmesis Disorders |
US8697090B2 (en) | 2011-05-05 | 2014-04-15 | Allergan, Inc. | Method of treating persistent genital arousal disorder with a neurotoxin |
GB201108108D0 (en) * | 2011-05-16 | 2011-06-29 | Syntaxin Ltd | Therapeutic fusion proteins |
US9764009B2 (en) | 2011-06-13 | 2017-09-19 | Allergan, Inc. | Treatment of psychological trauma |
EP2729163A1 (en) | 2011-07-08 | 2014-05-14 | Allergan, Inc. | Method for treatment of autonomic nervous system disorders |
US8992941B2 (en) | 2011-07-08 | 2015-03-31 | Allergan, Inc. | Method for treatment of esophageal spasm |
US9144600B2 (en) | 2011-07-14 | 2015-09-29 | Allergan, Inc. | Methods for treatment of incontinence associated with sexual activity |
US20130171122A1 (en) | 2011-12-29 | 2013-07-04 | Allergan, Inc. | Endopeptidase and neurotoxin combination treatment of bladder disorders |
WO2013102088A2 (en) | 2011-12-31 | 2013-07-04 | Allergan, Inc. | Highly Sensitive Cell-Based Assay to Detect the Presence of Active Botulinum Neurotoxin Serotype-A |
US20140056870A1 (en) * | 2012-08-27 | 2014-02-27 | Allergan, Inc. | Fusion proteins |
BR112015003591B1 (pt) | 2012-11-21 | 2022-02-01 | Ipsen Bioinnovation Limited | Usos de lys-c e métodos para fabricação de um polipeptídeo proteoliticamente processado |
EP2934571B1 (en) | 2012-12-18 | 2018-05-30 | Allergan, Inc. | Prophylactic treatment of herpes recurrence |
WO2014117148A1 (en) | 2013-01-28 | 2014-07-31 | New York University | Treatment methods using atoxic neurotoxin derivatives |
US11897921B2 (en) | 2014-12-09 | 2024-02-13 | New York University | Propeptide fusion comprising a mutated clostridium botulinum neurotoxin and a VHH domain |
EP3436054B2 (en) | 2016-09-13 | 2022-07-27 | Allergan, Inc. | Stabilized non-protein clostridial toxin compositions |
US11129906B1 (en) | 2016-12-07 | 2021-09-28 | David Gordon Bermudes | Chimeric protein toxins for expression by therapeutic bacteria |
EP3858264A1 (en) | 2017-12-26 | 2021-08-04 | Goodman Co., Ltd. | Hemostatic device |
US11965191B2 (en) | 2018-01-18 | 2024-04-23 | California Institute Of Technology | Programmable protein circuits in living cells |
WO2019147478A2 (en) * | 2018-01-18 | 2019-08-01 | California Institute Of Technology | Programmable protein circuits in living cells |
DE102018114028A1 (de) * | 2018-06-12 | 2019-12-12 | Bundesrepublik Deutschland (Robert Koch-Institut) | Probenpräparation für proteomische Untersuchungen |
US11453893B2 (en) | 2018-08-30 | 2022-09-27 | California Institute Of Technology | RNA-based delivery systems with levels of control |
US11542305B2 (en) | 2018-08-31 | 2023-01-03 | California Institute Of Technology | Synthetic protein circuits detecting signal transducer activity |
WO2020146627A1 (en) | 2019-01-10 | 2020-07-16 | California Institute Of Technology | A synthetic system for tunable thresholding of protein signals |
EP4277654A1 (en) | 2021-01-18 | 2023-11-22 | Conserv Bioscience Limited | Coronavirus immunogenic compositions, methods and uses thereof |
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