JP2016102129A - 骨・軟部に発生する巨細胞性腫瘍または軟骨肉腫の予防または治療剤 - Google Patents
骨・軟部に発生する巨細胞性腫瘍または軟骨肉腫の予防または治療剤 Download PDFInfo
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- chondrosarcoma
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Abstract
Description
骨巨細胞腫は、若年〜中高年の膝関節周囲に好発する良性腫瘍で、男女比は1:1.3〜1.5で女性の罹患率が高い。また、全骨腫瘍のうちの約5%、良性骨腫瘍のうちの約20%を占めており、良性腫瘍ではあるが、再発率が10〜30%と高く、また時に肺転移や悪性転化により治療に難渋する場合がある。病理所見では多核巨細胞と単球細胞の増生が主体で、間に紡錘型細胞をみとめる。腫瘍の本体は、この多核巨細胞ではなく、間質に存在する線維芽細胞様の紡錘形細胞と考えられている。さらに膝関節、肩関節、手関節などの関節近傍に発生するため、いかに再発を予防しかつ関節機能を温存する治療を行うかが重要である。
腱鞘巨細胞腫は、腱鞘、関節、滑液包の滑膜から発生する腫瘍性疾患である。病変の増殖型に基づいて限局型とびまん型に分類され、一般的に限局型の病変は腱鞘巨細胞腫、びまん型の腱鞘巨細胞腫は色素性絨毛結節性滑膜炎と同義とされている。腱鞘巨細胞腫は、30〜50歳代の女性に好発し、手指の関節近傍や屈筋腱上に約85%が発生し、次いで足趾に発生する。骨内に浸潤することもある。病理所見では、卵円形〜紡錘形の組織球様単核細胞が主体で、多核巨細胞と泡沫細胞にヘモジデリン沈着を伴う。治療は、良性腫瘍に準じて腫瘍切除術(単純摘出術)を行うが、再発率は4〜30%と報告されている。
色素性絨毛結節性滑膜炎は、40歳以下の比較的若年成人でやや女性に多く、膝関節が最も多く、股・足・肘・肩関節などにも発生する。関節内に滑膜の絨毛像や結節様の増殖をきたし、関節血症をしばしば認め、また骨内にも浸潤するため二次変形性関節症を生じる。病理所見では、滑膜細胞様の単核細胞と多核巨細胞、泡沫細胞、ヘモジデリン貪食細胞、炎症性細胞などが混在する。治療は、手術で腫瘍を切除するが全切除が困難で、再発率は40〜50%と高い。
骨巨細胞腫、腱鞘巨細胞腫、色素性絨毛結節性滑膜炎はいずれも、現時点では手術以外の有効な治療法は開発されていない。
軟骨肉腫は原発性悪性骨腫瘍の約20%を占め、骨肉腫に次いで頻度が高い。組織学的に通常型軟骨肉腫、骨膜性軟骨肉腫、間葉性軟骨肉腫、脱分化型軟骨肉腫、淡明細胞型軟骨肉腫、骨外性粘液型軟骨肉腫などに分類される。通常型は、30〜50歳代に好発しやや男性に多い。骨盤骨に最も多く発生し、次いで肋骨・大腿骨近位・上腕骨近位・大腿骨遠位に多い。間葉性軟骨肉腫は通常型軟骨肉腫よりも若い10〜30歳代に好発し、顎骨・脊椎・腸骨・肋骨・大腿骨遠位部などに好発する。脱分化型軟骨肉腫は、低悪性通常型軟骨肉腫から非軟骨性高悪性腫瘍が生じるもので、両者は明瞭な境界をもって隣接している。50〜60歳代に好発し、大腿骨が最も多く、次いで骨盤・上腕骨に多い。淡明細胞型軟骨肉腫は、20〜50歳代に好発し、約2/3は上腕骨骨頭・大腿骨骨頭に発生する。その他、頭蓋骨・脊椎・手足の骨に発生する。骨外性粘液型軟骨肉腫は、40〜50歳代に好発し、大腿などの四肢の近位部や体幹の深部軟部組織や四肢末端部や縦隔、後腹膜などの軟部組織に生じることがある。これらは、現在のところ手術以外の有効な治療は開発されていない。
本発明者らは、これらの知見に基づいてさらに研究を重ねた結果、本発明を完成するに至った。
[1]非ステロイド性抗炎症剤またはチアゾリジン誘導体を有効成分として含有する、骨・軟部に発生する巨細胞性腫瘍または軟骨肉腫の予防または治療剤;
[2]非ステロイド性抗炎症剤がザルトプロフェン、ジクロフェナク、インドメタシン、オキサプロジン、アセトアミノフェンおよびケトプロフェンからなる群から選択される、前記[1]に記載の予防または治療剤;
