本發(fā)明涉及用于確定存在胰腺癌的可能性的方法。

背景技術(shù)：

臨床上胰腺癌經(jīng)常顯現(xiàn)于晚期，這是因為在疾病過程中癥狀出現(xiàn)晚，因此直到發(fā)展到遠處轉(zhuǎn)移之后病人才被診斷出[1]。其存活率在人類實體瘤中最低，存活期中位數(shù)為只有六個月[2]。胰腺癌被分為可切除的(i-ii期；10-20％)、局部晚期(iii期；30％)或遠處轉(zhuǎn)移(iv期；60％)[3]。患有可切除的癌癥的病人可通過完整的手術(shù)切除有可能被治愈[4]。因此，新型無創(chuàng)性方法至關(guān)重要，以便提高早期檢測。就臨床效果而言，血清由于其低侵襲性和簡單的樣本處理成為具吸引力的生物標(biāo)志物源。生物標(biāo)志物的發(fā)現(xiàn)至關(guān)重要，因為目前只有糖類抗原ca19-9可用作胰腺癌的血清腫瘤標(biāo)志物。就敏感性和特異性而言，ca19-9的屬性均不足以用于早期診斷[5]。由于低陽性預(yù)測值以及良性胰腺疾病和所有形式的膽道梗阻可提高ca19-9水平的事實，并不推薦將ca19-9作為胰腺癌篩查試驗使用。

生物標(biāo)志物的臨床適用性取決于若干因素，例如分析技術(shù)的可用性、簡易性或穩(wěn)健性，生物標(biāo)志物為其提供足夠高的敏感性和特異性，用于常規(guī)臨床實踐期間的成功確定。

質(zhì)譜技術(shù)的最新進展已經(jīng)使得復(fù)雜蛋白質(zhì)混合物中的蛋白質(zhì)表達譜的研究以及疾病-擾亂的蛋白質(zhì)的識別和定量成為可能。傳統(tǒng)上，二維凝膠電泳(2-de)已經(jīng)成為用于基于質(zhì)譜的蛋白組學(xué)分析的主要方法[6]。然而，2-de受因素局限，例如實驗上費力，并且難以可再現(xiàn)地進行，因此對于高通量分析具挑戰(zhàn)性[7]。作為2-de方法的替代，“bottom-up”鳥槍法蛋白質(zhì)組學(xué)應(yīng)運而生。鳥槍法方法使用蛋白水解酶例如胰蛋白酶來產(chǎn)生可以用lc-ms/ms分析的肽[8-10]。不過，考慮到血清和血漿蛋白質(zhì)組的復(fù)雜性，僅有幾項研究調(diào)查了利用鳥槍法蛋白質(zhì)組學(xué)在血液中發(fā)現(xiàn)胰腺癌生物標(biāo)志物[11]。一個原因是需要嚴格的流行病學(xué)項目或臨床試驗來確定生物標(biāo)志物的準(zhǔn)確性、可靠性、可解釋性和可行性。這必須通過考慮變量例如年齡、性別、個體內(nèi)在差異、組織定位和生物標(biāo)志物的持久性來建立。

因此，基于分析來源于病人樣本的相關(guān)生物標(biāo)志物的改進的方法對于改進的胰腺癌的診斷是需要的。

技術(shù)實現(xiàn)要素：

鑒于上文所提及的缺陷，本發(fā)明的一個目的是提供一種能夠補充或獨立評估主體(例如病人)相比于參考主體(例如健康個體)患胰腺癌的可能性的方法。

根據(jù)本發(fā)明的第一方面，提供了一種用于確定主體患胰腺癌的可能性的方法，包括下述步驟：(i)提供來自于待測定患胰腺癌可能性的主體的第一樣本，并確定第一樣本中血小板糖蛋白v(gp5)或其肽片段的水平；(ii)提供來自于未患胰腺癌的參考主體的第二樣本，并確定第二樣本中血小板糖蛋白v(gp5)或其肽片段的水平；和(iii)比較第一和第二樣本中血小板糖蛋白v(gp5)或其肽片段的水平。步驟(i)和(ii)可以按任何順序進行。第一樣本中升高水平的gp5或其肽片段表示患胰腺癌的可能性增大。

在一些形式中，第一樣本中g(shù)p5或其肽片段的血清濃度比第二樣本中g(shù)p5或其肽片段的血清濃度高至少30％表示患胰腺癌的可能性增大。在一些形式中，第一樣本中g(shù)p5的濃度為1.978μg/l表示患胰腺癌的可能性增大。

在一些形式中，步驟(i)和(ii)還包括確定第一和第二樣本中至少一種其它蛋白質(zhì)或多肽的水平，所述一種蛋白質(zhì)或多肽選自由cea(癌胚抗原)、腫瘤標(biāo)志物ca242、tag-72(腫瘤相關(guān)糖蛋白72)、hnrnpcl1、ca19-9、g7d、kat2b、kif20b、smc1b和/或spag5蛋白構(gòu)成的組。另外，步驟(iii)還包括比較第一和第二樣本中至少一種其它蛋白質(zhì)或多肽的水平，并且其中升高水平的gp5或其肽片段和所述蛋白質(zhì)或多肽表示患胰腺癌的可能性增大。在一些形式中，至少一種蛋白質(zhì)或多肽選自由不均一核糖核蛋白c-like1(hnrnpcl1)和糖類抗原19-9(ca19-9)構(gòu)成的組，并且與第二樣本相比，第一樣本中升高水平的gp5或其肽片段和不均一核糖核蛋白c-like1(hnrnpcl1)和/或糖類抗原19-9(ca19-9)表示患胰腺癌的可能性增大。在一些形式中，至少一種蛋白質(zhì)或多肽是糖類抗原19-9(ca19-9)，并且其中值為2.729或更大(對于0.562417*log(以μg/l計的gp5水平)+0.400120*log(以μg/l計的ca19-9水平))表示患胰腺癌的可能性增大。

在一些形式中，步驟(i)和(ii)包括用蛋白酶處理所述樣本或其衍生物。所述蛋白酶在賴氨酸和精氨酸殘基的羧基側(cè)選擇性裂開構(gòu)成蛋白質(zhì)及其多肽的至少一部分肽鍵，這提供了多個多肽片段。測定來自所述樣本中由seqidno30、seqidno31、seqidno32構(gòu)成的組的多個多肽片段中的至少一個多肽片段的水平，其中片段水平直接與所述樣本中血小板糖蛋白v(gp5)的初始水平關(guān)聯(lián)。

根據(jù)本發(fā)明的另一方面，提供了一種用于確定主體患胰腺癌的可能性的方法，包括下述步驟：(i)提供來自于待測定患胰腺癌可能性的主體的樣本，并確定樣本中血小板糖蛋白v(gp5)或其肽片段的水平；和，(ii)將血小板糖蛋白v(gp5)或其肽片段的水平與根據(jù)來自于已知患胰腺癌的主體的樣本中血小板糖蛋白v(gp5)或其肽片段的水平和來自于健康主體的樣本中血小板糖蛋白v(gp5)或其肽片段的水平確定的參考值進行比較。所述樣本中血小板糖蛋白v(gp5)或其肽片段的水平在參考值之上表示患胰腺癌的可能性增大。

在一些形式中，參考值是1.978μg/l。在一些形式中，所述樣本中g(shù)p5或其肽片段的血清濃度超過1.978μg/l但小于4.5μg/l表示患i-ii期胰腺癌的可能性增大。在一些形式中，所述樣本中g(shù)p5或其肽片段的血清濃度超過4.5μg/l表示患iii-iv期胰腺癌的可能性增大。在一些形式中，參考值是血小板糖蛋白v(gp5)或其肽片段的水平和糖類抗原19-9(ca19-9)的水平的組合，并且值為2.729或更大(對于0.562417*log(以μg/l計的gp5水平)+0.400120*log(以μg/l計的ca19-9水平))表示患胰腺癌的可能性增大。

根據(jù)本發(fā)明的第三方面，血小板糖蛋白v(gp5)或其肽片段被用作胰腺癌的生物標(biāo)志物。在一些形式中，ca19-9和/或hnrnpcl1也被用作共生物標(biāo)志物。

根據(jù)本發(fā)明的第四方面，結(jié)合到血小板糖蛋白v(gp5)或其肽片段上的元件用于檢測血小板糖蛋白v(gp5)或其肽片段，作為表示來自主體樣本中胰腺癌的生物標(biāo)志物。在一些形式中，所述結(jié)合到血小板糖蛋白v(gp5)或其肽片段上的元件是抗體或其片段。在一些形式中，所述元件被用在elisa(酶聯(lián)免疫吸附測定)或eia(酶免疫測定)中。

根據(jù)本發(fā)明的第五方面，提供了一種包括用于測量來自于主體樣本中的血小板糖蛋白v(gp5)或其肽片段的水平的裝置的試劑盒。

本發(fā)明的其它有優(yōu)勢的特征被限定在從屬權(quán)利要求中。此外，本發(fā)明的有利特征在本文所披露的實施例中詳細描述。

附圖說明

本發(fā)明能夠?qū)崿F(xiàn)的這些和其它方面、特征和優(yōu)勢將會從本發(fā)明的下文描述中變得顯而易見并得以闡明，參見附圖，其中：

圖1是高分辨質(zhì)譜法(hdms^e)的實驗傳遞路徑(experimentalpipeline)的示意圖。uplc，超高效色譜。

圖2是三次注射疊加的未加工hdms^e數(shù)據(jù)的軟件可視化。

圖3是具有雙向無人監(jiān)督分層聚類的蛋白質(zhì)和血清樣本的熱圖圖表。每行代表一種蛋白質(zhì)，而每列代表一個樣本。蛋白質(zhì)聚類樹在左側(cè)示出，而樣本聚類樹在頂部呈現(xiàn)。圖中所示的比例表示蛋白質(zhì)跨所有樣本的相對表達水平。該分析識別出134個差異表達蛋白(p<0.0009)。與患良性胰腺疾病的病人和健康對照組相比，有40個在胰腺癌中表達上調(diào)的蛋白質(zhì)的聚類(表3)。

圖4的圖表示出了胰腺癌、良性胰腺疾病和健康對照組之間在差異表達蛋白上的主成分分析。

圖5是在血清樣本中識別出的蛋白質(zhì)的基因本體論分類，示出以鐘表機構(gòu)順序(clockworkorder)開始的鐘表機構(gòu)樣式(clockworkfashion)的分子功能。

圖6示出了gp5豐度對于診斷包括癌癥i-ii期和iii-iv期的胰腺癌的圖表，并且roc曲線示出了通過改變gp5豐度的閾值所獲得的對于癌癥預(yù)測的敏感度和特異性的范圍。

圖7示出了gp5和ca19-9豐度對于診斷包括癌癥i-ii期和iii-iv期的胰腺癌的圖表，并且roc曲線示出了通過改變gp5豐度的閾值所獲得的對于癌癥預(yù)測的敏感度和特異性的范圍。

圖8示出了gp5豐度對于胰腺癌i-ii期和iii-iv期之間差異的圖表，并且roc曲線示出了通過改變gp5豐度的閾值所獲得的對于癌癥預(yù)測的敏感度和特異性的范圍。

