JP6603133B2 - ヤシ果実を用いたdna損傷およびミトコンドリア機能障害の治療 - Google Patents
ヤシ果実を用いたdna損傷およびミトコンドリア機能障害の治療 Download PDFInfo
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Description
本願は、アメリカ合衆国仮出願番号61/761,473、「ヤシ油果汁サプリメントおよびその使用」2013年2月6日出願、および同仮出願番号61/791,162、名称「ヤシ果汁を用いたDNA損傷およびミトコンドリア機能障害の治療」、2013年3月15日出願の優先権を主張する出願である。これらの各仮出願は、その全部をここに参照として組み込まれる。
前記方法のいくつかの実施形態では、対象は癌を持っているか、または癌を発症する素因がある。特定の実施形態において、被験体は、ゲノムDNAの損傷の可能性を増大させる条件にさらされていた。
本願は、ミトコンドリア機能障害、ミトコンドリアDNA(mtDNA)変異および/またはゲノムDNA変異を治療および/または予防するための方法及びキットを提供する。幾つかの態様において、提供される方法には、ヤシ果汁(PFJ)全部および/またはその中に含まれる生理活性物質として投与される(例えば、天然源から得られた、または合成的に製造されたフェノール類)部分の投与および/または消費を含む。
ヤシ果汁とヤシ果汁内に含まれるフェノール類はAZTや他の遺伝毒性薬物によって引き起こされるミトコンドリア損傷を含む、DNA損傷を低減する。PFJとPFJ中のポリフェノールは、例えば、種々の薬剤や加齢、病気などの自然現象によって引き起こされるROS媒介ミトコンドリアDNAの損傷を防止することにおいて、有用である。
本明細書で使用する場合、用語「投与する」は、被験体に、栄養補助食品または医薬品または組成物を提供すること、および、これらに限定されないが、医療専門家および自己投与することによって投与することを含む。
用語「薬剤」は、化学化合物、小分子(例えば、核酸、抗体、抗体フラグメント、タンパク質またはペプチドのような)の化学化合物および/または生物学的高分子の混合物を示すために本明細書中で使用される。薬剤は、本明細書で以下に記載の試験をスクリーニングすることによって特定の活性を有すると同定され得る。このような薬剤の活性は、対象において局所的または全身的に作用する生物学的、生理学的、または薬理的に活性な物質である「治療薬」とされ得る。
本明細書で使用する場合、用語「癌」は、しかし、固形腫瘍および血液由来の腫瘍に限定されるものではない。用語「癌」は、皮膚、組織、臓器、骨、軟骨、血液および血管の疾患を含む。 「癌」という用語はさらに、一次および転移性癌を含む。
ヤシ油は2種のヤシ科の種のアブラヤシ(西アフリカ原産)とアブラヤシ属のアブラヤシ(中南米が原産)を含む。最も一般的にはヤシ油の生産の商業的農業で使用され、成熟した木は20メートル高さに成長する。果実は受粉から成熟するために5〜6ヶ月かかり、単一の種(カーネル)を有する油性、肉質の外層(果皮)を含む。オイルヤシは、複製物を産生せず、種子を播種することによって増殖する。果実のクラスタ(塊)は、40〜50キロの重量になり得る。
加えて、当業者に知られている他の香料および添加剤は十分にそれらをより口に合うようにも製剤に添加することができる。例えば、製剤は、ショウガ、ボスウェリア、フルーツ香味剤、着色剤、保存剤などを含んでいてもよい。
本明細書において、治療又はミトコンドリア機能障害および/またはミトコンドリアDNA損傷を防止することを助けるために治療および/または予防する方法が開示されている。このような方法は、例えば加齢性ミトコンドリア疾患の治療において有用である。特定の実施形態において、この方法は、被験体(例えば、それを必要とする被験体)に、本明細書に記載の組成物(例えば、ヤシ果汁および/またはヤシ果汁中で見出された合成フェノール類を含む組成物)を投与する工程を含む。
30日試験がHepG2肝癌細胞株(ATCC、マナッサス、バージニア州)を用いて行われた。実験は、未処理、AZT処理、PFJ処理、およびAZTおよびPFJ-処理した培養物の分析が含まれている。各条件を三回試験した。
反応成分および条件は以下の如くであった:
過剰プライマー: 5‘−ACTTCAGGGTCATAAAGCCTAAATAGC (SEQ ID NO:2)
限定プライマー:5‘−AATAGAGGGGGTAGAGGGGGTGCTATAGGGT (SEQ ID NO:3)
過剰プライマー: 5‘−TCCTTATCTGCTTCCTAGTCCTGTATGC (SEQ ID NO:4)
限定プライマー:5‘− AACATAAGAACAGGGAGGTTAGAAGTAGGGTCTTGGT (SEQ ID NO:5)
過剰プライマー:5‘− CGCCCCGACCTTAGCTCT (SEQ ID NO:6)