[3]チアゾリジン誘導体がトログリタゾン、ロシグリタゾン、ピオグリタゾン、バラグリタゾンおよびリボグリタゾンからなる群から選択される、前記[1]に記載の予防または治療剤;
[4]骨・軟部に発生する巨細胞性腫瘍が、骨巨細胞腫、腱鞘巨細胞腫および色素性絨毛結節性滑膜炎からなる群から選択される、前記[1]から[3]のいずれか1つに記載の予防または治療剤;
[5]以下の工程を含む、骨・軟部に発生する巨細胞性腫瘍または軟骨肉腫の予防または治療剤のスクリーニング方法
(1)骨・軟部に発生する巨細胞性腫瘍または軟骨肉腫由来細胞を被検物質の存在下または非存在下で培養する工程、
(2)両条件下、PPARγ遺伝子の発現、および
(i)アポトーシス関連遺伝子の発現、または
(ii)脂肪細胞分化関連遺伝子の発現もしくは脂質の発現
をそれぞれ測定する工程、
(3)被検物質非存在下と比較して、PPARγ遺伝子の発現、および
(i)アポトーシス関連遺伝子の発現、または
(ii)脂肪細胞分化関連遺伝子の発現もしくは脂質の発現
を有意に変動させる被検物質を選択する工程;
[6]骨・軟部に発生する巨細胞性腫瘍が、骨巨細胞腫、腱鞘巨細胞腫および色素性絨毛結節性滑膜炎からなる群から選択される、前記[5]に記載のスクリーニング方法;
[7]非ステロイド性抗炎症剤またはチアゾリジン誘導体の有効量を対象に投与することを含む、骨・軟部に発生する巨細胞性腫瘍または軟骨肉腫の予防または治療方法;
[8]非ステロイド性抗炎症剤がザルトプロフェン、ジクロフェナク、インドメタシン、オキサプロジン、アセトアミノフェンおよびケトプロフェンからなる群から選択される、前記[7]に記載の予防または治療方法;
[9]チアゾリジン誘導体がトログリタゾン、ロシグリタゾン、ピオグリタゾン、バラグリタゾンおよびリボグリタゾンからなる群から選択される、前記[7]に記載の予防または治療方法;
[10]骨・軟部に発生する巨細胞性腫瘍が、骨巨細胞腫、腱鞘巨細胞腫および色素性絨毛結節性滑膜炎からなる群から選択される、前記[7]から[9]のいずれか1つに記載の予防または治療方法;
[11]骨・軟部に発生する巨細胞性腫瘍または軟骨肉腫の予防または治療に使用するための、非ステロイド性抗炎症剤またはチアゾリジン誘導体;
[12]非ステロイド性抗炎症剤がザルトプロフェン、ジクロフェナク、インドメタシン、オキサプロジン、アセトアミノフェンおよびケトプロフェンからなる群から選択される、前記[11]に記載の非ステロイド性抗炎症剤またはチアゾリジン誘導体;
[13]チアゾリジン誘導体がトログリタゾン、ロシグリタゾン、ピオグリタゾン、バラグリタゾンおよびリボグリタゾンからなる群から選択される、前記[11]に記載の非ステロイド性抗炎症剤またはチアゾリジン誘導体;
[14]骨・軟部に発生する巨細胞性腫瘍が、骨巨細胞腫、腱鞘巨細胞腫および色素性絨毛結節性滑膜炎からなる群から選択される、前記[11]から[13]のいずれか1つに記載の非ステロイド性抗炎症剤またはチアゾリジン誘導体;
などを提供する。
また、本発明の予防または治療剤が適用できる軟骨肉腫としては、通常型軟骨肉腫、骨膜性軟骨肉腫、間葉性軟骨肉腫、脱分化型軟骨肉腫、淡明細胞型軟骨肉腫、骨外性粘液型軟骨肉腫などが挙げられる。
あるいは、本発明の予防または治療剤は、PPARγの発現を認める腫瘍に用いることもできる。PPARγの発現を認める腫瘍としては、乳癌、大腸癌、肺癌、甲状腺癌、食道癌、胃癌、膵臓癌、肝臓癌、腎臓癌、膀胱癌、卵巣癌、子宮頸癌、前立腺癌、悪性黒色腫、白血病、悪性リンパ腫、脂肪肉腫、平滑筋肉腫、骨肉腫などが挙げられる。
PCRにおいてプライマーとして用いられるオリゴヌクレオチドのセットとしては、例えば、前述のPPARγ遺伝子の転写産物を特異的に検出し得る核酸プライマーを挙げることができる。1つの好ましい態様においては、本発明の検査方法に用いられる核酸プライマーとしては、約15塩基以上、好ましくは約15〜約50塩基、より好ましくは約15〜約30塩基、いっそう好ましくは約15〜約25塩基の連続したヌクレオチド配列の長さを有し、約100bp〜数kbpのDNA断片を増幅するようにデザインされたポリヌクレオチド(センス鎖)配列に相補的なポリヌクレオチド、及び前記のポリヌクレオチド配列に相補的なヌクレオチド配列を有するポリヌクレオチド(アンチセンス鎖)にハイブリダイズし得るポリヌクレオチドのオリゴヌクレオチドのセットが挙げられる。