具體實施方式

本發(fā)明的實施例將在下文結(jié)合附圖進行更為詳細地描述，以便本領(lǐng)域技術(shù)人員能夠?qū)嵤┍景l(fā)明。不過，本發(fā)明可以以多種不同的形式體現(xiàn)，并且不應(yīng)當(dāng)被解釋為局限于本文所述的實施例。而是，提供這些實施例以便本公開內(nèi)容是徹底的和完整的，并且會向本領(lǐng)域技術(shù)人員充分傳達本發(fā)明的范圍。實施例并不限制本發(fā)明，而是本發(fā)明僅受所附權(quán)利要求的限制。此外，附圖中所示用于具體實施例的詳細說明的術(shù)語并不旨在限制本發(fā)明。

為了突破傳統(tǒng)質(zhì)譜分析法的限制，高分辨質(zhì)譜分析法(hdms^e)的使用可以提供額外的高效離子淌度分離的維度，以實現(xiàn)更深的蛋白質(zhì)組覆蓋[12]。在本發(fā)明當(dāng)前的發(fā)現(xiàn)中，用hdms^e的鳥槍法蛋白組學(xué)用于檢查來自于患可切除胰腺癌的病人以及患良性胰腺疾病的病人和健康對照組的血清蛋白質(zhì)。識別出的血清蛋白質(zhì)組差異接受蛋白質(zhì)網(wǎng)絡(luò)分析，用于研究蛋白質(zhì)-蛋白質(zhì)相互作用。

胰腺癌通常發(fā)現(xiàn)于晚期，此時腫瘤已不再經(jīng)得起手術(shù)切除。因此，迫切需要發(fā)現(xiàn)疾病早期的生物標(biāo)志物。顯示高分辨質(zhì)譜分析法(hdms^e)可用于識別與胰腺癌早期相關(guān)的血清蛋白質(zhì)改變，其代表胰腺癌早期的潛在的生物標(biāo)志物。對來源于診斷為具有可動手術(shù)的腫瘤的胰腺癌病人以及患良性胰腺疾病的病人和健康對照組的血清樣本進行分析。synaptg2-si平臺以數(shù)據(jù)獨立形式結(jié)合離子淌度使用。用已知濃度的酵母乙醇脫氫酶胰蛋白酶消化來稀釋樣本使得每種被識別的蛋白質(zhì)的估算量能夠被計算。當(dāng)以三份注射時，ms光譜聚集緊密并顯示高度可重現(xiàn)的分離，證實重復(fù)的次數(shù)可被降低至兩次，從而減少分析時間。

利用無標(biāo)記定量和生物信息分析進行三組研究的總體蛋白表達比較，三組研究為：i)胰腺癌，ii)良性胰腺疾病和iii)健康對照組。具有134個差異表達蛋白(p<0.0009)的雙向無監(jiān)督分層聚類成功地將胰腺癌病人從對照組分類出，并識別出在胰腺癌組中顯示顯著上調(diào)的40個蛋白質(zhì)，從而代表胰腺癌早期的潛在的生物標(biāo)志物。

該區(qū)別可靠性進一步通過主成分分析(pca)證實。差異表達候選者與蛋白網(wǎng)絡(luò)分析匹配，并連接到與胰腺腫瘤發(fā)生相關(guān)的生物途徑。胰腺疾病連接關(guān)聯(lián)可以關(guān)聯(lián)到p53，它是胰腺癌中最頻繁改變的腫瘤抑制基因。這些胰腺癌研究候選者可能為胰腺腫瘤分層的基于非侵入性血液的診斷提供新的研究途徑。

正如已經(jīng)提到的，由于缺乏精確的診斷生物標(biāo)志物，早期胰腺癌檢測和治療受到阻礙。為了降低胰腺癌患者的死亡率，在可治愈階段檢測到癌癥是目前最好的方法。來源于我們的southswedishpancreasbiobank(瑞典南部胰腺生物標(biāo)本庫)的疾病和對照樣本中的血清蛋白質(zhì)表達譜的綜合系統(tǒng)性表征可有利于開發(fā)診斷胰腺癌的生物標(biāo)志物。發(fā)現(xiàn)胰腺癌生物標(biāo)志物的一個重要策略是體液(包括血液)的基于質(zhì)譜分析的蛋白質(zhì)組學(xué)分析[11]。不過，盡管血清和血漿是研究胰腺癌相關(guān)的生物標(biāo)志物的重要來源，它們的蛋白質(zhì)組的復(fù)雜性是個挑戰(zhàn)。在本研究中，嘗試了用于發(fā)現(xiàn)胰腺癌生物標(biāo)志物的系統(tǒng)性方法：(1)血清中專用樣本制備，(2)利用內(nèi)部標(biāo)準(zhǔn)，hdms^e用于識別無標(biāo)記定量的差異表達蛋白，(3)分層聚類和(4)pca。

在本可行性研究中，證實了hdms^e可用于發(fā)現(xiàn)胰腺癌患者血清中的潛在的生物標(biāo)志物。平臺提供三維的分辨率并允許高峰容量分析，使蛋白質(zhì)鑒定最大化同時保持無標(biāo)記定量能力。利用無標(biāo)記方法進行三條件(threeconditions)的相對定量分析。數(shù)據(jù)的分層聚類和pca顯示胰腺癌和對照組表型之間的清晰差異。

根據(jù)一個實施例，主體相對于參考主體患胰腺癌的可能性可包括第一步驟，所述第一步驟提供表示主體的蛋白質(zhì)組的第一樣本。第一樣本可以是血液、血漿或組織樣本。第二步驟可涉及用蛋白酶處理第一樣本或其衍生物。蛋白酶通常會在賴氨酸和精氨酸殘基的羧基側(cè)選擇性裂解第一樣本中蛋白質(zhì)和多肽的至少一部分肽鍵，以提供多個多肽片段。第一樣本的衍生物可以是第一樣本處理后剩余的蛋白質(zhì)和多肽，例如，純化以去除與胰腺癌不相關(guān)的蛋白質(zhì)，或分裂s-s鍵以提供線性蛋白質(zhì)序列。合適的蛋白酶的一個示例是胰蛋白酶，例如，豬胰蛋白酶，通過還原性甲基化通過修飾使其抗蛋白水解消化。第三步驟可以是確定第二步驟中所獲得的多個多肽片段中的至少一個多肽片段的存在或水平。通?？闪炕舾伤龆嚯钠危詾榕c參考樣本(例如來自于參考主體的樣本)進行比較提供更好的基礎(chǔ)，以便使假陽性或陰性結(jié)果的風(fēng)險最小化。表示參考主體的蛋白質(zhì)組的第二樣本可被設(shè)置為第四步驟。優(yōu)選地，第二樣本可具有與第一樣本相同的類型。作為第五步驟，可以在相同條件下處理第二樣本或其衍生物，優(yōu)選通過采用與第二步驟過程中的第一樣本相同的方案。第二樣本的任何衍生物可以優(yōu)選地按照與提供第一樣本的衍生物相同的方案而獲得。作為第六步驟，在相應(yīng)處理第二樣本后，隨后可確定在蛋白酶處理第一樣本或其衍生物后在所得到的成分中測定的相同多肽片段的存在或水平。作為最后的第七步驟，由第一和第二樣本所獲得的每個相關(guān)多肽片段的水平或存在進行相互比較。與源自第二樣本的相應(yīng)樣本相比，源自第一樣本的樣本中更高水平的多肽片段(由內(nèi)源蛋白質(zhì)或多肽經(jīng)肽酶輔助裂解引起，在胰腺癌存在的情況下增大)表示與參考主體患胰腺癌的可能性相比，主體患胰腺癌的可能性更高。相應(yīng)地，與源自第二樣本的相應(yīng)樣本相比，源自第一樣本的樣本中更低水平的多肽片段(由內(nèi)源蛋白質(zhì)或多肽經(jīng)肽酶輔助裂解引起，在胰腺癌存在的情況下減少)表示與參考主體患胰腺癌的可能性相比，主體患胰腺癌的可能性更高。

根據(jù)一個實施例，內(nèi)源蛋白質(zhì)或多肽(與本文所述的健康主體相比，在胰腺癌存在的情況下增大或減少)可以通過lc-ms、lc-ms/ms、凝膠電泳或通過采用適于選擇性結(jié)合到至少一個所述內(nèi)源蛋白質(zhì)或多肽的可檢測的部分定量測定。

根據(jù)一個實施例，通過用胰蛋白酶處理內(nèi)源蛋白質(zhì)或多肽所獲得的多肽片段(與本文所述的健康主體相比，在胰腺癌存在的情況下增大或減少)可以通過lc-ms、lc-ms/ms、凝膠電泳或通過采用適于選擇性結(jié)合到至少一個所述多肽片段的可檢測的部分定量測定。

研究導(dǎo)致40個蛋白質(zhì)標(biāo)志物集(40-proteinpanel)的鑒定，看似將胰腺癌與良性和健康對照組區(qū)分開。為了更好地理解胰腺癌中重要的潛在當(dāng)前機制，利用實驗中鑒定的差異調(diào)控蛋白進行一系列的蛋白質(zhì)網(wǎng)絡(luò)分析。在該蛋白質(zhì)集中，發(fā)現(xiàn)在胰腺癌中豐度升高的蛋白質(zhì)的示例包括gp5、hnrnpc、g7d、kat2b、kif20b、smc1b和spag5。這些蛋白質(zhì)是在血流中以低濃度存在的蛋白質(zhì)，因此揭示了鑒定低豐度的候選癌癥生物標(biāo)志物的我們策略的成功可能性。

根據(jù)一個實施例，與健康個體的相應(yīng)樣本相比，當(dāng)已用胰蛋白酶處理時在主體的蛋白質(zhì)組樣本中的下述肽或多肽或多肽片段(括號內(nèi))一個或多個的水平顯著升高，可能表示主體中胰腺癌的存在：seqidno118(seqidno3,seqidno4,seqidno5,seqidno6,seqidno7,seqidno8,seqidno9,seqidno10),seqidno120(seqidno15,seqidno16,seqidno17,seqidno18),seqidno122(seqidno27,seqidno28),seqidno123(seqidno29),seqidno124(seqidno30,seqidno31,seqidno32),seqidno126(seqidno41a,seqidno42,seqidno43,seqidno44,seqidno45,seqidno46,seqidno47,seqidno48,seqidno49),seqidno128(seqidno69,seqidno70,seqidno71,seqidno72,seqidno73,seqidno74,seqidno75,seqidno76,seqidno77,seqidno78,seqidno79,seqidno80,seqidno81),seqidno132(seqidno85,seqidno86),seqidno134(seqidno88,seqidno89),seqidno135(seqidno90),seqidno137(seqidno95,seqidno96),seqidno140(seqidno99,seqidno100,seqidno101),seqidno143(seqidno104)；seqidno144(seqidno105)和seqidno145(seqidno106,seqidno107,seqidno108,seqidno109,seqidno110,seqidno111)。