5‘GCTCGCCACACACACACGACCCATCCTACCCGCCCCCAACATAACTACTCTAATCATCATACCCTCACCCTCCCCTTTTATTACACAATCAACCCCCCACTGACAATTTTCACGTATGGCGGTTTTCTATTTTAAACTTTAGACCAATCCGACCACAATCCCAAGAAACAAAAACCCCAAACCGTCTCTACACAAATTCACGACACCGGTCTTCGCCCCCTCCCCCCCAAACCACCTTTAAAAAACAATACTACAGACACACCTTTCACCGACACGTCTGTAAGTTAACAATAATAATACAGGATGTTCGTAATTAATTAATTGTGTGAAATCATTCATACAAGCGGACATTATAACTTGCATCCACGCTATTTATTATCCTACTCCGTCCTTAGTTTCTGTCTATGACGCTGTATCCCACGAGGCCGAGGTCGCAGAGCGTTACGATAGCGCACGTATGGGGGGTCTGCTTTTATGGTTTACGTACCTCTCGAGGGCACTCACCAATTATCCCACTATCTGGACACTAGGTAGCACTACAGAATAAATTCCCCTTGCACACCCGATAAATCCGAAATACTGGGACTTCA (SEQ ID NO:7)
5‘CCCGAGATCTCCCCCATCTCCCCCACGATATCCCATTTATGCCCGGGATAAAGTTTCTAAAAATCCCCTTAATTAAGATCCTGCTACCCGTACTTTGACACCAAACGAGGTGTCTAAAGTCTCGTAACTGGCATCATATGGGGGCCAGCACATCGCCACTTTCACCAAACCAAATCTGCAGGCCCTTAACGTAGACAAAAATTCGGATTACACCCCTGTCGAGTACTCACGTTCTGCAGAACACTACATTAATAATATGCTTACCCCCGAAGTTAGCCCTCATGATGAGCTAACAGTTGCAGTTCCTCAGCGTCCAGCGGACCAAGATCCTTATTACCCCCTTCATACATCCTCAACTTCTAATCAGGCGGCATCAGCCACATGAGCATCCAAGTCATGGTAACCACCGGTTAACTAAACTACCATTCCCTCCCTAGCAACTGGAGCAGACAATACATTTCCTACGCATCCCTACCCTCCCGCTACTCCTGATCCTACTACCGCCCGTCCTATCAAGTCTGCCAAAGATAAAGGACTCGCAGACTCTACAATCATAATCAATCAAAACAACACTCACAATCCTTTTCCCGTATGTCCTGATCCTTCGTCTATTCCT (SEQ ID NO:8)
5’AAGTATTCTTGTCCCTCCAATCTTCATCCCAGAACCACTGTTTTATACAACACATCTCAAGTCCCCTCTCACGCAGTATACAACAAGGATCCTTCTAACATCACCACTCCCACAAATAATATTATTACAAACACATAAGCCGATACTTCTTATCCCGCTTCCCCGGACGCCGCATAAGCTACAACTTCGGACTCTGATCAAGCCTGAGGGGAAGCCGTTCCAGCTTCCCCCAAGCCAACCAGAGACGATCACACCTCTATTTAGTATAATACCGGTTCCCAGTACTACCGTCCTCATTAGTCTCCACAAGAACACAACACTATTCCCACCTCTCCAATTTCCTCGGTGAATAATCATTACAACTATCATCTTACTACCGATCCCACTGAAGTATACTCTAACAAACCCGATGACGAGCGTCACGCGGCTAGTCCCGCATCAAACTCAAACTACGAGTGGGACTAGTCTCCTAACTCATTTGCCGATCCGATCTCCACCGATCTTATTTATCCTCCGGATCCAACTCCAACTGGTCCCCCAACCCATACCCCTCCCCCCAAGTATCATCTTCTCGCTACCACTCTCGATTCCAGCCCCGC (SEQ ID NO:9)
オン1:
5’-クェーサー670-TGGTTAGGGTTCTTTATTTTGGGGTTCA−BHQ2 (SEQ ID NO:10)
オフ1:
5’−AATGTGAAATCTGCTTGGGCTGGT−BHQ2 (SEQ ID NO:11)
オン2:
5‘−BHQ2−AATGGCAGAGATGTCTTTAAGTGCTGTTT−クェーサー 670 (SEQ ID NO:12)
オフ2:
5‘−BHQ2−GGCTAGGAGTTGGGGAGGGCGGGTT−C3 (SEQ ID NO:13)
オン 3:
5‘−BHQ2−AAATGTAATCGCGTTCATATCACCCAGTT−クェーサー 670 (SEQ ID NO:14)
オフ3:
5‘−BHQ2−ACGAGAGTACCCAACGCATGGAGAG−C3 (SEQ ID NO:15)
オン 4:
5‘−クェーサー 670−TAATTGAACATAGGTACGATAAATAATTA−BHQ2 (SEQ ID NO:16)
オフ4:
5‘−TTTAGTAAATGTGTTCACCTGTAAT−BHQ2 (SEQ ID NO:17)
オン5:
