JP4307249B2 - 診断および治療における可溶性サイトケラチン1断片の使用 - Google Patents
診断および治療における可溶性サイトケラチン1断片の使用 Download PDFInfo
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Description
A. Beishuizen et al.、"Endogenous Mediators in Sepsis and Septic Shock", Advances in Clinical Chemistry, Vol. 33, 1999年55〜131頁 C. Gabay et al.、"Acute Phase Proteins and Other Systemic Responses to Inflammation", The New England Journal of Medicine, Vol. 340, No. 6, 1999年、448〜454頁 K. Reinhart et al.、"Sepsis and septischer Schock" [Sepsis and septic shock]、Intensivmedizin, Georg Thieme Verlag, Stuttgart, New York, 2001年56〜760頁 M. Assicot et al.、"High serum procalcitonin concentrations in patients with sepsis and infection"、The Lancet, Vol. 341, No. 8844, 1993年、515〜518頁
内毒素注射によりプロカルシトニン分泌を刺激するためにヒヒで実施された実験をもとに(H. Redl et al., "Procalcitonin release patterns in a baboon model of trauma and sepsis: Relationship to cytokines and neopterin", Crit Care Med 2000, Vol. 28, No. 11, 3659-3663頁およびH. Redl et al., "Non-Human Primate Models of Sepsis", in: Sepsis 1998年、2:243-253年参照)、ヒヒ(オス、約2歳、体重27から29kg)に、それぞれ静脈内で、体重1kg当たりLPS(Salmonella Typhimuriumuからのリポ多糖類、供給元:Sigma)100μgを投与した。注射の5から5.5時間後に、ドレタール(doletal)10mlを静脈内投与することにより、動物を死亡させた。死亡の60分以内に、全ての臓器および組織を解剖し、液体窒素中で凍結させることにより、安定化した。
個々の組織の試料を、免疫発光試験(immunoluminometric)を用いて行ったが、これは(ヒトプロカルシトニンを測定するために開発された本出願人のLU-MItest(登録商標)PCTと同様)、一方では、ポリスチレン管に固定化されたヒヒカルシトニンに対する抗体およびアクリジニウムエステルで標識され、ヒヒプロカルシトニンのN-末端を対象とするモノクローナル抗体を用いて行われる。このテストを用いて、個々の試料中のヒヒプロカルシトニンの含有率を、組換えヒトプロカルシトニンを使用する試験の校正の後に、測定した。
一方では健康なヒヒ(対照)の、かつ他方ではLPSを注射されたヒヒの細胞質肝臓細胞タンパク質抽出物を、プロテオーム分析で使用した。当初分析2Dゲル電気泳動で、タンパク質100μgを含有する肝臓抽出物を、9Mの尿素、70mMのDTT、両性電解質(pH2〜4)2%で安定化させ、次いで、J. Klose et al.、"Two-dimensional electrophoresis of proteins: An updated protocol and implications for a functional analysis of the genome", Electrophoresis 1995年、16, 1034-1059頁に記載されているように、分析2Dゲル電気泳動により分離する。2D塩基英道ゲル中のタンパク質の可視化を、銀染色法により行った(J. Heukeshoven et al.、"Improved silver staining procedure for fast staining in PhastSystem Development Unit. I. Staining of sodium dodecyl gels", Electrophoresis 1988年、9, 28〜32頁参照)。
図1(A)および1(B)に示されているように、LPS注射を投与されたヒヒの肝細胞抽出物は特に、既知の分子量を有するマーカー物質と比較して、約15700±500ダルトンの分子量がゲル電気泳動データをもとに推定されていて、かつ約5.5から6.5の等電点が、第1の次元からのタンパク質の相対位置から推測されている新規のタンパク質を含有した。
前記の可溶性サイトケラチン1断片の血清濃度を、敗血症マーカーであるプロカルシトニン(PCT)に関して高い値が見られた敗血症患者からの20の血清で測定した。敗血症血清の95%で、著しく高い濃度(3ng/ml以上)が見られた。
