JPWO2010061781A1 - ヒト単球由来治療用幹細胞およびその誘導方法 - Google Patents
ヒト単球由来治療用幹細胞およびその誘導方法 Download PDFInfo
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Abstract
Description
項1. 単球を(i)M−CSFおよび(ii)ガングリオシド及び水溶性植物抽出物からなる群から選ばれる少なくとも1種の存在下で培養し、脱分化させることにより得られる幹細胞。
項2. 水溶性植物抽出物の単球を脱分化させる有効成分が糖もしくは複合糖質である、項1に記載の幹細胞。
項3. 水溶性植物抽出物の単球を脱分化させる有効成分の分子量が1000〜500000である項1に記載の幹細胞。
項4. 水溶性植物抽出物の単球を脱分化させる有効成分が、ConAカラムに吸着される、項1に記載の幹細胞。
項5. 水溶性植物抽出物の単球を脱分化させる有効成分が、アニオン交換樹脂に吸着される項1に記載の幹細胞。
項6. 水溶性植物抽出物が植物由来Folch抽出水相画分もしくはその精製物である、項1に記載の幹細胞。
項7. 単球がヒト単球である項1記載の幹細胞。
項8. 未分化マーカーNanog, Nestin, c-Kit, CD9, Oct3/4の少なくとも1種を発現しており、単球をM-CSF単独存在下培養した場合に得られた幹細胞と比較した場合、CXCR4遺伝子が有意に強く発現していることを特徴とする項1〜7のいずれかに記載の幹細胞。
項9. 未分化マーカーNanog, Nestin, c-Kit, CD9, Oct3/4の少なくとも1種を発現し、かつCXCR4遺伝子が有意に強く発現していることを特徴とする幹細胞。
項10. 単球を(i)M−CSFおよび(ii)ガングリオシド及び水溶性植物抽出物からなる群から選ばれる少なくとも1種の存在下で培養することを特徴とする幹細胞の生産方法。
項11. 培養期間が7日から14日間である項6記載の方法。
項12. (i)M−CSFおよび(ii)ガングリオシド及び水溶性植物抽出物からなる群から選ばれる少なくとも1種を含む単球の脱分化誘導培地。
項13. 項1〜9のいずれかに記載の幹細胞を有効成分として含有する医薬組成物。
項14. 項1〜9のいずれかに記載の幹細胞を有効成分として含有する細胞医薬用剤。
項15. (i)M−CSFおよび(ii)ガングリオシド及び水溶性植物抽出物からなる群から選ばれる少なくとも1種を有効成分とする脱分化誘導剤。
項16. ガングリオシド及び水溶性植物抽出物からなる群から選ばれる少なくとも1種を有効成分とする細胞、組織もしくは器官の損傷に関係する疾患の治療剤。
項17. 前記疾患が外傷、炎症性疾患、骨・軟骨の損傷、循環器疾患、神経疾患、肝疾患および腎疾患、糖尿病、アトピー性皮膚炎、GVHDからなる群から選ばれる、項16に記載の治療剤
項18. 前記疾患が外傷、膵炎、放射線損傷、皮膚筋炎、多発性筋炎、壊死性筋膜炎、慢性気管支炎、骨折、骨粗鬆症、骨軟骨骨折、骨軟骨炎、拡張型心筋症、心筋梗塞、虚血性心筋症、心不全、心筋肥大、うっ血性心不全、再狭窄、不整脈、アテローム性動脈硬化症、血管炎、末梢ニューロパシー、ニューロパシー痛、脳卒中、脳炎、髄膜炎、糖尿病性ニューロパシー、注意欠陥障害、自閉症、アルツハイマー病、パーキンソン病、クロイツフェルト−ヤコブ病、脳または脊髄外傷もしくは虚血、肝硬変、慢性肝炎、慢性腎不全、糸球体腎炎、腎虚血、糖尿病、アトピー性皮膚炎、GVHDからなる群から選ばれる、項16に記載の治療剤。
項19. 少なくとも項1〜9記載の幹細胞を必須構成成分とする細胞医薬用キット。
項20. (i)M−CSFおよび(ii)ガングリオシド及び水溶性植物抽出物からなる群から選ばれる少なくとも1種を必須構成成分とする脱分化細胞産生キット。
項21. さらに単球を構成成分として含む項20記載のキット。
項22. ガングリオシドがGD1a、GD1b、GD2、GD3、GM1、GM2、GM3、GT1b、およびGQ1bからなる群から選ばれる少なくとも1種である、項1〜21のいずれかに記載の幹細胞、幹細胞の生産方法、単球の脱分化誘導培地、細胞医薬用剤、治療剤、脱分化誘導剤、細胞医薬用キットまたは脱分化細胞産生キット。
(i)単球をM-CSF単独存在下で培養した場合に得られた幹細胞と比較した場合、CXCR4遺伝子が有意に強く発現していること、