5‘−クェーサー 670−AACTGGGTGAAAAGTGACTATGCGGACTT−BHQ2 (SEQ ID NO:18)
オフ5:
5‘−TGGGGGAAGTTTTTTCTTATTATGT−BHQ2 (SEQ ID NO:19)
オン1:
5‘−BHQ2−AAACTACTCGATTATCAACGTCAAGGATT−Cal Red 590 (SEQ ID NO:20)
オフ1:
5‘−BHQ2−GTCGCAGGACGCCTAGTTTTAGGAA−C3 (SEQ ID NO:21)
オン2:
5‘−BHQ2−AAAATGGGGGAAGTTTGTATGAGTTGATT−Cal Red 590 (SEQ ID NO:22)
オフ2:
5‘−BHQ2−AGATAAGTTCGCTGTATTCGGTGT−C3 (SEQ ID NO:23)
オン3:
5‘−Cal Red 590−AAACGATTGGGGACTTTAATTGGGAGTTT−BHQ2 (SEQ ID NO:24)
オフ3:
5‘−AGACGTCTTATGTTGTAATTAT−BHQ2 (SEQ ID NO:25)
オン 4:
5‘−Cal Red 590−TTTGTAAAGAATGCGTAGAGATAGGAGAA−BHQ2 (SEQ ID NO:26)
オフ4:
5‘−GAGGCATTGTTCACGTCGTTTGTTA−BHQ2 (SEQ ID NO:27)
オン5a:
5‘−BHQ2−TTTTTATACGTACGGCAATTACATCTGAA−Cal Red 590 (SEQ ID NO:28)
オフ5a:
5‘−BHQ2−TTTTTAAATTTAATATGGGGATAGC−C3 (SEQ ID NO:29)
オン5b:
5‘−BHQ2−AGTGACCATAATATACCTCCGGCT−Cal Red 590 (SEQ ID NO:30)
オフ5b:
5‘−BHQ2−TCGTATAGTGGTCAATGTGGTATGG−C3 (SEQ ID NO:31)
オン1:
5‘−Cal Orange 560−AAGTTCGGTTGGTTTTTGCTGGTGTGGTT−BHQ1 (SEQ ID NO:32)
オフ1:
5‘−TTCGGCAATGTCGAGGGGG−BHQ1 (SEQ ID NO:33)
オン2:
5‘−BHQ1−AATATGAAGAATAGAGCGAAGAGGCCTTT−Cal オレンジ 560 (SEQ ID NO:34)
オフ2:
5‘−BHQ1−GCGGCCTATTCCATGTTGACGCCTG−C3 (SEQ ID NO:35)
オン3:
5‘−BHQ1−TTAAGGTTGTAGTGATGGGGGTGTTTAAA−Cal Orange 560 (SEQ ID NO:36)
オフ3:
5‘−BHQ1−TTATAATAATCTTTGTGTTTTCGGC−C3 (SEQ ID NO:37)
オン4:
5‘−BHQ1−AATTGATCAAGGGGTTTGGTATAGGGATT−Cal オレンジ 560 (SEQ ID NO:38)
オフ4:
5‘−BHQ1−GGGAGGTTTATAGTAAAAGAGAGAT−C3 (SEQ ID NO:39)
オン5:
5‘−BHQ1−TTAGATAAACCATAGTATGTCCGAGGGAA−Cal オレンジ 560 (SEQ ID NO:40)
オフ5:
5‘−BHQ1−TCATGATTGCAGTAGTGGTAAGAGG−C3 (SEQ ID NO:41)
肝癌細胞株(HepG2細胞、ATCC、マナッサス、ヴァージニア州)は、88μMのINH(Sigma、セントルイス、ミズーリ州)または88μMのINH+50μg/mlの没食子酸当量(GAE)PFJの存在下で30日間増殖させた。これらの添加剤を含まない培地は、非処理対照として用いられた。細胞を、イーグル最小必須培地(ATCC、マナッサス、ヴァージニア州)中で増殖させた。培地は、25mMのHEPES、10%ウシ胎児血清(BioWest)、50単位/mlのペニシリンG、50単位/mlのストレプトマイシン、および37oCにおける6ウェルプレート中の0.25μgのアムホテリシンB(ハイクローン抗生物質/抗真菌ソリューション100X)および5%CO2で補充した。培地および添加剤は、一日おきに補充した。細胞を、1×105細胞/mlの初期密度で、ATCCの指示書に従って継代した。
75μg/mlのGAE当量PFJの存在下または非存在下で、HepG2細胞の培養物はAZTの濃度を増加させて(0μM、10μM、30μM、50μM、70μM、100μM)に設定した。各培養物は、最初に1×105の細胞/mlを播種した。培養条件は、実施例2で説明したものであった。図4は、培養の6日後に回収された生存細胞パーセントを示した(塗りつぶされていないバー、AZTで処置された細胞;黒色のバー、AZTおよびPFJで処置された細胞)。アスタリスクは、AZTおよびAZT/PFJから回収された生存細胞の割合の差が、統計的に有意であったサンプル示す。結果は、AZTの濃度増加の細胞毒性効果を示し、AZT毒性に対するPFJ処置の緩和効果を示す。
当業者は、本明細書に記載の本発明の特定の実施形態の多くの均等物を認識し、または日常的な実験のみを用いて確認することができるであろう。このような均等物は、以下の特許請求の範囲に包含されることが意図されている。