ポリスチレン管(Greiner製)を、PBS300μl中のペプチド(PLY17;SEQ ID NO:1)100ngで被覆した。室温で20時間インキュベーションした後に、BSA1%を含有するPBS2×4mlで洗浄した。次いで、ペプチド被覆された管を、続く測定を実施するための固体相として使用し、この測定で、固定化ペプチドおよび試料からのサイトケラチン1断片を、前記の部分配列に対するヒツジ抗体と競合させたが、この際、この抗体を、抗血清の形で加えた。
1. 試料100μg(敗血症結成または対照血清または校正物質溶液)を前記の管にピペット注入し;
2. 抗血清200μl(PBSで1:5000に希釈)をピペット注入し;
3. 振盪しながら、室温で3時間インキュベーションし;
4. 管から、未結合の抗体を洗い流し(PBS1mlを4回充填し、デカンテーションする);
5. 固体相-結合抗体を調製するために、PBS300ml、BSA1%中のアクリジニウムエステル標識されたロバ抗ヒツジ抗体(B.R.A.H.M.S Diagnostica)を加え;
6. 室温で2時間インキュベーションした後に、未結合の標識抗体を除去し、4と同様に洗い流し;
7. ルミノメーター(luminometer、Berthold製)を用いて、既知の方法で、固体相に結合しているアクリジニウムエステルを測定する。
Claims (5)
- 敗血症のin vitro測定のためのマーカーペプチドとしての、サイトケラチン1(SEQ ID NO:3)の完全アミノ酸配列中のアミノ酸185〜297(SEQ ID NO:5)およびサイトケラチン1の完全アミノ酸配列中の隣接アミノ酸20個までの配列を有し、ゲル電気泳動により測定して、15700±500ダルトンの分子量を有するか、または、前記断片のアミノ酸配列と少なくとも90%の相同性を有する、体液または体組織由来の可溶性サイトケラチン1断片の使用。
- 患者の生体液または組織試料中の選択された可溶性サイトケラチン1断片のin vitro定量による、敗血症の鑑別早期検出における、請求項1に記載の可溶性サイトケラチン1断片の使用。
- 敗血症を鑑別早期検出および検出するための方法において、サイトケラチン1(SEQ ID NO:3)の完全アミノ酸配列中のアミノ酸185〜297(SEQ ID NO:5)およびサイトケラチン1の完全アミノ酸配列中の隣接アミノ酸20個までの配列を有し、ゲル電気泳動により測定して、15700±500ダルトンの分子量を有する可溶性サイトケラチン1断片の存在および/または量を、患者の生体液または組織試料中でin vitroで測定し、測定した断片の存在および/または量から、敗血症の存在についての結論を導き出すことを特徴とする方法。
- in vitro免疫学的定量法であることを特徴とする、請求項3に記載の方法。
- 請求項4に記載のin vitro免疫学的定量法における特異的結合試薬としての、サイトケラチン1(SEQ ID NO:3)の完全アミノ酸配列中のアミノ酸185〜297(SEQ ID NO:5)およびサイトケラチン1の完全アミノ酸配列中の隣接アミノ酸20個までの配列を有し、ゲル電気泳動により測定して、15700±500ダルトンの分子量を有する可溶性サイトケラチン1断片に特異的に結合する抗体の使用。
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DE10130985A DE10130985B4 (de) | 2001-06-27 | 2001-06-27 | Verfahren zur Diagnose von Sepsis und schweren Infektionen unter Bestimmung löslicher Cytokeratin-1-Fragmente |
PCT/EP2002/006473 WO2003002600A1 (de) | 2001-06-27 | 2002-06-12 | Verwendung löslicher cytokeratin-1-fragmente in diagnostik und therapie |
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ATE282831T1 (de) | 2001-12-04 | 2004-12-15 | Brahms Ag | Verfahren zur diagnose von sepsis unter bestimmung löslicher cytokeratinfragmente |
DE50105971D1 (de) * | 2001-12-04 | 2005-05-25 | Brahms Ag | Verfahren zur Diagnose von Sepsis unter Bestimmung von CA 125 |
DE50103032D1 (de) | 2001-12-04 | 2004-09-02 | Brahms Ag | Verfahren zur Diagnose von Sepsis unter Bestimmung von CA 19-9 |
DE50103030D1 (de) | 2001-12-04 | 2004-09-02 | Brahms Ag | Verfahren zur Diagnose von Sepsis unter Bestimmung von S100B |
EP1318407B1 (de) | 2001-12-07 | 2004-09-29 | B.R.A.H.M.S Aktiengesellschaft | Verwendungen der Aldose-1-Epimerase (Mutarotase) für die Diagnose von Entzündungserkrankungen und Sepsis |