(ii) c-Kitを発現していること、および
(iii) Nanog, Nestin, CD9およびOct3/4からなる群から選ばれる少なくとも1種の未分化マーカーを発現していること。
GD1a=aNeu5Ac(2-3)bDGalp(1-3)bDGalNAc(1-4)[aNeu5Ac(2-3)]bDGalp(1-4)bDGlcp(1-1)Cer
GD1b=bDGalp(1-3)bDGalNAc(1-4)[aNeu5Ac(2-8)aNeu5Ac(2-3)]bDGalp(1-4)bDGlcp(1-1)Cer
GD2=bDGalpNAc(1-4)[aNeu5Ac(2-8)aNeu5Ac(2-3)]bDGalp(1-4)bDGlcp(1-1)Cer
GD3=aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer
GM1=bDGalp(1-3)bDGalNAc[aNeu5Ac(2-3)]bDGalp(1-4)bDGlcp(1-1)Cer
GM2=bDGalpNAc(1-4)[aNeu5Ac(2-3)]bDGalp(1-4)bDGlcp(1-1)Cer
GM3=aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer
GT1b=aNeu5Ac(2-3)bDGalp(1-3)bDGalNAc(1-4)[aNeu5Ac(2-8)aNeu5Ac(2-3)]bDGalp(1-4)bDGlcp(1-1)Cer
GQ1b=aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-3)bDGalNAc(1-4)[aNeu5Ac(2-8)aNeu5Ac(2-3)]bDGalp(1-4)bDGlcp(1-1)Cer
aNeu5Ac = 5-アセチル-α-ノイラミン酸(5-acetyl-α-neuraminic acid)
aNeu5Ac9Ac = 5,9-ジアセチル-α-ノイラミン酸(5,9-diacetyl-α-neuraminic acid)
bDGalp = β-D-ガラクトピラノース(β-D-galactopyranose)7
bDGalpNAc = N-アセチル-β-D-ガラクトピラノース(N-acetyl-β-D-galactopyranose)
bDGlcp = β-D-グルコピラノース(β-D-glucopyranose)
0Cer = セラミド (general N-acylated sphingoid)
本発明はまた、本発明の幹細胞を必須構成成分とする細胞医薬用キット、(i)M-CSFおよび(ii)ガングリオシド水溶性植物抽出物を必須構成成分とする脱分化細胞産生キットを提供する。
幹細胞の適応できる分野全般に関して使用することが可能である。特に、近年話題になっている細胞医薬の分野での使用を考えることができ、このような分野での使用の場合においては、短期間に使用細胞を作製し提供する必要がある。しかも、拒絶反応の問題を考慮すれば、自己細胞を使用し脱分化幹細胞を調製した後生体に戻す手法がもっとも安全面で重要である。自己細胞を摂取した後短期間にある程度まとまった幹細胞を生産できることが重要になる。本発明は、このような観点からも重要である。
本発明は、ガングリオシド及び水溶性植物抽出物からなる群から選ばれる少なくとも1種と必要に応じたM−CSFをヒトなどの哺乳動物に投与することにより、外傷、炎症性疾患、骨・軟骨の損傷、循環器疾患、神経疾患、肝疾患および腎疾患、糖尿病、アトピー性皮膚炎、GVHDなどの疾患を治療することができる。これは、投与される被験体の単球、必要に応じて更にM-CSFがガングリオシド及び植物由来Folch抽出水相画分からなる群から選ばれる少なくとも1種の作用により、前記疾患を修復可能な幹細胞に変化し、これが疾患部位に移動して治療剤として作用する。あるいは、ガングリオシド及び植物由来Folch抽出水相画分からなる群から選ばれる少なくとも1種が、単球以外の細胞に直接または間接的に作用することも否定しない。
本脱分化誘導剤において作製された脱分化幹細胞は適当な保存処理を施された後にキットとして使用することができる。
ヒト単球(LONZA社、PT038)を本発明に従い、以下の添加物1から5を基礎培地に添加して培養を行った(濃度は最終濃度(以下「FC」で示す)として表す)。結果を図1に示す。図1の縦軸は、生細胞数に相当し、横軸は、培養日数である。ファンドリッヒ(Fandrich)やフーバーマン(Huberman)らによって報告された方法と比べてみても、本発明の単球由来幹細胞の増殖性は、非常に高いことが判る。