Claims (10)
- アブラヤシの果実から得られた水溶性抽出物を含む、被験体におけるミトコンドリアDNA損傷の治療または予防用医薬組成物であって、
前記ミトコンドリアDNA損傷は、前記被験体へ投与される医薬品の副作用であり、
前記医薬品が、3’−アジド−3’−デオキシチミジン(AZT)を含むヌクレオシド系逆転写酵素阻害剤(NRTI)、又はイソニアジドを含む抗結核薬である、
被験体におけるミトコンドリアDNA損傷の治療または予防用医薬組成物。 - アブラヤシの果実から得られた水溶性抽出物に存在する1または2以上のフェノール化合物を含む、請求項1に記載の医薬組成物。
- アブラヤシの果実から得られた水溶性抽出物に存在する1または2以上の有機化合物を含む、請求項1に記載の医薬組成物。
- 前記1または2以上の有機化合物が、砂糖、フェノール化合物およびシキム酸からなる群から選択される、請求項3に記載の医薬組成物。
- 前記被験体がミトコンドリア疾患または障害を有している、請求項1から4のいずれか一項に記載の医薬組成物。
- 前記ミトコンドリア疾患または障害が、ミトコンドリアDNAの減少である、請求項5に記載の医薬組成物。
- 前記被験体が、加齢性疾患または障害を抱えている、請求項1から4のいずれか一項に記載の医薬組成物。
- 前記加齢性疾患または障害は、アルツハイマー病筋萎縮性側索硬化症、関節炎、アテローム性動脈硬化症、悪液質、癌、心肥大、心不全、心臓肥大、心臓血管疾患、白内障、大腸炎、慢性閉塞性肺疾患、認知症、糖尿病、虚弱、心臓病、肝臓脂肪症、高い血中コレステロール、高血圧、ハンチントン病、高血糖、高血圧症、不妊症、炎症性腸疾患、インスリン抵抗性障害、嗜眠、メタボリックシンドローム、筋ジストロフィー、多発性硬化症、神経障害、腎症、肥満、骨粗しょう症、パーキンソン病、乾癬、網膜変性、サルコペニア、睡眠障害、敗血症および卒中からなる群から選択される、請求項7に記載の医薬組成物。
- 前記被験体が、ミトコンドリアDNAの突然変異体を抱えている、請求項1から8のいずれか一項に記載の医薬組成物。
- 請求項1から9のいずれか一項に記載の医薬組成物を含む、被験体におけるミトコンドリアDNA損傷の治療または予防用キットであって、
前記ミトコンドリアDNA損傷は、前記被験体へ投与される医薬品の副作用であり、
前記医薬品が、3’−アジド−3’−デオキシチミジン(AZT)を含むヌクレオシド系逆転写酵素阻害剤(NRTI)、又はイソニアジドを含む抗結核薬である、被験体におけるミトコンドリアDNA損傷の治療または予防用キット。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361761473P | 2013-02-06 | 2013-02-06 | |
US61/761,473 | 2013-02-06 | ||
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PCT/US2014/015110 WO2014124140A1 (en) | 2013-02-06 | 2014-02-06 | Treatment of dna damage and mitochondrial dysfunction using palm fruit juice |
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EP (1) | EP2953639B1 (ja) |
JP (1) | JP6603133B2 (ja) |
CN (1) | CN105377283A (ja) |
AU (1) | AU2014214847B2 (ja) |
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WO2012158018A2 (en) * | 2011-05-18 | 2012-11-22 | Malaysian Palm Oil Board | Compositions comprising extracts or materials derived from palm oil vegetation liguor for inhibition of vision loss due to angiogenesis and method of preparation thereof |
EP2953639B1 (en) | 2013-02-06 | 2021-06-02 | Brandeis University | Treatment of dna damage and mitochondrial dysfunction using palm fruit juice |
MY197031A (en) * | 2015-12-31 | 2023-05-22 | Malaysian Palm Oil Board | Oil palm phenolics composition for the protection of humans, organs, cells and tissues against the injurious effects of exposure to ionizing radiation |