本発明の人工骨に用いる材料としては、公知の整形外科用生体材料、例えば、金属材料、セラミックス材料、高分子材料、タンパク質材料またはこれらの複合材料が挙げられる。
上記金属材料としては、例えば、チタン、チタン合金、ステンレス、コバルト−クロム合金等が挙げられる。
上記セラミックス材料としては、例えば、アルミナセラミック、単結晶アルミナセラミック、ジルコニアセラミック等のバイオイナート・セラミックス、バイオグラス(Hench等、Biomed.Master.Symp.,2,117(1972))、ヒドロキシアパタイト(青木ら、セラミックス,10,469(1975))、アパタイト−ウオラストナイト(AW)−ガラス(Bull.Inst.Chem.Res.KyotoUni.,60,260(1982))、TCPセラミックス(Ca3(PO4)2)等のバイオアクティブ・セラミックスが挙げられる。
上記高分子材料としては、例えば、ポリメチルメタクリレート(PMMA)、高密度ポリエチレン(HDP)、シリコンラバー、テフロン(登録商標)、ポリエステル、ポリ乳酸、PVAハイドロゲル等が挙げられる。
上記タンパク質材料としては、例えば、コラーゲン、フィブリン、キチン、キトサン等が挙げられる。
(1)骨・軟部に発生する巨細胞性腫瘍または軟骨肉腫由来細胞を被検物質の存在下または非存在下で培養する工程、
(2)両条件下、PPARγ遺伝子の発現、および
(i)アポトーシス関連遺伝子の発現、または
(ii)脂肪細胞分化関連遺伝子の発現もしくは脂質の発現
をそれぞれ測定する工程、
(3)被検物質非存在下と比較して、PPARγ遺伝子の発現、および
(i)アポトーシス関連遺伝子の発現、または
(ii)脂肪細胞分化関連遺伝子の発現もしくは脂質の発現を有意に変動させる被検物質を選択する工程。
本発明において、被検物質は、特に制限があるわけではなく、例えば、ペプチド、タンパク質、非ペプチド性化合物、合成化合物、発酵生産物、細胞抽出液、植物抽出液、動物組織抽出液などが用いられ、これら化合物は新規な化合物であってもよいし、公知の化合物であってもよい。そのなかでも、PPARγの発現誘導活性を有し、かつPPARγの作動活性を有する物質であることが好ましく期待される。そのような被検物質としては、非ステロイド性抗炎症剤が挙げられる。非ステロイド性抗炎症剤としては、上記と同様に、ザルトプロフェン、ジクロフェナク、インドメタシンなどが挙げられる。また、非ステロイド性抗炎症剤以外では、例えば、上記と同様にチアゾリジン誘導体が挙げられる。チアゾリジン誘導体としては、例えば、ロシグリタゾン、ピオグリタゾン、トログリタゾン、バラグリタゾン、リボグリタゾンなどが挙げられる。
GCT培養細胞(case1:右大腿骨遠位部骨巨細胞腫患者、20歳代;case2:右大腿骨遠位部骨巨細胞腫患者、20歳代)を、96wellの培養プレートで培養し、ザルトプロフェンを各濃度(5、10、50、100、200μM)で添加し、24時間後にCell Counting Kit−8(CCK−8)(Dojindo社)で発色し、3時間後に450nmの吸光度を測定した(図1)。その結果、ザルトプロフェン濃度依存的に、細胞増殖が抑制されていることが確認できた。
また、上記case1のGCT培養細胞を、チャンバーカバースライドガラス上に培養し、24時間後にザルトプロフェンを、各濃度(100、200μM)で添加した。8時間後と24時間後に、4%パラホルムアルデヒドで固定し、Caspase3の染色と、Tunel assayを行いアポトーシスの有無について解析した。観察は、Keyence社の蛍光顕微鏡(BZ−9000)で行い、各濃度における陽性像を定量的に観察した(図2−5)。その結果、ザルトプロフェン濃度および投与時間依存的に、Tunel陽性率およびCaspase3陽性率が上昇されていることが確認できた。