添加物1: M-CSF(FC: 25ng/ml)+Gangliosides(Bovine Brain GD1a SIGMA)(FC: 100ug/ml)
添加物2: M-CSF(FC: 5ng/ml)+IL-3(FC: 0.5ng/ml)(非特許文献2)
添加物3: M-CSF(FC: 25ng/ml)+IL-6(FC: 20ng/ml)&LIF(FC: 1000unit/ml)(非特許文献3)
添加物4: M-CSF(FC: 25ng/ml)
添加物5: M-CSF(FC: 25ng/ml)+糖脂質(植物(サツマイモ)の乾燥重量1gのFolch抽出水相画分を培地500mlに溶解したもの)
Nanog F 5′-GCTTGCCTTGCTTTGAAGCA-3′(配列番号1)
R 5′-TTCTTGACTGGGACCTTGTC-3′(配列番号2)
Nestin F 5′-CTCTGACCTGTCAGAAGAAT-3′(配列番号3)
R 5′-GACGCTGACACTTACAGAAT-3′(配列番号4)
Oct3/4 F 5′-GAGCAAAACCCGGAGGAGT-3′(配列番号5)
R 5′-TTCTCTTTCGGGCCTGCAC-3′(配列番号6)
c-Kit F 5′-CCAAGTCATTGTTGGATAAG-3′(配列番号7)
R 5′-CTTAGATGAGTTTTCTTTCAC-3′(配列番号8)
CXCR4
F 5′-ATCTTCCTGCCCACCATCTACTCCATCATC-3′(配列番号9)
R 5′-ATCCAGACGCCAACATAGACCACCTTTTCA-3′(配列番号10)
レーン構成(濃度は最終濃度(以下「FC」で示す)として表す)
1: M-CSF(FC: 25ng/ml)+Gangliosides(Bovine Brain GD1a SIGMA)(FC: 100ug/ml)
2: M-CSF(FC: 5ng/ml)+IL-3(FC: 0.5ng/ml)(非特許文献2)
3: M-CSF(FC: 25ng/ml)+IL-6(FC: 20ng/ml) +LIF(FC: 1000unit/ml) (非特許文献3)
4: M-CSF(FC: 25ng/ml)
5: M-CSF(FC: 25ng/ml)+ 植物由来Folch抽出水相画分
6: No Culture
7: No Culture
1-6:ヒト単球、7:ヒト骨髄(Clontech社 Human Bone Marrow Marathon-Ready cDNA)
rhM-CSFは、終濃度25ng/mlになるように添加した。その結果、培養二週間目の生細胞の数をcell-titer Glo(Promega社)によってルシフェラーゼ活性として定量化した。つまり、GM1、GD1a、GT1bおよびそれらのMixを用いて培養を行ったが、いずれにも同程度に、強い幹細胞誘導活性を示した(図3)。また、細胞の形態にも差は認められなかった(写真は培養二週間目)(図4)。
1: GM1 (FC: 25ng/ml)、
2: GD1a(FC: 25ng/ml)、
3: GT1b FC: 25ng/ml)、
4: GM1, GD1a, GT1bの等量混合物(Mix)、合計のFC: 25ng/ml)、
5: M-CSFのみ、
6: 血清のみ。
レンコン、琉球朝顔の茎からの抽出は、いずれも前述サツマイモの茎と同条件にて抽出した。尚、活性の比較は、抽出に用いた乾燥重量を元に標準化した。
幹細胞投与動物モデルによる治癒効果(肝硬変モデルマウスを用いた治療試験例)
四塩化炭素(1ml/kg体重)週2回投与を12週間連続して実験用マウスに人為的に肝硬変を引き起こす。この肝硬変モデルマウスに本発明のヒト単球由来脱分化幹細胞(hMDDSC)を尾静脈より2回投与し(1投与後1週間目に2回目、1個体あたり1 x 105細胞)、2回目の投与後1週後(最初の投与から2週間目)に肝臓を採取し、組織切片による病理解析と生化学的分析を行った。四塩化炭素によって誘導された肝炎では、ウイルス性肝炎同様に炎症部でSDF1(Stromal cell derived factor-1)が高発現することが報告されており(Jung et al., 2006)、本発明のhMDDSCはSDF1のレセプターであるCXCR4を高発現しているため、これらの結合を介してhMDDSCが炎症部に集積し、組織周囲に治癒効果を及ぼすことが期待される(Kollet et al., 2003; Nervi et al., 2006)。