根據(jù)一個實施例，與健康個體的相應(yīng)樣本相比，當(dāng)已用胰蛋白酶處理時在主體的蛋白質(zhì)組樣本中的下述肽或多肽或多肽片段(括號內(nèi))的一個或多個的水平顯著降低，可能表示主體中胰腺癌的存在：seqidno117(seqidno1,seqidno2),seqidno119(seqidno11,seqidno12,seqidno13,seqidno14),seqidno121(seqidno19,seqidno20,seqidno21,seqidno22,seqidno23,seqidno24,seqidno25,seqidno26),seqidno125(seqidno33,seqidno34,seqidno35,seqidno36,seqidno37,seqidno38,seqidno39,seqidno40),seqidno127(seqidno50,seqidno51,seqidno52,seqidno53,seqidno54,seqidno55,seqidno56,seqidno57,seqidno58,seqidno59,seqidno60,seqidno61,seqidno62,seqidno63,seqidno64,seqidno65,seqidno66,seqidno67,seqidno68),seqidno129(seqidno82),seqidno130(seqidno83),seqidno131(seqidno84),seqidno133(seqidno87),seqidno136(seqidno91,seqidno92,seqidno93,seqidno94),seqidno138(seqidno97),seqidno139(seqidno98),seqidno141(seqidno102),seqidno142(seqidno103),seqidno146(seqidno112,seqidno113),seqidno147(seqidno114)和seqidno148(seqidno115,seqidno116)。

如表3可見，差異表達候選者，與胰腺癌中最頻繁改變的腫瘤抑制基因p53連接關(guān)聯(lián)，也可制備用于baz2a、cdk13、dapk1、dst、exosc3、inhbe、kat2b、kif20b、smc1b和spag5。

因此，根據(jù)一個實施例，與健康個體的相應(yīng)樣本相比，已用胰蛋白酶處理時在主體的蛋白質(zhì)組樣本中下述肽或多肽或多肽片段(括號內(nèi))的水平顯著降低，可能表示主體中胰腺癌的存在：seqidno117(seqidno1,seqidno2)。

根據(jù)一個實施例，與健康個體的相應(yīng)樣本相比，已用胰蛋白酶處理在主體的蛋白質(zhì)組樣本中下述肽或多肽或多肽片段(括號內(nèi))的水平顯著升高，可能表示主體中胰腺癌的存在：seqidno123(seqidno29)。

根據(jù)一個實施例，與健康個體的相應(yīng)樣本相比，已用胰蛋白酶處理在主體的蛋白質(zhì)組樣本中下述肽或多肽或多肽片段(括號內(nèi))的水平顯著降低，可能表示主體中胰腺癌的存在：seqidno119(seqidno11,seqidno12,seqidno13,seqidno14)。

蛋白質(zhì)組學(xué)方法的最近進展使得在細胞、組織和生物流體中系統(tǒng)表征復(fù)雜蛋白質(zhì)組和鑒定差異表達蛋白成為可能。為了找到可能的癌癥生物標(biāo)志物，必須非常小心限定臨床應(yīng)用并選擇用于蛋白質(zhì)組學(xué)分析的相關(guān)樣本[13]。當(dāng)通過蛋白質(zhì)組學(xué)方法分析血清或血漿時，可能出現(xiàn)有若干可變性來源。導(dǎo)致錯誤發(fā)現(xiàn)的最重要因素之一始于足夠?qū)φ战M的選擇。炎癥和急性期蛋白質(zhì)的變化經(jīng)常發(fā)生在包括胰腺癌的惡性條件下[14]。相比于癌癥特異性變化，這些變化可能反映當(dāng)前的慢性疾病(如慢性胰腺炎)。因此，血清或血漿中的非特異性變化需要與潛在的特異性生物標(biāo)志物區(qū)分開。這就是為什么除了健康對照組樣本外，還包括來自于患慢性胰腺炎和其它良性胰腺疾病的患者的樣本，以便足以鑒定疾病擾亂的蛋白質(zhì)。

此外，與健康對照組樣本和來自于患慢性胰腺炎的患者的樣本進行比較使得能夠確定閾值，以區(qū)分健康和患病的樣本，具有足夠的敏感度和特異性。用于所述測定的方法在本領(lǐng)域是已知的。作為一個示例，可以使用接受者操作特征(roc)曲線分析。

生物標(biāo)志物的臨床適合性取決于若干因素，例如分析技術(shù)的可用性、簡易性或穩(wěn)健性(robustness)。此外，生物標(biāo)志物必須為分析技術(shù)提供足夠高的敏感度(即真陽性率)和特異性(即真陰性率)，以便在常規(guī)臨床實踐期間成功測定。

固相酶聯(lián)免疫吸附測定(elisa)是一種既用于一般生物醫(yī)學(xué)研究又作為診斷工具的經(jīng)驗證的方法。它允許在非常低的濃度和定量下檢測生物分子。它利用抗原結(jié)合到特異性抗體的概念，并且所述方法通常使來自流動相的抗原固定到96孔板中?？乖Y(jié)合到特異性抗體，所述抗體本身隨后由第二酶偶聯(lián)的抗體檢測。elisa的高靈敏度來自于利用酶作為報告組，并且酶的顯色底物產(chǎn)生可見的顏色變化或熒光，表示抗原的存在。定量或定性測量法可以基于所述比色法讀取被評估。通過elisa，可以在微克或甚至納克水平進行抗體定量。elisa的高度特異性是由于抗體或抗原的選擇性。elisa還增加的優(yōu)勢是不需要放射性同位素(放射性物質(zhì))或昂貴的輻射計數(shù)器(輻射計數(shù)裝置)，例如在放射免疫測定(ria)測試，使得elisa在大多數(shù)標(biāo)準(zhǔn)實驗室環(huán)境中成為易用技術(shù)。

選擇包含gp5、hnrnpc、g7d、kat2b、kif20b、smc1b和spag5蛋白質(zhì)的一隊(cohort)生物標(biāo)志物，利用elisa方法來確定其臨床適用性。

elisa定量對于本領(lǐng)域技術(shù)人員來說是公知的方法。作為一個示例，對于gp5elisa定量，將抗重組gp5的兔多克隆抗體預(yù)涂在微量滴定板上。固定量的血液血清樣本被添加在板中并在板中溫育。溫育后，將液體和包含檢測抗體的溶液交換，所述檢測抗體結(jié)合生物素。進一步溫育后，洗滌孔并添加包含辣根過氧化物酶(hrp)的溶液。hrp是糖蛋白，當(dāng)與適當(dāng)?shù)牡孜锢?,3’,5,5’-四甲基聯(lián)苯胺(tmb)溫育時，產(chǎn)生標(biāo)記的分子的有色的、熒光測定的或發(fā)光的衍生物。tmb充當(dāng)氫供體，通過hrp將過氧化氫還原成水，產(chǎn)生藍色的二亞胺，其可以在650nm波長下在分光光度計被讀取。溫育后，添加tmb底物。如果樣本中有g(shù)p5，包含生物標(biāo)志物、結(jié)合了生物素的抗體和結(jié)合了酶的親和素的孔會顯現(xiàn)顏色變化，所述顏色變化與血液血清樣本中存在的gp5的量相關(guān)。通過這種方式，可以測定主體樣本中血小板糖蛋白v(gp5)的水平。

在一個實施例中，結(jié)合到血小板糖蛋白v(gp5)或其肽片段的元件用于檢測來自于主體的樣本中的血小板糖蛋白v(gp5)或其肽片段，作為表示胰腺癌的生物標(biāo)志物。所述元件可用于elisa(酶聯(lián)免疫吸附測定)或eia(酶免疫測定)中。正如本領(lǐng)域技術(shù)人員所認識到的，結(jié)合到血小板糖蛋白v(gp5)或其肽片段的元件可以是抗體或其片段。可用的抗體片段可以選自由f(ab')2、fab’、fab、scfvdi-scfv、sdab片段構(gòu)成的組。元件可被修飾或連接到功能基團上，例如生物素、鏈霉親和素或親和素，用于結(jié)合元件，或酶，例如辣根過氧化物酶(hrp)、堿性磷酸酶(ap)、β-半乳糖苷酶、乙酰膽堿酯酶和過氧化氫酶，連同相應(yīng)底物用作報告基團。

在另一個實施例中，提供了一種包括用于測量來自于主體的樣本中的血小板糖蛋白v(gp5)或其肽片段的水平的裝置的試劑盒。所述試劑盒可用于實施本文所披露的不同方法。對于elisa，所述試劑盒可包括捕獲抗體，優(yōu)選地涂覆或固定在微孔板上，結(jié)合到血小板糖蛋白v(gp5)或其肽片段的第一抗原位點。此外，結(jié)合到血小板糖蛋白v(gp5)或其肽片段的第二抗原位點的檢測抗體通常是試劑盒的一部分。在多個相同抗原結(jié)合位點存在的情況下，第一和第二抗原結(jié)合位點可以是相同的。此外，酶聯(lián)第二抗體結(jié)合到所述檢測抗體并且底物通過所述酶被轉(zhuǎn)換成可檢測形式。此外，試劑盒可包括結(jié)合到血小板糖蛋白v(gp5)的檢測抗體、結(jié)合到檢測抗體的酶聯(lián)第二抗體和被所述酶轉(zhuǎn)換為可檢測形式的底物。此外，試劑盒還可包括結(jié)合到血小板糖蛋白v(gp5)的捕獲抗體，并結(jié)合到表面，例如微孔板。

在直接elisa中，抗原(這里是血小板糖蛋白v(gp5))被直接吸收到塑料表面(如微孔板孔)。蛋白質(zhì)例如牛血清白蛋白隨后被充足地添加，以封閉所有其它結(jié)合位點。酶-抗體復(fù)合物隨后被應(yīng)用并結(jié)合到抗原。在過量的抗體被洗掉后，酶的底物可被應(yīng)用于elisa分析。這使得能夠使用單個酶連接的抗體。在一個實施例中，試劑盒因此包括結(jié)合到血小板糖蛋白v(gp5)的初級酶聯(lián)抗體和被所述酶轉(zhuǎn)換為可檢測形式的底物。

所有選定的生物標(biāo)志物，即gp5、hnrnpc、g7d、kat2b、kif20b、smc1b和spag5，為適合性滿足若干標(biāo)準(zhǔn)，例如在血流中釋放以及在胰腺癌中上調(diào)/下調(diào)。在同生群中(outofthecohort)，利用穩(wěn)健和靈敏的elisa技術(shù)，發(fā)現(xiàn)gp5(人類血小板糖蛋白v)具有最高的臨床適合性。結(jié)果概括在表4中，其中利用同生群(cohort)的elisa方法，gp5明顯突出作為最好的胰腺生物標(biāo)志物。

gp5是表面糖蛋白的ib-v-ix系統(tǒng)的一部分，構(gòu)成血管假性血友病因子(vwf；mim613160)的受體，并調(diào)節(jié)血小板粘附到動脈循環(huán)中受傷的血管表面，這是止血中關(guān)鍵的始發(fā)事件。凝血酶以及不同的金屬蛋白酶裂解gp5，產(chǎn)生肽片段，所述肽片段易于在血清中利用酶聯(lián)免疫吸附測定(elisa)進行定量。此外，升高的肽血小板gp5的血漿水平和血栓形成的發(fā)展相連，表示患不可切除的胰腺癌患者的主要并發(fā)癥之一。

表一中通過elisa方法證實的全部elisa患者組的gp5豐度在表五中詳細說明。gp5為測定主體患胰腺癌的可能性提供了高靈敏度和特異性，這在圖7中更為詳細地示出。還示出了健康的患者在關(guān)于胰腺癌患者的明確的群組中被群集在一起。用于從健康對照組區(qū)別開胰腺癌的auc(曲線下的面積)達到了91％，在90％特異性下敏感度為77％。