WO2018165780A1 (en) * | 2017-03-17 | 2018-09-20 | Malaysian Palm Oil Board | Antioxidant, anti-inflammatory compositions and uses thereof |
CN108570495A (zh) * | 2018-01-15 | 2018-09-25 | 新开源博畅(武汉)生物科技有限公司 | 一种hla高分辨基因位点的快速扩增诊断试剂盒及扩增方法 |
MY194335A (en) * | 2018-03-08 | 2022-11-29 | Malaysian Palm Oil Board | Composition for delaying ageing process and increasing longevity in a subject and methods thereof |
CN108379246A (zh) * | 2018-05-16 | 2018-08-10 | 中国人民解放军第二军医大学 | 莽草酸在制备预防或治疗脱髓鞘疾病药物中的应用 |
CN109172712A (zh) * | 2018-10-09 | 2019-01-11 | 昆明理工大学 | 棕榈果提取物的用途 |
CN109394932A (zh) * | 2018-10-09 | 2019-03-01 | 昆明理工大学 | 棕榈果不同状态多酚提取物的制备方法及应用 |
CN109464561A (zh) * | 2018-10-09 | 2019-03-15 | 昆明理工大学 | 棕榈果提取物的用途 |
WO2020139057A2 (ko) * | 2018-12-28 | 2020-07-02 | 연세대학교 산학협력단 | 팔각회향 추출물 또는 시킴산을 함유하는 근육 질환 예방 및 치료용 또는 근 기능 개선용 조성물 |
CN111621555A (zh) * | 2019-06-13 | 2020-09-04 | 中国科学院广州生物医药与健康研究院 | 生物标志物及其应用 |
WO2021046450A1 (en) | 2019-09-04 | 2021-03-11 | Amare Global | Nutritional supplements and methods of supplementation affecting the endocannabinoid system |
WO2021046459A1 (en) * | 2019-09-04 | 2021-03-11 | Amare Global | Nutritional supplements and methods of nutritional supplementation affecting heart/brain axis |
WO2021046396A1 (en) | 2019-09-04 | 2021-03-11 | Amare Global | Nutritional supplements and methods of nutritional supplementation affecting mood and focus in children |
US20230346871A1 (en) * | 2019-11-22 | 2023-11-02 | Malaysian Palm Oil Board | Compositions comprising aqueous oil palm fruit extract for increasing tyrosine hydroxylase levels and improving brain health |
CN111849789B (zh) * | 2020-08-10 | 2022-02-08 | 南京财经大学 | 一种金针菇线粒体提取方法 |
WO2023192505A2 (en) * | 2022-03-30 | 2023-10-05 | Primefour Therapeutics, Inc. | Method for treating cancer with a dna damage repair enzyme inhibitor |
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FR2687292B3 (fr) | 1992-02-18 | 1994-05-27 | Raymond Bontemps | Procede de preparation de compliments alimentaires a base de substances mesenchymateuses type microsepteurs. |
US5817350A (en) | 1993-03-11 | 1998-10-06 | Triarco Industries | Carbohydrase enzyme food supplement composition |