上記case1のGCT培養細胞を、チャンバーカバースライドガラス上に培養し、24時間後に、ザルトプロフェンを、各濃度(10、50、100、200μM)で添加した。24時間後に、4%パラホルムアルデヒドで固定し、PPARγの染色を行った。観察は、Keyence社の蛍光顕微鏡(BZ−9000)で行い、各濃度における陽性像を定量的に観察した(図6、7)。その結果、ControlではPPARγの発現は約15%であったが、ザルトプロフェン濃度依存的に、PPARγの発現が亢進していることが確認できた。
PPARγは、脂肪細胞分化に必須の転写因子であることが報告されている。そこで、上記case1のGCT培養細胞を、チャンバーカバースライドガラス上に培養し、コンフレントとなったところで、ザルトプロフェンを、各濃度(10、50、100μM)で添加した。24時間後より脂肪分化誘導培地(STREMPRO Adipogenesis Differentiation Kit;Invitrogen)で7〜14日培養し、脂肪細胞への分化をHCS LipidTOX Green neutral lipid stain(Invitrogen)で解析した(図8、9)。その結果、ControlではHCS LipidTOX Greenの陽性像がわずかであったが、ザルトプロフェン濃度依存的に、HCS LipidTOX Greenの陽性像が亢進していることが確認できた。
腫瘍による疼痛に対して、ザルトプロフェン錠であるソレトン錠80(一般名:ザルトプロフェン80mg、日本ケミファ株式会社)を3錠/日で約28日間投与された後に手術を施行した30代の男性の手術切除標本と、対象としてザルトプロフェン未投与の骨巨細胞腫の手術切除標本をCaspase3の染色と、Tunel assayを行いアポトーシスの有無について解析した。観察は、Keyence社の蛍光顕微鏡(BZ−9000)で行った(図10)。その結果、ザルトプロフェン未投与のGCT患者由来の細胞ではTunel陽性細胞およびCaspase3陽性細胞がほとんど確認できなかったが、ザルトプロフェン投与された患者由来の細胞では、Tunel陽性細胞およびCaspase3陽性細胞が確認できた。
腫瘍による疼痛に対して、ザルトプロフェン錠であるソレトン錠80(一般名:ザルトプロフェン80mg、日本ケミファ株式会社)を3錠/日で約28日間投与された後に手術を施行した30代の男性の手術切除標本と、対象としてザルトプロフェン未投与の骨巨細胞腫の手術切除標本をPPARγの染色を行い、PPARγの発現を解析した。観察は、Keyence社の蛍光顕微鏡(BZ−9000)で行った(図11)。その結果、ザルトプロフェン未投与のGCT患者由来の細胞ではPPARγ発現細胞がほとんど確認できなかったが、ザルトプロフェン投与された患者由来の細胞では、PPARγ発現細胞が確認でき、さらに脂肪分化が確認された。
実施例1と同様の方法で、GCT培養細胞(case1、case2)を培養し、非ステロイド性抗炎症剤(アセトアミノフェン、インドメタシンまたはジクロフェナク)またはトログリタゾンを各濃度で添加して450nmの吸光度を測定した(図12、13)。その結果、非ステロイド性抗炎症剤濃度依存的に、細胞増殖が抑制されていることが確認できた。
96wellの培養プレートで細胞(case1、case2)を培養し、PPARγsiRNA、ネガティブコントロールsiRNAおよびトランスフェクション試薬のみ(Thermo Scientific DharmaFECT:Thermo Scientific社)を48時間反応させたのちに通常の培養液で48時間培養し、その後ザルトプロフェンを200μMまたはトログリタゾンを60μMで添加し、72時間後にCell Counting Kit−8(CCK−8)(Dojindo社)で発色し、3時間後に450nmの吸光度を測定した(図14、15)。その結果、PPARγ siRNA添加群では、ザルトプロフェンの効果が有意に抑制されたことが確認できた。