本發(fā)明的一個實施例因此涉及利用血小板糖蛋白v(gp5)或其肽片段作為胰腺癌的生物標(biāo)志物。

此外，本發(fā)明的一個實施例涉及一種通過利用gp5作為生物標(biāo)志物來確定主體患胰腺癌的可能性的方法。這通過比較樣本中血小板糖蛋白v(gp5)或其肽片段的水平相對于來自于未患胰腺癌的參考主體的參考樣本中g(shù)p5或其肽片段的水平來實現(xiàn)。此外，主體樣本中血小板糖蛋白v(gp5)或其肽片段的水平可以與參考值進行比較，所述參考值代表來自于未患胰腺癌的主體樣本中糖蛋白v(gp5)或其肽片段的水平。升高水平的gp5或其肽片段表示患胰腺癌的可能性增大。此外，另一個實施例涉及用于識別主體患胰腺癌的方法，例如，診斷或輔助診斷胰腺癌。所述方法與確定主體患胰腺癌的可能性的方法類似，因為升高水平的gp5或其肽片段表示患胰腺癌的可能性增大。因此，通過所述方法，具有升高水平的gp5或其肽片段的主體可被診斷為具有胰腺癌。

根據(jù)一個實施例，確定主體患胰腺癌的可能性涉及將主體相對于健康參考主體或參考值(如下文所披露)分層為患胰腺癌的可能性沒有升高的第一組，或患胰腺癌的可能性升高的第二組。此外，如下文所闡述，gp5或其肽片段的實際水平可用于將主體分層為胰腺癌i-ii期的第一組，或胰腺癌iii-iv期的第二組，如下文進一步所討論。根據(jù)另一個實施例，確定主體患胰腺癌的可能性涉及用于輔助診斷或診斷主體中的胰腺癌的方法。升高水平的gp5或其肽片段表示主體患胰腺癌。

這可以通過提取主體的蛋白質(zhì)組的樣本，例如血液、血漿或組織樣本來實現(xiàn)。優(yōu)選地，樣本是血液樣本，例如血漿或血清樣本。樣本中血小板糖蛋白v(gp5)或其肽片段的水平隨后可利用方法例如elisa、ms或lc-ms(如在材料與方法中所述)來測定。類似地，樣本(一個或若干)可以按類似的方式從未患胰腺癌的參考主體(一個或若干)提取。參考樣本中的血小板糖蛋白v(gp5)或其肽片段的水平以類似的方式測定。由于可能使用若干個參考樣本，所測定的參考水平可能是平均值。通過比較主體和參考主體的血小板糖蛋白v(gp5)或其肽片段的測定水平，可以確定主體患胰腺癌的可能性，因為升高水平的gp5或其肽片段表示患胰腺癌的可能性增大。對于顯示患胰腺癌的可能性增大的主體，隨后可進行進一步檢查，例如第二水平腹部成像，以確定或排除胰腺癌。因此，gp5可以在篩查胰腺癌中用作生物標(biāo)志物，以允許胰腺癌的早期檢測。

人類gp5具有細胞外拓撲域、跨膜域和胞漿域和n末端信號肽，可以在不同位點裂解。此外，具有已知的gp5的突變，其中一些和已知的出血性疾病關(guān)聯(lián)。

在本發(fā)明的一個實施例中，血小板糖蛋白v(gp5)包括多肽序列，所述多肽序列至少90％同源，例如至少95％同源、或甚至同源于seqidno124，或者其中其肽片段至少90％同源，優(yōu)選地至少95％同源，或者甚至同源于seqidno124的相應(yīng)部分。

根據(jù)一個實施例，主體中的gp5濃度比健康對照組的gp5濃度高出至少30％，高出至少40％，或者甚至高出至少50％表示區(qū)別主體的胰腺癌。因此，主體的gp5的外周血液水平比健康個體中的gp5的外周血液水平高出至少30％，高出至少40％，或者甚至高出至少50％表示主體患有胰腺癌。利用更高的值會提高靈敏度，但是降低特異性，正如技術(shù)人員所領(lǐng)會。

根據(jù)一個實施例，血小板糖蛋白v(gp5)的參考水平是至少兩個、通常若干個(即3、4、5、10、15、20、25、50或更多)來自于至少兩個、通常若干個(即3、4、5、10、15、20、25、50或更多)不同的參考主體的先前確定的值的平均值。正如已經(jīng)解釋的，所述水平可以利用方法例如elisa、ms或lc-ms來測定。通過比較主體的血小板糖蛋白v(gp5)的測定的水平和代表參考主體的若干個先前確定的值的平均值，可以確定主體患胰腺癌的可能性。

在一個實施例中，主體和參考主體是相同的人，但是來自于他(她)的用作參考樣本的樣本采集自他(她)未患胰腺癌的時候。通過比較主體和代表參考主體的采集自主體未患胰腺癌時的樣本的血小板糖蛋白v(gp5)的測定的水平，可以確定主體患胰腺癌的可能性。

生物標(biāo)志物的可靠性或重復(fù)性對于臨床適合性至關(guān)重要。生物標(biāo)志物試驗可以表示生物標(biāo)志物的臨床靈敏度和特異性。靈敏度測量正確識別(即正確識別患病病人)的陽性比例，而特異性測量正確識別(即正確識別健康病人)的陰性比例。在理想的情況下，生物標(biāo)志物具有清楚的預(yù)測值，但在很多情況下，需要通過臨床試驗和統(tǒng)計分析來建立。當(dāng)選擇用于確定疾病提供高靈敏度的截止值時，這經(jīng)常以降低特異性即得到較高的假陽性率為代價。

對于胰腺癌，重要的是使錯誤的陰性診斷最小化，因為疾病癥狀經(jīng)常在晚期檢測到，而癌癥可能發(fā)展迅速并且在早期可以得到更有效的治療。不過，同樣重要的是使假陽性率最小化，因為陽性檢驗將必須通過診斷方法隨診，例如計算機斷層掃描(ct掃描)和超聲內(nèi)鏡(eus)超聲診斷或細針穿刺活檢，這會既牽扯醫(yī)學(xué)資源又對病人造成焦慮。

接受者操作特征曲線的使用可以為確定在靈敏度和假陽性率方面的最佳選擇提供必要的工具，如圖7-9所示。利用統(tǒng)計分析，利用elisa方法用于確定病人的胰腺癌的合適的截止值(cut-offvalue)在外周血樣本中測定為1.978μg/l。不過，同樣可以使用更高和更低的截止值，取決于期望的靈敏度和特異性。

根據(jù)一個實施例，測得的gp5血清水平為1.978μg/l或更高表示將胰腺癌和健康對照組區(qū)分開。因此，主體的gp5的外周血水平低于1.978μg/l表示主體沒有胰腺癌。類似地，主體的gp5外周血水平為1.978μg/l或更高表示主體有胰腺癌，或者至少患胰腺癌的可能性增大。

根據(jù)另一個實施例，提供了一種用于測定主體患胰腺癌的可能性的方法。在所述方法中，測定來源于待測定患胰腺癌可能性的主體的樣本中的血小板糖蛋白v(gp5)或其肽片段的水平。然后將樣本中的血小板糖蛋白v(gp5)或其肽片段的水平和參考值比較。所述第一樣本中高于參考值的血清濃度表示患胰腺癌的可能性增大。如前文所述，合適的參考值可以根據(jù)來源于已知患胰腺癌的主體的樣本中的血小板糖蛋白v(gp5)的水平和來源于健康主體的樣本中的血小板糖蛋白v(gp5)的水平來確定。此外，來源于良性胰腺疾病主體的樣本中的血小板糖蛋白v(gp5)的水平也可以用于確定合適的參考值。為了合適起見，即提供特異性和選擇性，參考值通常稍微高于來源于健康主體的樣本中的血小板糖蛋白v(gp5)的平均水平。根據(jù)一個實施例，參考值是1.978μg/l。

傳統(tǒng)生物標(biāo)志物pdac診斷利用ca19-9(糖抗原19-9)(唾液酸化路易斯血型抗原(sialylatedlewisbloodgroupantigen)的表位)，已知它具有若干缺點。在缺乏路易斯的病人(高加索人群中為大約10％)中，ca19-9沒有表達，產(chǎn)生假陰性。假陽性表達也可能出現(xiàn)在良性病理狀態(tài)下，例如梗阻性黃疸。不過，通過將gp5和ca19-9結(jié)合用于胰腺癌篩查，可以提高測定的靈敏度和特異性。此外，各生物標(biāo)志物缺點，例如上文針對ca19-9所述，在測定依賴于gp5和ca19-9時不會對測定產(chǎn)生嚴重影響。

圖8示出了gp5分析連同ca19-9在確定主體患胰腺癌可能性中的優(yōu)勢。用于將胰腺癌和健康對照組區(qū)分開的auc達到了96％，在90％特異性時靈敏度為97％。利用gp5結(jié)合ca19-9不僅會提供改進的預(yù)測，而且與傳統(tǒng)治療相比還會大大降低假陽性或陰性的風(fēng)險，從而降低延誤治療或粗暴對待的風(fēng)險。

根據(jù)一個實施例，不但測定gp5的水平，而且還測定ca19-9。升高水平的gp5或其肽片段和糖抗原19-9(ca19-9)表示患胰腺癌的可能性增大。在其中將gp5和ca19-9的水平與參考值進行比較的實施例中，對于0.562417*log(以μg/l計的gp5水平)+0.400120*log(以μg/l計的ca19-9水平)的值為2.729或更大可能表示患胰腺癌的可能性增大。

在利用elisa方法確定生物標(biāo)志物同生群(cohort)的臨床適合性中，還發(fā)現(xiàn)不均一核糖核蛋白c-like1(hnrnpcl1)有希望。如表4所示，顯示利用gp5連同hnrnpcl1在確定主體患胰腺癌的可能性中提供了改進的預(yù)測。不均一核糖核蛋白(hnrnps)是存在于細胞核中的rna和蛋白質(zhì)的復(fù)合物。蛋白質(zhì)結(jié)合到前體mrna分子信號上，前體mrna還沒有被充分加工并準(zhǔn)備好輸出到細胞質(zhì)中。多數(shù)細胞核中的rna結(jié)合蛋白作為異質(zhì)核糖核蛋白粒子存在。剪接后，其中前體mrna內(nèi)含子被去掉并且外顯子被連接，蛋白質(zhì)依然結(jié)合至剪接的內(nèi)含子上，之后被定向用于降解。已知升高的hnrnpc表達在遺傳性維生素d抗性中發(fā)揮作用。此外，已顯示hnrnpc和生長因子受體結(jié)合蛋白2(grb2)相互作用，grb2是涉及信號轉(zhuǎn)導(dǎo)/細胞通訊的銜接蛋白。

在一個實施例中，主體的gp5因此和不均一核糖核蛋白c-like1(hnrnpcl1)一起被測定。通過將gp5和hnrnpcl1的測定水平與代表參考主體的若干先前測定值的平均值進行比較，可以確定主體患胰腺癌的可能性，因為升高的水平表示患胰腺癌的可能性增大。

根據(jù)一個實施例，不但測定gp5的水平，而且測定不均一核糖核蛋白c-like1(hnrnpcl1)的水平。升高水平的gp5或其肽片段和hnrnpcl1表示患胰腺癌的可能性增大。

gp5可以和表3中胰腺癌的其它上調(diào)蛋白一起使用，尤其是和g7d、kat2b、kif20b、smc1b和/或spag5蛋白質(zhì)一起使用。在一個實施例中，測定主體的gp5和選自由cea(癌胚抗原)、腫瘤標(biāo)志物ca242、tag-72(腫瘤相關(guān)的糖蛋白72)、hnrnpcl1、ca19-9、g7d、kat2b、kif20b、smc1b和spag5蛋白質(zhì)構(gòu)成的組的蛋白質(zhì)或多肽。通過將測定水平的gp5和選定的蛋白質(zhì)與代表參考主體的若干先前測定值的平均值進行比較，可以確定主體患胰腺癌的可能性，因為升高的水平表示患胰腺癌的可能性增大。