採取固定されたマウス肝臓からパラフィン切片を作製し、抗コラーゲンI抗体で線維構造の主成分であるコラーゲン線維を検出した(図7、茶褐色)。同時に細胞核を青色に染色した(ヘマトきシレン染色)。
上段は肝硬変誘導後hMDDSC投与を行わず生理食塩水を投与した対照実験、下段はhMDDSCを2回静脈投与したのもの各3例を示した。hMDDSC投与により抗コラーゲン抗体で検出される太い線維束(上段矢印)が顕著に消失している。
2.生化学的解析
A)III型プロコラーゲンペプチド
同様マウスモデルによる肝硬変治療実験で血中のIII型プロコラーゲンペプチドの血中濃度を測定した。III型プロコラーゲンペプチド(Pro-collagen type III peptide (PIIIP)) はコラーゲン前駆体に存在する末端ペプチドであり、コラーゲン産生時に消化されてペプチドとして血中、組織中に遊離するため、コラーゲンの生産量を反映したマーカーとして用いられている(Giannini et al., 2001)。2週間の治療試験直後のマウス尾部より血液を採取し、血漿中のPIIIPをELISA法(CUSABIO CSB-E08095)により測定した(表2)。
肝組織内部の総線維量を組織から直接的に定量する目的で、コラーゲンの構成分子であるヒドロキシプロリンの肝組織中の含有量を測定した。2週間の治療処置後採取された肝臓を破砕均質化し、水酸化ナトリウム処理によって含有タンパク質を分解し、Chloramine T とdimethylaminobenzaldehydeのヒドロキシプロリン特異的呈色反応によりヒドロキシプロリン濃度を測定した(表3、Reddy et al, 1996)。
マウス肝硬変モデルにおいて本発明のhMDDSCを用いた治療はこのようにわずか2投与2週間の治療処置/期間で、大幅な線維生産の抑制と、線維組織の除去減少を引き起こすことを特徴とする。その結果、肝硬変状態からの速やかな脱出と正常肝組織への修復に働き、肝再生を促す画期的な治療システムである。
Jung YJ, Ryu KH, Cho SJ, Woo SY, Seoh JY, Chun CH, Yoo K, Moon IH, Han HS. Syngenic bone marrow cells restore hepatic function in carbon tetrachloride-induced mouse liver injury. Stem Cells Dev. 2006, 15, 687-695.
Kollet O, Shivtiel S, Chen YQ, Suriawinata J, Thung SN, Dabeva MD, Kahn J, Spiegel A, Dar A, Samira S, Goichberg P, Kalinkovich A, Arenzana-Seisdedos F, Nagler A, Hardan I, Revel M, Shafritz DA, Lapidot T. HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver. J Clin Invest. 2003, 112, 160-169.
Nervi B, Link DC, DiPersio JF. Cytokines and hematopoietic stem cell mobilization. J Cell Biochem. 2006, 99, 690-705.
Giannini E, Caglieris S, Ceppa P, Risso D, Lantieri PB, Testa R. Serum pro-collagen III peptide levels are related to lobular necrosis in untreated patients with chronic hepatitis C. Eur J Gastroenterol Hepatol. 2001, 13, 137-141.
Reddy GK, Enwemeka CS. A simplified method for the analysis of hydroxyproline in biological tissues. Clin Biochem. 1996, 29, 225-229.