実施例1と同様に、腱鞘巨細胞腫培養細胞(右膝腱鞘巨細胞腫患者、30歳代)および色素性絨毛結節性滑膜炎培養細胞(左膝色素性絨毛結節性滑膜炎患者、30歳代)を培養し、ザルトプロフェンまたはトログリタゾンを各濃度で添加し、吸光度を測定した(図16、17)。その結果、ザルトプロフェンまたはトログリタゾン濃度依存的に、細胞増殖が抑制されていることが確認できた。
また実施例1と同様に、腱鞘巨細胞腫培養細胞および色素性絨毛結節性滑膜炎培養細胞について、Caspase3の染色およびTunel assayを行いアポトーシスの有無を解析した(図18−25)。その結果、ザルトプロフェンを濃度400μMまたはトログリタゾンを濃度200μMで添加された細胞は、Controlに比べて、Tunel陽性率およびCaspase3陽性率が上昇していることが確認できた。
実施例2と同様に、腱鞘巨細胞腫由来細胞または色素性絨毛結節性滑膜炎由来細胞に、ザルトプロフェンを濃度400μMまたはトログリタゾンを濃度200μMで添加し、PPARγ陽性像を観察した(図26−29)。その結果、ザルトプロフェンまたはトログリタゾン添加細胞ではPPARγの発現が確認できた。
実施例3と同様に、PPARγは、脂肪細胞分化に必須の転写因子であることが報告されている。そこで、腱鞘巨細胞腫由来細胞または色素性絨毛結節性滑膜炎由来細胞に、ザルトプロフェンを濃度400μMで添加し、脂肪細胞への分化を解析した(図30、31)。その結果、ザルトプロフェン添加細胞ではHCS LipidTOX Greenの陽性像がControlに比べて亢進していることが確認できた。
実施例1と同様の方法で、GCT培養細胞(case1、case2)、腱鞘巨細胞腫(GCT of tendon sheath)由来細胞または色素性絨毛結節性滑膜炎(diffuse−type GCT)由来細胞を培養し、チアゾリジン誘導体であるピオグリタゾンを各濃度で添加して450nmの吸光度を測定した(図32)。その結果、ピオグリタゾン濃度依存的に、細胞増殖が抑制されていることが確認できた。
骨巨細胞腫患者、腱鞘巨細胞腫患者または色素性絨毛結節性滑膜炎患者に対して、ソレトン錠80(一般名:ザルトプロフェン80mg、日本ケミファ株式会社)を3錠/日(朝・昼・夕に1錠ずつ服用)で服用させ、数か月ごとにMRIで腫瘍のサイズを評価した。代表症例として、骨巨細胞腫の骨盤部再発例(34歳、女性:図33、34)において、2ヶ月後(図35)、4ヵ月後(図36)において次第に腫瘍の縮退が確認できた。また、右膝の色素性絨毛結節性滑膜炎の再発例(26歳、女性:図37、38)において、3ヵ月後(図39、40)にMRI造影効果の減弱が確認でき、疼痛・膝関節可動域に改善が見られた。さらに、別の右膝の色素性絨毛結節性滑膜炎の再発例(38歳、女性:図41、42)において2ヵ月後(図43、44)に腫瘤の縮小が確認でき、疼痛改善が見られた。
実施例1と同様に、軟骨肉腫由来細胞株を培養し、トログリタゾン、ピオグリタゾンまたはザルトプロフェンを各濃度で添加し、吸光度を測定した(図45)。その結果、トログリタゾン、ピオグリタゾンまたはザルトプロフェン濃度依存的に、細胞増殖が抑制されていることが確認できた。
また実施例1と同様に、軟骨肉腫由来細胞株について、Caspase3の染色を行いアポトーシスの有無を解析した(図46、47)。その結果、ザルトプロフェンを濃度200μM、トログリタゾンを濃度100μMまたはピオグリタゾンを濃度200μMで添加された細胞は、Controlに比べて、Caspase3陽性率が上昇していることが確認できた。
実施例2と同様に、軟骨肉腫由来細胞株に、ザルトプロフェンを濃度200μM、トログリタゾンを濃度100μMまたはピオグリタゾンを濃度200μMで添加し、PPARγ陽性像を観察した(図48、49)。その結果、ザルトプロフェン、トログリタゾンまたはピオグリタゾン添加細胞ではPPARγの発現が確認できた。
本出願は、日本で出願された特願2012−070351(出願日:平成24年3月26日)および特願2012−235784(出願日:平成24年10月25日)を基礎としており、その内容はすべて本明細書に包含されるものとする。
Claims (13)