表4還示出了將gp5和不均一核糖核蛋白c-like1(hnrnpcl1)和糖抗原19-9(ca19-9)結(jié)合起來的結(jié)果。該結(jié)合顯示非常好的結(jié)果，具有100％靈敏度和100％特異性，用于將胰腺癌從健康對照組中區(qū)分開的auc(曲線下方區(qū)域)為100％。因此，與傳統(tǒng)治療相比大大地降低了假陽性或陰性的風(fēng)險。

在一個實施例中，因此測定主體的gp5和糖抗原19-9(ca19-9)和不均一核糖核蛋白c-like1(hnrnpcl1)。通過將測定水平的gp5和ca19-9和hnrnpcl1與代表參考主體的若干先前測定值的平均值進行比較，可以確定主體患胰腺癌的可能性，因為升高的水平表示患胰腺癌的可能性增大。

gp5可以和其它既有的生物標(biāo)志物一起使用，例如cea(癌胚抗原)、腫瘤標(biāo)志物ca242、tag-72(腫瘤相關(guān)的糖蛋白72)和與胰腺癌相連的循環(huán)核小體，例如包括核小體相關(guān)的甲基化dna(5-甲基胞嘧啶)和組蛋白修飾h2ak119ub、h3k4me2以及組蛋白序列變異體h2az和mh2a1.1。在一個實施例中，測定主體的gp5和選自由cea(癌胚抗原)、腫瘤標(biāo)志物ca242、tag-72(腫瘤相關(guān)的糖蛋白72)和與胰腺癌相連的循環(huán)核小體構(gòu)成的組的生物標(biāo)志物。通過將測定水平的gp5和選定的生物標(biāo)志物與代表參考主體的若干先前測定值的平均值進行比較，可以確定主體患胰腺癌的可能性，因為升高的水平表示患胰腺癌的可能性增大。

為了幫助決定胰腺癌患者的治療方案，將胰腺腫瘤分為i-iv的類別，表示疾病的嚴重程度以及手術(shù)移除是否可行，因為這是目前該癌癥的唯一療法。當(dāng)疾病仍處于早期時(i期和ii期)，腫瘤的手術(shù)切除通常是可行的。對于iii期和iv期，腫瘤可能是不能手術(shù)的，要么應(yīng)當(dāng)考慮新輔助療法以便腫瘤降期以允許隨后的切除，要么允許有其它治療方案例如化療和放療，以延長生命或提高生存質(zhì)量。盡管在術(shù)前成像模式上有改進，許多可能可切除的腫瘤在開腹手術(shù)下發(fā)現(xiàn)是不可切除的。因此，重要性高的是盡可能早地確定胰腺腫瘤的類別。

如圖9所示，gp5血清水平不僅可用于識別患胰腺癌可能性增大的主體，而且還可用于區(qū)分對可能可切除的疾病正經(jīng)歷手術(shù)探查的胰腺癌患者。用于區(qū)分胰腺癌i-ii期和iii-iv期的auc達到了83％，在90％特異性下靈敏度為66.6％。因此，gp5水平可以在術(shù)前幫助確定胰腺癌的可切除性，從而避免不必要的開腹探查。在一個實施例中，gp5血清濃度用于確定胰腺癌主體是否患i-ii期胰腺癌或iii-iv期胰腺癌。

正如已經(jīng)解釋的，gp5血清濃度>1.978μg/ml表示患胰腺癌的可能性增大。根據(jù)一個實施例，gp5濃度高于1.978μg/ml但低于4.5μg/l表示患i-ii期胰腺癌的可能性增大，而gp5血清濃度為4.5μg/ml或更高表示患iii-iv期胰腺癌的可能性增大。類似地，gp5血清水平可以在胰腺癌圍手術(shù)治療期間作為胰腺腫瘤手術(shù)移除成功的指示，或者用于監(jiān)測切除后再發(fā)生和疾病發(fā)展。如果主體中g(shù)p5水平在胰腺癌切除后降低，這表示胰腺腫瘤或部分腫瘤成功手術(shù)移除。如果主體中g(shù)p5水平在胰腺癌切除后升高，這表示切除后再發(fā)生。因此，主體中的gp5水平可用于監(jiān)測胰腺癌圍手術(shù)期間的疾病發(fā)展。

在一個實施例中，主體在胰腺癌手術(shù)移除后處于圍手術(shù)期，第一樣本提供自胰腺癌手術(shù)移除前的主體，而第二樣本提供自在胰腺癌手術(shù)移除后的圍手術(shù)期間?？赡艿兀龅谝缓偷诙颖究扇∽栽谝认侔┦中g(shù)移除后的圍手術(shù)期間的不同時間的主體。通過對比第一和第二樣本，可以隨時間跟蹤gp5血清水平，以確定圍手術(shù)期主體的疾病發(fā)展。

根據(jù)一個實施例，在手術(shù)移除胰腺癌后的圍手術(shù)期期間，gp5濃度隨時間降低(可通過對比第二樣本和第一樣本中的gp5水平確定)表示胰腺癌腫瘤的成功手術(shù)移除或在質(zhì)量上縮小。在手術(shù)移除胰腺癌后的圍手術(shù)期，主體中g(shù)p5濃度隨時間升高(可通過對比第二樣本和第一樣本中的gp5水平確定)表示切除后胰腺癌再發(fā)和胰腺癌疾病發(fā)展。

材料和方法

本研究中所包括的血清生物流體預(yù)期從胰腺癌患者、良性胰腺疾病患者、以及健康對照組取樣。研究的患者在瑞典隆德universityhospital,departmentofsurgery,lund,sweden在2012年3月至2014年6月期間經(jīng)受治療。外周血樣本在診斷中治療開始之前提取。健康對照血清在當(dāng)?shù)匮壕璜I中心取自獻血者。血液樣本采集在3.5mlbdsstiiadvance血清分離管(bectondickinson，franklinlakes,nj,usa)中，并在30分鐘凝結(jié)后在2000xg在25℃條件下離心10分鐘。血清樣本在-80℃保存在當(dāng)?shù)匾认偕飿颖編熘?，直到進一步使用。描述研究人口的臨床信息總結(jié)在表1中。

表1研究人口統(tǒng)計數(shù)據(jù)

對總共27個血清樣本進行質(zhì)譜和蛋白質(zhì)組學(xué)分析(圖1)。血清來自9個患有胰腺癌的病人(iia期和iib期)、9個患有良性胰腺疾病的病人和9個健康獻血者。在良性組中，病人有慢性胰腺炎(n＝4)、胰腺導(dǎo)管內(nèi)乳頭狀粘液腫瘤(ipmn,n＝3)、漿液性囊腺瘤(n＝1)和良性膽管狹窄(n＝1)。血液樣本采集在bdsstiiadvance管(血清分離管，3.5ml，產(chǎn)品編號368498；bectondickinson，franklinlakes,nj,usa)中。最短的凝結(jié)時間是30分鐘。樣本在2000xg在25℃條件下離心達10分鐘，血清以等分試樣采集并保存在-80℃。

為了富集低豐度蛋白質(zhì)，每個樣本耗盡血清中高豐度的7種蛋白質(zhì)(白蛋白、igg、iga、轉(zhuǎn)鐵蛋白、結(jié)合珠蛋白、抗胰蛋白酶和纖維蛋白原)。簡要地說，原始血清(10μl)用180μl緩沖液a(產(chǎn)品編號5185-5987；agilenttechnologies，santaclara,ca,usa)稀釋，然后通過0.22μm自旋過濾器(產(chǎn)品編號5185-5990；agilenttechnologies)在1000xg室溫條件下旋轉(zhuǎn)達5分鐘進行過濾。將稀釋的血清在緩沖液中注入多個親和去除系統(tǒng)自旋濾芯(產(chǎn)品編號5188-6408；agilenttechnologies)。結(jié)合的蛋白質(zhì)用緩沖液b洗脫(產(chǎn)品編號5185-5988；agilenttechnologies)。

蛋白質(zhì)用10mm二硫蘇糖醇(sigma-aldrich，st.louis,mo,usa)在56℃還原達1小時，并用50mm碘乙酰胺(sigma-aldrich)烷基化達30分鐘，在室溫保持避光。在該步驟之后，通過利用10kda截止自旋過濾器(cut-offspinfilter)(ym10過濾器,amicon,millipore,billerica,ma,usa)用50mm碳酸氫銨緩沖液(ph7.6)進行緩沖液交換。樣本用測序級胰蛋白酶(promega,madison,wi,usa)以比率1:50w/w(胰蛋白酶：蛋白質(zhì))在37℃過夜消化。通過添加30μl的1％甲酸(sigma-aldrich)使反應(yīng)停止。所得到的蛋白質(zhì)消化液用高速真空離心(speedvacuumcentrifugation)干燥，并在注射前用1％甲酸再懸浮。在分析前樣本用10fmol/μl的酵母乙醇脫氫酶(adh)內(nèi)標(biāo)胰蛋白酶消化液(waters,milford,ma,usa)稀釋至1:1。

復(fù)雜的胰蛋白酶肽混合物利用nanoacquityuplc(waters)進行納米級層析來分離。進行有截留(withtrapping)的一維反相(rp)nanoacquity實驗。

流動相a和b分別是0.1％(v/v)甲酸水溶液和0.1％(v/v)甲酸乙腈溶液。在symmetryc185μm,2cmx180μm捕獲柱(waters)上使肽脫鹽之后，利用5-40％乙腈水溶液在25cmx75μm分析rp柱(waters,usa)上采用反向梯度來分離肽超過90分鐘，流速為300nl/min，恒溫為35℃。

利用synaptg2-sihdms質(zhì)譜儀(waters,manchester,uk)進行復(fù)雜的肽混合物的分析，以數(shù)據(jù)獨立方式操作，結(jié)合離子遷移率(hdms^e)[13]。在陽性esi分辨率模式下操作質(zhì)譜儀，分辨率>250,000fwhm。在所有的實驗中，質(zhì)譜儀被編程為在triwave碰撞池上在低能量(4ev)和升高的(14-40ev)碰撞能量之間逐步上升，利用掃描時間為0.9s每功能超過50-2000m/z。

hdms^e數(shù)據(jù)獨立分析提供了檢測所有的前體和產(chǎn)物離子，具有精確的質(zhì)量測量。通過在數(shù)據(jù)處理和數(shù)據(jù)庫搜索期間將產(chǎn)物離子分配給母離子，通過漂移和保留時間比對前體和產(chǎn)物離子輔助肽識別[14,15]。通過利用uniprot人類數(shù)據(jù)庫progenesisqi的蛋白質(zhì)組版本1.0和人類uniprot數(shù)據(jù)庫獲得蛋白質(zhì)識別和定量信息?；虮倔w注釋從panther分類系統(tǒng)取回[16]。