Claims (22)
- 単球を(i)M−CSFおよび(ii)ガングリオシド及び水溶性植物抽出物からなる群から選ばれる少なくとも1種の存在下で培養し、脱分化させることにより得られる幹細胞。
- 水溶性植物抽出物の単球を脱分化させる有効成分が糖もしくは複合糖質である、請求項1に記載の幹細胞。
- 水溶性植物抽出物の単球を脱分化させる有効成分の分子量が1000〜500000である請求項1に記載の幹細胞。
- 水溶性植物抽出物の単球を脱分化させる有効成分が、ConAカラムに吸着される、請求項1に記載の幹細胞。
- 水溶性植物抽出物の単球を脱分化させる有効成分が、アニオン交換樹脂に吸着される請求項1に記載の幹細胞。
- 水溶性植物抽出物が植物由来Folch抽出水相画分もしくはその精製物である、請求項1に記載の幹細胞。
- 単球がヒト単球である請求項1記載の幹細胞。
- 未分化マーカーNanog, Nestin, c-Kit, CD9, Oct3/4の少なくとも1種を発現しており、単球をM-CSF単独存在下培養した場合に得られた幹細胞と比較した場合、CXCR4遺伝子が有意に強く発現していることを特徴とする請求項1〜7のいずれかに記載の幹細胞。
- 未分化マーカーNanog, Nestin, c-Kit, CD9, Oct3/4の少なくとも1種を発現し、かつCXCR4遺伝子が有意に強く発現していることを特徴とする幹細胞。
- 単球を(i)M−CSFおよび(ii)ガングリオシド及び水溶性植物抽出物からなる群から選ばれる少なくとも1種の存在下で培養することを特徴とする幹細胞の生産方法。
- 培養期間が7日から14日間である請求項6記載の方法。
- (i)M−CSFおよび(ii)ガングリオシド及び水溶性植物抽出物からなる群から選ばれる少なくとも1種を含む単球の脱分化誘導培地。
- 請求項1〜9のいずれかに記載の幹細胞を有効成分として含有する医薬組成物。
- 請求項1〜9のいずれかに記載の幹細胞を有効成分として含有する細胞医薬用剤。
- (i)M−CSFおよび(ii)ガングリオシド及び水溶性植物抽出物からなる群から選ばれる少なくとも1種を有効成分とする脱分化誘導剤。
- ガングリオシド及び水溶性植物抽出物からなる群から選ばれる少なくとも1種を有効成分とする細胞、組織もしくは器官の損傷に関係する疾患の治療剤。
- 前記疾患が外傷、炎症性疾患、骨・軟骨の損傷、循環器疾患、神経疾患、肝疾患および腎疾患、糖尿病、アトピー性皮膚炎、GVHDからなる群から選ばれる、請求項16に記載の治療剤
- 前記疾患が外傷、膵炎、放射線損傷、皮膚筋炎、多発性筋炎、壊死性筋膜炎、慢性気管支炎、骨折、骨粗鬆症、骨軟骨骨折、骨軟骨炎、拡張型心筋症、心筋梗塞、虚血性心筋症、心不全、心筋肥大、うっ血性心不全、再狭窄、不整脈、アテローム性動脈硬化症、血管炎、末梢ニューロパシー、ニューロパシー痛、脳卒中、脳炎、髄膜炎、糖尿病性ニューロパシー、注意欠陥障害、自閉症、アルツハイマー病、パーキンソン病、クロイツフェルト−ヤコブ病、脳または脊髄外傷もしくは虚血、肝硬変、慢性肝炎、慢性腎不全、糸球体腎炎、腎虚血、糖尿病、アトピー性皮膚炎、GVHDからなる群から選ばれる、請求項16に記載の治療剤。
- 少なくとも請求項1〜9記載の幹細胞を必須構成成分とする細胞医薬用キット。
- (i)M−CSFおよび(ii)ガングリオシド及び水溶性植物抽出物からなる群から選ばれる少なくとも1種を必須構成成分とする脱分化細胞産生キット。
- さらに単球を構成成分として含む請求項20記載のキット。
- ガングリオシドがGD1a、GD1b、GD2、GD3、GM1、GM2、GM3、GT1b、およびGQ1bからなる群から選ばれる少なくとも1種である、請求項1〜21のいずれかに記載の幹細胞、幹細胞の生産方法、単球の脱分化誘導培地、細胞医薬用剤、治療剤、脱分化誘導剤、細胞医薬用キットまたは脱分化細胞産生キット。
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CN102399741A (zh) * | 2010-09-19 | 2012-04-04 | 林雄斌 | 逆向分化体细胞产生造血干细胞的培养液、方法及用途 |
JPWO2018052082A1 (ja) * | 2016-09-14 | 2019-06-24 | 株式会社Tesホールディングス | Lin28a活性化剤及びその使用 |
CN107904202B (zh) * | 2017-11-22 | 2018-11-20 | 北京恩诺生物科技有限公司 | 一种制备多能干细胞样细胞的方法、组合物和应用 |
JP6375076B1 (ja) * | 2018-02-19 | 2018-08-15 | 株式会社 バイオミメティクスシンパシーズ | 間葉系幹細胞を用いたアトピー性皮膚炎治療における治療効果予測判定法 |
JP6574292B2 (ja) * | 2018-07-21 | 2019-09-11 | 株式会社 バイオミメティクスシンパシーズ | 間葉系幹細胞を用いたアトピー性皮膚炎治療における治療効果予測判定法 |
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US4778787A (en) * | 1985-12-20 | 1988-10-18 | Trustees Of Boston University | Method for treatment of angina and myocardial infarctions with omental lipids |
US5272138A (en) * | 1988-02-12 | 1993-12-21 | The Biomembrane Institute | Naturally occurring gangliosides containing de-N-acetyl-sialic acid and their applications as modifiers of cell physiology |