EP1355158A1 (de) * | 2002-04-19 | 2003-10-22 | B.R.A.H.M.S Aktiengesellschaft | Verfahren zur Diagnose von Entzündungserkrankungen und Infektionen unter Bestimmung des Phosphoproteins LASP-1 als Inflammationsmarker |
EP1355159A1 (de) * | 2002-04-19 | 2003-10-22 | B.R.A.H.M.S Aktiengesellschaft | Verwendungen von Fragmenten der Carbamoylphosphat Synthetase 1 (CPS 1) für die Diagnose von Entzündungserkrankungen und Sepsis |
JP4597741B2 (ja) * | 2005-03-31 | 2010-12-15 | 株式会社Mcbi | タンパク質、部分タンパク質および/もしくは部分ペプチド、またはそれらのプロファイルに基づく体外診断システム |
CN106442984B (zh) | 2010-04-21 | 2020-03-13 | 米密德诊断学有限公司 | 区分细菌与病毒感染的标记物和决定因素以及其使用方法 |
CN104204803B (zh) | 2012-02-09 | 2018-08-07 | 米密德诊断学有限公司 | 用于诊断感染的标记和决定因素和其使用方法 |
US10260111B1 (en) | 2014-01-20 | 2019-04-16 | Brett Eric Etchebarne | Method of detecting sepsis-related microorganisms and detecting antibiotic-resistant sepsis-related microorganisms in a fluid sample |
EP3699930B1 (en) | 2014-08-14 | 2024-02-07 | MeMed Diagnostics Ltd. | Computational analysis of biological data using manifold and a hyperplane |
WO2016059636A1 (en) | 2014-10-14 | 2016-04-21 | Memed Diagnostics Ltd. | Signatures and determinants for diagnosing infections in non-human subjects and methods of use thereof |
CN108699583B (zh) | 2016-03-03 | 2022-11-01 | 米密德诊断学有限公司 | 用于区分细菌和病毒感染的rna决定子 |
EP3482201B1 (en) | 2016-07-10 | 2022-12-14 | Memed Diagnostics Ltd. | Early diagnosis of infections |
EP3482200B1 (en) | 2016-07-10 | 2022-05-04 | Memed Diagnostics Ltd. | Protein signatures for distinguishing between bacterial and viral infections |
WO2018060998A1 (en) | 2016-09-29 | 2018-04-05 | Memed Diagnostics Ltd. | Methods of prognosis and treatment |
US11353456B2 (en) | 2016-09-29 | 2022-06-07 | Memed Diagnostics Ltd. | Methods of risk assessment and disease classification for appendicitis |
US10209260B2 (en) | 2017-07-05 | 2019-02-19 | Memed Diagnostics Ltd. | Signatures and determinants for diagnosing infections and methods of use thereof |
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US4727021A (en) | 1984-06-01 | 1988-02-23 | Sloan-Kettering Institute For Cancer Research | Human monoclonal antibodies to cytokeratin |
LU86654A1 (de) | 1986-11-10 | 1988-06-13 | Progen Biotechnik Gmbh | Verfahren und vorrichtung zum auffinden von zellaesionen |
DE3815932A1 (de) | 1988-01-26 | 1989-08-03 | Progen Biotechnik Gmbh | Verfahren zur identifizierung des ursprungs einer zellgewebsprobe |
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