利用來源于酵母的添加的內(nèi)標(biāo)蛋白質(zhì)adh的肽使實驗標(biāo)準(zhǔn)化。蛋白質(zhì)列表利用qlucoreomicsexplorerversion3.0處理。統(tǒng)計分析利用log2-轉(zhuǎn)換的標(biāo)準(zhǔn)化豐度(log2-transformednormalizedabundance)進行。多組對比用anova檢驗進行。采用層級聚類和主成分分析(pca)使組之間的任何統(tǒng)計上的顯著差異可視化。蛋白質(zhì)相互作用圖從retrievalofinteractinggenes/proteins(string)databaseversion9.1的searchtool獲得，其包含已知的和預(yù)測的物理的和功能的蛋白質(zhì)-蛋白質(zhì)相互作用[17]。p值低于0.05在統(tǒng)計上被認為是顯著的。

本研究中所包括的胰腺癌病人都接受了以治療為目的的胰腺切除。所有病人都在手術(shù)后接受持續(xù)6個月(中值6個周期)的輔助化療治療。

在本研究的第一個發(fā)展階段，來自每個組的單個樣本以三份被注射。hdms^e平臺產(chǎn)生高峰值容量，使蛋白質(zhì)識別最大化，同時保留無標(biāo)記的定量能力。為了評估lc/ms采集和數(shù)據(jù)處理的分析再現(xiàn)性，我們計算了相同血清樣本的三份采集的峰值之間的強度差異。對于每個周期運行，在數(shù)據(jù)中識別出一些4801個肽。

在分析發(fā)展的第二部分，我們通過重復(fù)注射繼續(xù)分析所有27個病人樣本。用progenesisqi詢問hdms^e數(shù)據(jù)文檔，用于蛋白質(zhì)組的蛋白質(zhì)識別和定量。所得到的蛋白質(zhì)然后在軟件中接受嚴格的獨立驗證。通過對每個運行的特定蛋白質(zhì)計算所有獨特的標(biāo)準(zhǔn)化的肽離子豐度的總和并然后比較樣本間的平均值來進行差異蛋白定量。因為研究跨越相當(dāng)?shù)臅r間周期進行，因此標(biāo)準(zhǔn)化程序是重要的，利用adh作為所有臨床樣本中的內(nèi)部控制/對照(具體參見實驗部分)。我們還通過在分析中把qc運行作為校準(zhǔn)物進行研究，頻率為在分析循環(huán)中為第8個樣本。

為了限定蛋白表達譜是否在胰腺癌和對照樣本中有區(qū)別，我們對對數(shù)變換的基線蛋白質(zhì)濃度進行了非監(jiān)督式的分層聚類，如圖3所概述。采用了雙向聚類方法，以便允許蛋白質(zhì)和樣本有意義的聚類。

通過使用代表構(gòu)成氨基酸的標(biāo)準(zhǔn)單字母代碼列出蛋白質(zhì)和多肽的序列。從左到右書寫的氨基酸順序?qū)?yīng)于相應(yīng)蛋白質(zhì)或多肽從其氨基到羧基末端的序列。內(nèi)源蛋白質(zhì)或多肽的序列被分配seqidnon格式的代碼，其中“n”是整數(shù)，編碼內(nèi)源蛋白質(zhì)或多肽可能在此被稱為相應(yīng)基因或通常公認名稱的替代，如表7所列。通常單個片段或通常多個片段的序列(可以通過使用胰蛋白酶全部或部分消化原始內(nèi)源蛋白質(zhì)或多肽在體外產(chǎn)生，在賴氨酸(k)和精氨酸(r)殘基的羧基側(cè)裂開，如本文所述)在本文類似地可替換地被稱為seqidnon格式的代碼，其中“n”是整數(shù)，其中表7列出片段所源自的內(nèi)源蛋白質(zhì)或多肽。

elisa被用于定量分析來源于表1所述的病人組的總的55個血清樣本。用于elisa分析的生物標(biāo)志物來源于由gp5、hnrnpc、g7d、kat2b、kif20b、smc1b和spag5構(gòu)成的組。血清樣本的gp5用酶聯(lián)免疫吸附測定(elisa)試劑盒(cloud-clonecorp.,huston,tx,usa)根據(jù)制造商的說明進行測量。簡要地說，將100μl血清樣本(質(zhì)量控制或標(biāo)準(zhǔn))加入預(yù)涂有培養(yǎng)抗重組生物標(biāo)志物的兔多克隆抗體的微量滴定板中，并在37℃溫育達2小時。在除去孔的內(nèi)容物后，孔進一步用結(jié)合生物素的檢測抗體在37℃溫育達1小時。然后洗滌孔，并在加入tmb底物以在包含生物標(biāo)志物、結(jié)合生物素的抗體和結(jié)合酶的親和素的孔中顯示顏色變化前，用檢測試劑(結(jié)合辣根過氧化物酶(hrp)的親和素)在37℃溫育達30分鐘。通過添加硫酸溶液使酶促反應(yīng)終止，并且在labsystemsmultiscanplusplatereader上采用分光光度法在450nm波長下測量顏色變化。利用deltasoftjv軟件(biometallicsinc.,princeton,nj,usa)由光密度(o.d.)值計算樣本中的生物標(biāo)志物的濃度。用于抗體產(chǎn)生的重組生物標(biāo)志物序列構(gòu)成2/3應(yīng)用于用hdms^e識別和定量生物標(biāo)志物的肽。

在瑞典隆德斯卡納大學(xué)醫(yī)院的臨床化學(xué)系(departmentofclinicalchemistry,skaneuniversityhospital,lund,sweden)根據(jù)標(biāo)準(zhǔn)化方法分析ca19-9水平。簡而言之，使用基于釕(ru)衍生物的單級免疫夾層法電化學(xué)發(fā)光免疫測定(ecli)檢測技術(shù)。樣本(抗原-ag)、結(jié)合生物素(綴合物，生物素-mak1)的鼠單克隆抗ca19-9抗體和ru(pak2-ru)標(biāo)記的鼠單克隆抗ca19-9抗體形成夾層復(fù)合物(生物素-mak1---ag---pak2-ru)。添加用鏈霉親和素覆蓋的順磁性粒子。夾層復(fù)合物通過生物素-鏈霉親和素-相互作用結(jié)合到順磁性粒子上(固相)，從而形成鏈霉親和素-生物素-mak1---ag---pak2-ru-形式。用電化學(xué)反應(yīng)檢測抗原-抗體復(fù)合物，導(dǎo)致光發(fā)射(電化學(xué)發(fā)光)，其強度被測量。光強度和樣本中的ca19-9濃度直接成比例。

此外，包括在本研究中的胰腺癌病人都經(jīng)歷了以有療效為目的的胰腺切除。物鏡上4μm的腫瘤部分在二甲苯中脫蠟并在梯度乙醇中再水化。

r統(tǒng)計編程語言用于所有統(tǒng)計分析。繪制接受者操作特征(roc)曲線以使靈敏度和特異性之間的相互關(guān)系可視化。計算曲線下方面積(auc)，并計算在限定特異性下的靈敏度，以測試用于差別診斷癌的生物標(biāo)志物的性能。p-值≤0.05被認為在統(tǒng)計上是顯著的。

這些分析的結(jié)果利用最優(yōu)聚類算法進行分析。在測量分析結(jié)果后，實施單個和多變量分析方法。利用fisher的線性判別分析(lda)來確定變量的加權(quán)和，在兩個診斷(例如癌癥vs健康)間提供最優(yōu)辨別。對于每個樣本，利用下列公式：

其中x是樣本的od(光密度)值，c是具有癌癥診斷的樣本的平均值，h是具有健康診斷的樣本的平均值，而s是協(xié)方差矩陣。

對蛋白質(zhì)gp5、hnrnpc、g7d、kat2b、kif20b、smc1b和spag5和生物標(biāo)志物ca19-9進行統(tǒng)計分析。此外，評估gp5+ca19-9、gp5+hnrnpc、gp5+hnrnpc+ca19-9、gp5+hnrnpc+kif20b和gp5+spag5+kif20b的組合。通過lda方法計算最佳的截止值(cut-off)：cut-off＝1/2(cbar+hbar)，其在箱線圖中對應(yīng)0。

結(jié)果

作為lc/ms采集和數(shù)據(jù)加工的分析再現(xiàn)性的測量，計算來自相同血清樣本的三份采集的峰值之間的強度差異。對于每個周期運行，在數(shù)據(jù)中識別出一些4801個肽。所有三份數(shù)據(jù)點顯示了低于4％的強度變化，而發(fā)現(xiàn)色譜再現(xiàn)性具有2-4％rsd。這些鳥槍法分析數(shù)據(jù)在圖2中示出，具有三份lc-ms覆蓋的bpi色譜，其中可以觀察到平臺性能在從親水性到疏水性肽序列的整個周期運行中高度恒定。來自不同重復(fù)的ms數(shù)據(jù)集群緊密，并顯示出具有高度再現(xiàn)性。

利用重復(fù)注射對所有27個病人樣本進行分析。在研究的本部分，我們生成了71,209個區(qū)別特征的數(shù)據(jù)輸出。hdms^e數(shù)據(jù)文檔用progenesisqi詢問，用于蛋白質(zhì)組的蛋白質(zhì)識別和定量。所得到的蛋白質(zhì)然后在軟件中經(jīng)歷嚴格的獨立驗證。通過采用80％肽可能性和99％蛋白質(zhì)可能性的識別標(biāo)準(zhǔn)，利用錯誤發(fā)現(xiàn)率<0.5％識別出總數(shù)目為7,947個獨特肽和715個獨特蛋白質(zhì)。

包括在hdms^e研究中的胰腺癌病人都經(jīng)歷了有療效目的的胰腺切除。病理上，腫瘤位于胰腺頭部，中值大小為3.0厘米(0.3-4.0厘米)。所有病人都被診斷為t3腫瘤，指的是腫瘤沒有涉及胰腺的周圍主要血管。在這些t3病人中，7個病人被診斷為n1期，即淋巴結(jié)轉(zhuǎn)移，同時病人中的兩個為n0期。這意味著沒有被診斷出淋巴結(jié)轉(zhuǎn)移。在9個病人中有5個檢測到淋巴血管浸潤。病人被進一步表征，9個病人中的7個有嗜神經(jīng)侵襲(神經(jīng)浸潤)。此外，我們發(fā)現(xiàn)9個病人中的7個有中度分化腫瘤，而兩個病人有低分化腫瘤。

所有病人都在手術(shù)后接受持續(xù)6個月(中值6個周期)的輔助化學(xué)療法治療。在后續(xù)中值為386天(258-658天)后，我們可以臨床證實所有病人都活著。我們在生物樣本庫管理數(shù)據(jù)庫中建立的所有臨床和組織病理學(xué)數(shù)據(jù)和特征的總結(jié)在表2和5中列出。

表2胰腺癌病人的臨床和組織病理學(xué)特征

5-fu,5-氟尿嘧啶；cap,卡培他濱(capecitabine)；gem,吉西他濱(gemcitabine)；lvi,淋巴血管浸潤(lymphovascularinvasion)；pni,圍神經(jīng)浸潤(perineuralinvasion).