US6084060A (en) * | 1996-12-09 | 2000-07-04 | Imclone Systems Incorporated | Composition and method for preserving progenitor cells |
DE19651443A1 (de) * | 1996-12-11 | 1998-06-18 | Hoechst Ag | Selbstverstärkende, pharmakologisch kontrollierbare Expressionssysteme |
EP0893493A3 (de) * | 1997-07-21 | 2002-12-04 | Aventis Pharma Deutschland GmbH | Genetisch veränderte Zellen und deren Verwendung in der Prophylaxe oder Therapie von Erkrankungen |
US20030157113A1 (en) * | 1999-12-28 | 2003-08-21 | Terman David S. | Compositions and methods for treatment of neoplastic disease |
DE10214095C1 (de) * | 2002-03-28 | 2003-09-25 | Bernd Karl Friedrich Kremer | Dedifferenzierte, programmierbare Stammzellen monozytären Ursprungs, sowie deren Herstellung und Verwendung |
TWI288779B (en) * | 2002-03-28 | 2007-10-21 | Blasticon Biotech Forschung | Dedifferentiated, programmable stem cells of monocytic origin, and their production and use |
CA2519803A1 (en) * | 2003-03-27 | 2004-10-14 | Janssen Pharmaceutica N.V. | Use of erythropoietin in stroke recovery |
CA2547570A1 (en) * | 2003-12-02 | 2005-06-23 | Celgene Corporation | 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione for induction of fetal hemoglobin in individuals having anemia |
US20050260748A1 (en) * | 2004-02-27 | 2005-11-24 | Michigan State University | Adult stem cells and uses thereof |
BRPI0720596B1 (pt) | 2006-12-29 | 2017-10-24 | Dow Agrosciences Llc | Methods for producing and transforming a single plant cell |
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CA2977820A1 (en) | 2010-06-03 |
TW201024415A (en) | 2010-07-01 |
JP5800505B2 (ja) | 2015-10-28 |
US20110223143A1 (en) | 2011-09-15 |
BRPI0921371A2 (pt) | 2014-11-18 |
CA2744289A1 (en) | 2010-06-03 |
RU2011126165A (ru) | 2013-01-10 |
IL212638A (en) | 2017-08-31 |
CO6341484A2 (es) | 2011-11-21 |
MX336067B (es) | 2016-01-06 |
EP2365061A1 (en) | 2011-09-14 |
KR20110094084A (ko) | 2011-08-19 |
AU2009320881B2 (en) | 2015-01-22 |
ZA201103268B (en) | 2012-07-25 |
KR101682731B1 (ko) | 2016-12-05 |
WO2010061781A1 (ja) | 2010-06-03 |
AR074406A1 (es) | 2011-01-12 |
US9169463B2 (en) | 2015-10-27 |
CA2977823A1 (en) | 2010-06-03 |
TWI539000B (zh) | 2016-06-21 |
CN102245757B (zh) | 2014-11-26 |
MX2011005480A (es) | 2011-06-20 |
AU2009320881A1 (en) | 2010-06-03 |
EP2365061A4 (en) | 2013-03-13 |
RU2573906C2 (ru) | 2016-01-27 |
CN102245757A (zh) | 2011-11-16 |
IL212638A0 (en) | 2011-07-31 |
US20160008434A1 (en) | 2016-01-14 |
UA110691C2 (uk) | 2016-02-10 |
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