US5656312A (en) | 1994-09-02 | 1997-08-12 | Erasmus; Udo | Dietary food supplement and method of preparing |
CN1092938C (zh) | 1996-04-12 | 2002-10-23 | 贝斯以色列护理医疗中心有限公司 | 用于糖尿病患者的补充食品条 |
KR100213895B1 (ko) | 1996-10-14 | 1999-08-02 | 박원훈 | 감귤류 과피 추출물, 이로부터 분리 정제된 헤스페리딘 또는 나린진을 포함하는 심혈관 질환 예방및 치료제 조성물 |
US5902797A (en) | 1997-11-10 | 1999-05-11 | Beth Israel Deaconess Medical Center | Nutritional supplement for use in the treatment of attention deficit |
MY134878A (en) | 1998-09-24 | 2007-12-31 | Palm Oil Res And Dev Board | Treatment of liquors derived from oil-bearing fruit. |
WO2002079139A1 (de) | 2001-03-29 | 2002-10-10 | Basf Aktiengesellschaft | Konjugierte ungesättigte glyceridgemische und verfahren zur ihrer herstellung |
JP2005506057A (ja) * | 2001-06-11 | 2005-03-03 | 1304854 オンタリオ・リミテッド | 健康科学のための診断ツールとしての全ミトコンドリアゲノム配列 |
EP2241195A1 (en) | 2005-04-06 | 2010-10-20 | Nestec S.A. | A method and composition for nutritionally improving glucose control and insulin action |
US8470861B2 (en) * | 2005-11-22 | 2013-06-25 | University Of Rochester | Mitochondria-targeted antioxidant prodrugs and methods of use |
MY184667A (en) | 2007-07-23 | 2021-04-15 | Malaysian Palm Oil Board | An antiviral composition |
US8877239B2 (en) | 2010-08-12 | 2014-11-04 | Nutritional Therapeutics, Inc. | Lipid supplements for maintaining health and treatment of acute and chronic disorders |
US8071143B2 (en) | 2008-04-02 | 2011-12-06 | Brandeis University | Methods for the treatment or prevention of diabetes mellitus and other metabolic imbalances |
US9637790B2 (en) | 2010-12-03 | 2017-05-02 | Brandeis University | Detecting mutations in DNA |
EP2953639B1 (en) | 2013-02-06 | 2021-06-02 | Brandeis University | Treatment of dna damage and mitochondrial dysfunction using palm fruit juice |
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EA201591476A1 (ru) | 2016-02-29 |
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CN105377283A (zh) | 2016-03-02 |
EP2953639A1 (en) | 2015-12-16 |
AU2014214847B2 (en) | 2018-11-15 |
WO2014124140A1 (en) | 2014-08-14 |
AU2014214847A1 (en) | 2015-09-24 |
EP2953639B1 (en) | 2021-06-02 |
US10813972B2 (en) | 2020-10-27 |
EP2953639A4 (en) | 2016-11-16 |
JP2016509010A (ja) | 2016-03-24 |
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