進行基因本體論分析，以評估識別的蛋白質(zhì)的整體生物作用和分子功能。注釋突出了涉及結(jié)合和催化過程方面的物種的顯著部分。在生物過程方面，蛋白質(zhì)被那些涉及代謝和細胞過程的蛋白質(zhì)高度代表(參見圖5)。這和胰腺研究團隊所期望的一致。類似的本體論組群被其它研究組在近期研究中鑒定[18，19]。

如圖3所示，我們能夠在對134個差異表達蛋白(p<0.0009)所得到的熱圖中在每個研究組中發(fā)現(xiàn)組特異性調(diào)控。此外，分析顯示出可用于分類目的的數(shù)個集群。特別是，胰腺癌組中包含40個蛋白質(zhì)的一個集群顯示顯著上調(diào)，如表3所示。通過這些統(tǒng)計計算，提供低q-值(都在0.005以下)，表示低錯誤發(fā)現(xiàn)率。

表3胰腺癌中按照雙向非監(jiān)督式分層聚類的上調(diào)蛋白質(zhì)

聚類分析后這些在胰腺癌和對照表型間觀察到的差異蛋白圖譜特征進一步通過pca確認。在pca得分圖(scoreplot)中(圖4)，具有相似蛋白表達圖譜的樣本彼此接近。發(fā)現(xiàn)這和臨床分層很好地關(guān)聯(lián)。我們還觀察到和健康樣本相比，胰腺癌和良性案例間在蛋白表達上的較大變化。這在pca圖中示出，和健康樣本(粉色)相比，癌癥樣本(藍色)和良性案例(黃色)分布更分散。這些發(fā)現(xiàn)暗示癌癥和良性人口比對應(yīng)健康人口更異質(zhì)。此外，如圖(plot)中所示，第一主要組分包含38％的總差異，顯然使胰腺癌組從剩余的亞型脫離?？偟膩碚f，這些數(shù)據(jù)提供了胰腺癌同生群(cohort)可以被我們的獨特蛋白質(zhì)組分層的證據(jù)。

利用elisa分析，發(fā)現(xiàn)在gp5、hnrnpc、g7d、kat2b、kif20b,smc1b和spag5蛋白質(zhì)中，gp5(人類血小板糖蛋白v)在高特異性水平下提供極好的靈敏度，如表4所總結(jié)。

表4elisa生物標(biāo)志物試驗

利用elisa的研究的所有病人的gp5豐度的完整總結(jié)在表5中總結(jié)。

表5gp5研究人口統(tǒng)計資料

圖6具體示出gp5為確定主體患胰腺癌的可能性提供高靈敏度和特異性。用于將胰腺癌從健康對照組區(qū)分開的auc達到91％；90％特異性時靈敏度為77％。

利用線性判別(lda)公式計算用于胰腺癌預(yù)測的gp5最優(yōu)截止值為log(gp5)≤0.934，對于健康個體gp5豐度≤1.978μg/l。

圖7示出gp5和ca19-9一起使用用于胰腺癌預(yù)測，把胰腺癌從健康對照組區(qū)分開的auc達到96％；90％特異性時靈敏度為97％。

表6示出elisa試驗測量gp5和其它生物標(biāo)志物的組合的結(jié)果。這里gp5豐度連同hnrnpc和ca19-9提供95％的auc，示出了對于病人組的極好的胰腺癌可預(yù)測性。

表6gp5和其它生物標(biāo)志物組合

圖8示出gp5用于區(qū)分胰腺癌i期和ii期對比iii期和iv期。把胰腺癌i-ii期從胰腺癌iii-iv期區(qū)分開的auc達到83％；90％特異性時靈敏度為66.6％。

蛋白質(zhì)和多肽序列

下面的表格中，上面列出的內(nèi)源蛋白質(zhì)或多肽的代碼與相應(yīng)的基因或通常公認的名稱或進一步描述相關(guān)聯(lián)。

表7蛋白質(zhì)或多肽的列表

實施例

當(dāng)實施本發(fā)明的方法時，得到主體相對于參考主體患胰腺癌的可能性。下文是根據(jù)不同實施例的各種情況的示例。技術(shù)人員會容易理解怎樣實施本發(fā)明并以最佳方式解釋結(jié)果。

實施例1-主體是沒有診斷出胰腺癌的人，而參考主體是已知高度確認未患胰腺癌的健康個體。

當(dāng)實施本發(fā)明的方法時，結(jié)果可能是下面兩種可能的結(jié)果之一：a-發(fā)現(xiàn)主體患胰腺癌的可能性顯著高于參考主體患胰腺癌的可能性。b-沒有檢測到主體和參考主體患胰腺癌的可能性具有顯著差異。在結(jié)果a的情況，因為懷疑主體可能患有胰腺癌，可能有必要對主體進行進一步調(diào)查或用其它適當(dāng)?shù)拇胧?，例如?jīng)常監(jiān)控胰腺癌的其它跡象。在結(jié)果b的情況，結(jié)果可被解釋為陰性，即，沒有發(fā)現(xiàn)主體胰腺癌存在的跡象。

實施例2-主體是診斷出胰腺癌的人，而參考主體是同一個人，但是代表人蛋白質(zhì)組的樣本采集自不同時間，例如，不同的周或不同的月。

當(dāng)實施本發(fā)明的方法時，結(jié)果可能是下面三種可能的結(jié)果之一：a-發(fā)現(xiàn)主體患胰腺癌的可能性顯著高于參考主體患胰腺癌的可能性。b-沒有檢測到主體和參考主體患胰腺癌的可能性具有顯著差異。c-發(fā)現(xiàn)主體患胰腺癌的可能性顯著低于參考主體患胰腺癌的可能性。在結(jié)果a的情況，解釋可能是胰腺癌已經(jīng)隨時間發(fā)展到更嚴重狀態(tài)，假如來自主體的樣本采集自采集參考主體的樣本之后的時間。因此可能促使治療方案的改變。在結(jié)果b的情況，解釋可能是胰腺癌狀態(tài)沒有隨時間而變化。在結(jié)果c的情況，解釋可能是胰腺癌已經(jīng)隨時間留在癥狀更輕的狀態(tài)，假如來自主體的樣本采集自采集參考主體的樣本之后的時間。

在權(quán)利要求中，術(shù)語“包括(comprises/comprising)”并未排除其它元件或步驟的存在。此外，盡管單個列出，可以實施多個裝置、元件或方法步驟。此外，盡管各特征可被包括在不同的權(quán)利要求中，這些可能被有利地組合，并且不同權(quán)利要求中的包含并不暗示特征的組合不是可行的和/或有利的。此外，單數(shù)指代并不排除多個。術(shù)語“a”、“an”、“第一”、“第二”等并不排除多個。

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gluglucysalaalalys

15

<210>20

<211>11

<212>prt

<213>人(human)

<400>20

gluglucysalaalalyscysglugluasplys

1510

<210>21

<211>11

<212>prt

<213>人(human)

<400>21

gluglnglncysvalilemetalagluasnarg

1510

<210>22

<211>12

<212>prt

<213>人(human)

<400>22

gluglnglncysvalilemetalagluasnarglys

1510

<210>23

<211>8

<212>prt

<213>人(human)

<400>23

lysglnleuglyalaglyserarg

15

<210>24

<211>9

<212>prt

<213>人(human)

<400>24

metargaspalavalleupheglulys

15

<210>25

<211>24

<212>prt

<213>人(human)

<400>25

serglyglnglygluproleuaspasptyrvalasnthrglnglypro

151015

serleupheservalthrlyslys

20

<210>26

<211>6

<212>prt

<213>人(human)

<400>26

serserileileilearg

15

<210>27

<211>8

<212>prt

<213>人(human)

<400>27

aspserlyspheleuleuprolys

15

<210>28

<211>4

<212>prt

<213>人(human)

<400>28

leugluglulys

1

<210>29

<211>6

<212>prt

<213>人(human)

<400>29

aspvalaspasnleulys

15

<210>30

<211>32

<212>prt

<213>人(human)

<400>30

alaleupheargasnleuserserleugluservalglnleuasphis

151015

asnglnleugluthrleuproglyaspvalpheglyalaleuproarg

202530

<210>31

<211>11

<212>prt

<213>人(human)

<400>31

alaglnpropheprocysproproalacyslys

1510

<210>32

<211>15

<212>prt

<213>人(human)

<400>32

metvalleuleugluglnleupheleuasphisasnalaleuarg

151015

<210>33

<211>9

<212>prt

<213>人(human)

<400>33

alavalleuhisglyasnleuglulys

15

<210>34

<211>28

<212>prt

<213>人(human)

<400>34

alavalglnleuargglnglualacysalathrleuleuleuglnasn

151015

glyalaasnproasnilethraspphepheglyarg

2025

<210>35

<211>13

<212>prt

<213>人(human)

<400>35

leuleuserhisglythrasnilegluglucysserlys

1510

<210>36

<211>9

<212>prt

<213>人(human)

<400>36

argcysgluleuasnleucysasparg

15

<210>37

<211>21

<212>prt

<213>人(human)

<400>37

thralaleuhisleualacysalathrglyglnproglumetvalhis

151015

leuleuvalserarg

20

<210>38

<211>5

<212>prt

<213>人(human)

<400>38

thrproleuilelys

15

<210>39

<211>7

<212>prt

<213>人(human)

<400>39

trpprothrleumetgluarg

15

<210>40

<211>11

<212>prt

<213>人(human)

<400>40

tyrleuleuleuthrtyrtyraspalaasnlys

1510

<210>41

<211>4

<212>prt

<213>人(human)

<400>41

gluaspleulys

1

<210>42

<211>6

<212>prt

<213>人(human)

<400>42

glugluphetyrserarg

15

<210>43

<211>12

<212>prt

<213>人(human)

<400>43

phemetprometaspasnleuserglyglyglulys

1510

<210>44

<211>16

<212>prt

<213>人(human)

<400>44

lysalaglugluasncysleuglnthrvalasngluleumetalalys

151015

<210>45

<211>12

<212>prt

<213>人(human)

<400>45

leulystyrserglnasngluleuglumetilelys

1510

<210>46

<211>12

<212>prt

<213>人(human)

<400>46

argaspilegluleuglualaserglnleuasparg

1510

<210>47

<211>13

<212>prt

<213>人(human)

<400>47

argphemetprometaspasnleuserglyglyglulys

1510

<210>48

<211>12

<212>prt

<213>人(human)

<400>48

serglyvalileserglyglyserseraspleulys

1510

<210>49

<211>9

<212>prt

<213>人(human)

<400>49

servalgluthrleuleuasnglnlys

15

<210>50

<211>13

<212>prt

<213>人(human)

<400>50

cysglnilevalasnvalalaalagluilepheleulys

1510

<210>51

<211>27

<212>prt

<213>人(human)

<400>51

aspvalasnthrserleuglygluvalalaasngluthrsergluasn

151015

gluthrleuglyaspphesergluglnilelys

2025

<210>52

<211>4

<212>prt

<213>人(human)

<400>52

gluaspleuarg

1

<210>53

<211>18

<212>prt

<213>人(human)

<400>53

glugluthrgluasnalasergluproleuglytyrglusermetala

151015

serlys

<210>54

<211>11

<212>prt

<213>人(human)

<400>54

ileglyileseralamettyrphetyrhislys

1510

<210>55

<211>16

<212>prt

<213>人(human)

<400>55

lysalacysilealaglnglnthrpheilevalproaspleuvallys

151015

<210>56

<211>22

<212>prt

<213>人(human)

<400>56

leuaspserasnserasncysleuserservalseralavalglupro

151015

thrleumetvalilelys

20

<210>57

<211>4

<212>prt

<213>人(human)

<400>57

leuglnmetarg

1

<210>58

<211>4

<212>prt

<213>人(human)

<400>58

leuserglulys

1

<210>59

<211>4

<212>prt

<213>人(human)