- 非ステロイド性抗炎症剤またはPPARγアゴニストであるチアゾリジン誘導体を有効成分として含有する、骨・軟部に発生する巨細胞性腫瘍患者または軟骨肉腫患者における、腫瘍細胞増殖抑制剤。
- 非ステロイド性抗炎症剤またはPPARγアゴニストであるチアゾリジン誘導体を有効成分として含有する、骨・軟部に発生する巨細胞性腫瘍患者または軟骨肉腫患者における、腫瘍サイズ縮小剤。
- 非ステロイド性抗炎症剤またはPPARγアゴニストであるチアゾリジン誘導体を有効成分として含有する、骨・軟部に発生する巨細胞性腫瘍患者または軟骨肉腫患者における、関節可動域改善剤。
- 非ステロイド性抗炎症剤またはPPARγアゴニストであるチアゾリジン誘導体を有効成分として含有する、骨・軟部に発生する巨細胞性腫瘍患者または軟骨肉腫患者における、アポトーシスまたは脂肪細胞分化誘導剤。
- 非ステロイド性抗炎症剤またはPPARγアゴニストであるチアゾリジン誘導体を有効成分として含有する、骨・軟部に発生する巨細胞性腫瘍患者または軟骨肉腫患者における、PPARγ発現誘導剤。
- 非ステロイド性抗炎症剤またはPPARγアゴニストであるチアゾリジン誘導体を有効成分として含有する、骨・軟部に発生する巨細胞性腫瘍患者または軟骨肉腫患者における、疼痛改善剤。
- 非ステロイド性抗炎症剤またはPPARγアゴニストであるチアゾリジン誘導体を有効成分として含有する、骨・軟部に発生する巨細胞性腫瘍の予防または治療剤。
- 非ステロイド性抗炎症剤がザルトプロフェン、ジクロフェナク、インドメタシン、オキサプロジン、アセトアミノフェンおよびケトプロフェンからなる群から選択される、請求項1〜7のいずれか1項に記載の剤。
- チアゾリジン誘導体がトログリタゾン、ロシグリタゾン、ピオグリタゾン、バラグリタゾンおよびリボグリタゾンからなる群から選択される、請求項1〜8のいずれか1項に記載の剤。
- 骨・軟部に発生する巨細胞性腫瘍が、骨巨細胞腫、腱鞘巨細胞腫および色素性絨毛結節性滑膜炎からなる群から選択される、請求項1〜9のいずれか1項に記載の剤。
- 非ステロイド性抗炎症剤がザルトプロフェンである、請求項1〜10のいずれか1項に記載の剤。
- 非ステロイド性抗炎症剤がザルトプロフェンであり、ザルトプロフェンが240mg/日で投与される、請求項1〜11のいずれか1項に記載の剤。
- 非ステロイド性抗炎症剤がザルトプロフェンであり、ザルトプロフェンが28日〜4か月連続で投与される、請求項1〜12のいずれか1項に記載の剤。
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AU2013238126C1 (en) | 2018-06-14 |
AU2013238126B2 (en) | 2017-12-21 |
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AU2013238126A1 (en) | 2014-11-06 |
EP2832367A1 (en) | 2015-02-04 |
CA2868311C (en) | 2021-06-22 |
US10660882B2 (en) | 2020-05-26 |
CN104302322A (zh) | 2015-01-21 |
JP6205403B2 (ja) | 2017-09-27 |
US20150045396A1 (en) | 2015-02-12 |
WO2013146435A1 (ja) | 2013-10-03 |
CA2868311A1 (en) | 2013-10-03 |
JP5865995B2 (ja) | 2016-02-17 |
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CN106267210A (zh) | 2017-01-04 |
EP2832367A4 (en) | 2015-12-16 |
KR20140139070A (ko) | 2014-12-04 |
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