<400>59

leutrpleulys

1

<210>60

<211>12

<212>prt

<213>人(human)

<400>60

glngluilethralavalleuglumetlysserarg

1510

<210>61

<211>20

<212>prt

<213>人(human)

<400>61

sergluleumetleuglngluasnglnmetilealaaspglylysglu

151015

alagluthrlys

20

<210>62

<211>5

<212>prt

<213>人(human)

<400>62

serleualaglulys

15

<210>63

<211>11

<212>prt

<213>人(human)

<400>63

serasnaspasptyrglnalaalavalgluarg

1510

<210>64

<211>22

<212>prt

<213>人(human)

<400>64

sersergluargglualatyrserproleugluleuleuaspasnleu

151015

serglyalaaspvalarg

20

<210>65

<211>9

<212>prt

<213>人(human)

<400>65

thrtrpprotyrtyrsercysalaarg

15

<210>66

<211>16

<212>prt

<213>人(human)

<400>66

thrtrpprotyrtyrsercysalaargileseralatrpcystrplys

151015

<210>67

<211>16

<212>prt

<213>人(human)

<400>67

thrtrpprotyrtyrsercysalaargileseralatrpcystrplys

151015

<210>68

<211>10

<212>prt

<213>人(human)

<400>68

tyrcyslysphehispheasnthrleuarg

1510

<210>69

<211>4

<212>prt

<213>人(human)

<400>69

aspgluleuarg

1

<210>70

<211>15

<212>prt

<213>人(human)

<400>70

glugluaspglugluglygluaspvalvalthrserthrglyarg

151015

<210>71

<211>9

<212>prt

<213>人(human)

<400>71

glyserleuserglnglumetalalys

15

<210>72

<211>12

<212>prt

<213>人(human)

<400>72

hisalatyrvalhislysprotyrleutyrserlys

1510

<210>73

<211>15

<212>prt

<213>人(human)

<400>73

lysgluthrgluglythrvalthrcysthrglyalagluglyarg

151015

<210>74

<211>4

<212>prt

<213>人(human)

<400>74

leugluglulys

1

<210>75

<211>12

<212>prt

<213>人(human)

<400>75

leusergluserleuhisvalvalaspgluasnlys

1510

<210>76

<211>4

<212>prt

<213>人(human)

<400>76

leuvalleulys

1

<210>77

<211>15

<212>prt

<213>人(human)

<400>77

thrglyaspgluthrgluleuhisserserglulysglyleulys

151015

<210>78

<211>26

<212>prt

<213>人(human)

<400>78

valgluaspleuseraspalaalaileileserthrserthralaglu

151015

cysmetproileseralaserileasparg

2025

<210>79

<211>7

<212>prt

<213>人(human)

<400>79

valgluglualaprovallys

15

<210>80

<211>40

<212>prt

<213>人(human)

<400>80

valleuileileserthrserthrthrasnasptyrthrproglnval

151015

seralailethraspvalgluglyglyleuseraspalaleuargthr

202530

glugluasnmetgluglythrarg

3540

<210>81

<211>25

<212>prt

<213>人(human)

<400>81

valthrthrgluglupheglualaprometproseralavalsergly

151015

aspaspserglnleuthralaserarg

2025

<210>82

<211>16

<212>prt

<213>人(human)

<400>82

alaasnproglyargaspleuleugluleuleuthrgluvalasnarg

151015

<210>83

<211>24

<212>prt

<213>人(human)

<400>83

glyleuglytyrglycysglyglypheglyglyleuglytyrglytyr

151015

glycysglycysglyserphearg

20

<210>84

<211>15

<212>prt

<213>人(human)

<400>84

glnthralaleuilealaileprometserserglnthrproarg

151015

<210>85

<211>17

<212>prt

<213>人(human)

<400>85

metalaserasnvalthrasnlysmetaspprohissermetasnser

151015

arg

<210>86

<211>6

<212>prt

<213>人(human)

<400>86

glngluvalgluvallys

15

<210>87

<211>11

<212>prt

<213>人(human)

<400>87

aspseralatrpaspproserglnthrmetlys

1510

<210>88

<211>12

<212>prt

<213>人(human)

<400>88

aspthrservalleuthrphethrphecysphelys

1510

<210>89

<211>24

<212>prt

<213>人(human)

<400>89

asncysaspalaleuleuhishisseralaileprogluasppheleu

151015

hisilepheleuleuleuglnlys

20

<210>90

<211>28

<212>prt

<213>人(human)

<400>90

gluglnaspalaleutrpglnglyleugluleuleuglnhisglygln

151015

alatrpphegluasphisleuargglualaglnarg

2025

<210>91

<211>48

<212>prt

<213>人(human)

<400>91

leusercysileaspthrthrileasngluileileasntyrglyval

151015

serserphevalilephevalproileglyleuilepheilesertyr

202530

valleuvalileserserileleuglnilealaseralagluglyarg

354045

<210>92

<211>49

<212>prt

<213>人(human)

<400>92

leusercysileaspthrthrileasngluileileasntyrglyval

151015

serserphevalilephevalproileglyleuilepheilesertyr

202530

valleuvalileserserileleuglnilealaseralagluglyarg

354045

lys

<210>93

<211>27

<212>prt

<213>人(human)

<400>93

thrphealathrcysvalserhisleuthrvalvalilevalhiscys

151015

glycysalaserilealatyrleulysprolys

2025

<210>94

<211>7

<212>prt

<213>人(human)

<400>94

tyrthrvalilemetserlys

15

<210>95

<211>7

<212>prt

<213>人(human)

<400>95

glupheileproglyglulys

15

<210>96

<211>16

<212>prt

<213>人(human)

<400>96

metasnglyserasnmetalaasnthrserproservallysserlys

151015

<210>97

<211>12

<212>prt

<213>人(human)

<400>97

glualaphethrprogluglnleuhisleuglulys

1510

<210>98

<211>22

<212>prt

<213>人(human)

<400>98

leuglytyrglyglyglytyrglyglytyrglytyrglyserglyphe

151015

glyglytyrglytyrarg

20

<210>99

<211>6

<212>prt

<213>人(human)

<400>99

aspgluserleutyrarg

15

<210>100

<211>5

<212>prt

<213>人(human)

<400>100

thrproleuleulys

15

<210>101

<211>12

<212>prt

<213>人(human)

<400>101

valproasnpheileglyglntyrtyrlystrplys

1510

<210>102

<211>18

<212>prt

<213>人(human)

<400>102

glygluleualaalaseralaasnhisglyhisserprocystyrpro

151015

gluarg

<210>103

<211>10

<212>prt

<213>人(human)

<400>103

alaleugluleugluglyalaproalalys

1510

<210>104

<211>26

<212>prt

<213>人(human)

<400>104

leuleuthrleugluglnproglnglyaspsermetmetthrcysglu

151015

glnalaglnleuleualaasnleualaarg

2025

<210>105

<211>19

<212>prt

<213>人(human)

<400>105

lyscysleuphethrhisasniletyrleuglnaspvalglnmetval

151015

hisprolys

<210>106

<211>4

<212>prt

<213>人(human)

<400>106

gluleuasplys

1

<210>107

<211>13

<212>prt

<213>人(human)

<400>107

pheproproserleusergluthrasnlysglyleuarg

1510

<210>108

<211>17

<212>prt

<213>人(human)

<400>108

glyleuileproalaglythrglnhissermetilealathrthrgly

151015

lys

<210>109

<211>22

<212>prt

<213>人(human)

<400>109

glysergluthraspthraspsergluilehisgluseralaserasp

151015

lysaspserleuserlys

20

<210>110

<211>4

<212>prt

<213>人(human)

<400>110

leugluglulys

1

<210>111

<211>5

<212>prt

<213>人(human)

<400>111

metglugluglnarg

15

<210>112

<211>30

<212>prt

<213>人(human)

<400>112

aspileglnmetthrglnserproserproleuseralaservalgly

151015

aspservalthrilethrcysglnalaserglnaspilearg

202530

<210>113

<211>16

<212>prt

<213>人(human)

<400>113

pheleuiletyraspalagluasnleugluileglyvalproserarg

151015

<210>114

<211>13

<212>prt

<213>人(human)

<400>114

metsertyrasncyscysserglyasnpheserserarg

1510

<210>115

<211>7

<212>prt

<213>人(human)

<400>115

leuglyhisasngluleulys

15

<210>116

<211>11

<212>prt

<213>人(human)

<400>116

leuglyhisasngluleulysglucysleulys

1510

<210>117

<211>147

<212>prt

<213>人(human)

<400>117

metvalhisphethralagluglulysalaalavalthrserleutrp

151015

serlysmetasnvalgluglualaglyglyglualaleuglyargleu

202530

leuvalvaltyrprotrpthrglnargphepheaspserpheglyasn

354045

leuserserproseralaileleuglyasnprolysvallysalahis

505560

glylyslysvalleuthrserpheglyaspalailelysasnmetasp

65707580

asnleulysproalaphealalysleusergluleuhiscysasplys

859095

leuhisvalaspprogluasnphelysleuleuglyasnvalmetval

100105110

ileileleualathrhispheglylysgluphethrprogluvalgln

115120125

alaalatrpglnlysleuvalseralavalalailealaleualahis

130135140

lystyrhis

145

<210>118

<211>3580

<212>prt

<213>人(human)

<400>118

metgluserasnpheasnglngluglyvalproargprosertyrval

151015

pheseralaaspproilealaargprosergluileasnpheaspgly

202530

ilelysleuaspleuserhisglupheserleuvalalaproasnthr

354045

glualaasnserphegluserlysasptyrleuglnvalcysleuarg

505560

ileargprophethrglnserglulysgluleuglusergluglycys

65707580

valhisileleuaspserglnthrvalvalleulysgluproglncys

859095

ileleuglyargleuserglulysserserglyglnmetalaglnlys

100105110

pheserpheserlysvalpheglyproalathrthrglnlysgluphe

115120125

pheglnglycysilemetglnprovallysaspleuleulysglygln

130135140

serargleuilephethrtyrglyleuthrasnserglylysthrtyr

145150155160

thrpheglnglythrglugluasnileglyileleuproargthrleu

165170175

asnvalleupheaspserleuglngluargleutyrthrlysmetasn

180185190

leulysprohisargserargglutyrleuargleuserserglugln

195200205

glulysglugluilealaserlysseralaleuleuargglnilelys

210215220

gluvalthrvalhisasnaspseraspaspthrleutyrglyserleu

225230235240

thrasnserleuasnileserglupheglugluserilelysasptyr

245250255

gluglnalaasnleuasnmetalaasnserilelyspheservaltrp

260265270

valserphephegluiletyrasnglutyriletyraspleupheval

275280285

provalserserlyspheglnlysarglysmetleuargleusergln

290295300

aspvallysglytyrserpheilelysaspleuglntrpileglnval

305310315320

seraspserlysglualatyrargleuleulysleuglyilelyshis

325330335

glnservalalaphethrlysleuasnasnalaserserargserhis

340345350

serilephethrvallysileleuglnilegluaspserglumetser

355360365

argvalileargvalsergluleuserleucysaspleualaglyser

370375380

gluargthrmetlysthrglnasngluglygluargleuarggluthr

385390395400

glyasnileasnthrserleuleuthrleuglylyscysileasnval

405410415

leulysasnserglulysserlyspheglnglnhisvalprophearg

420425430

gluserlysleuthrhistyrpheglnserphepheasnglylysgly

435440445

lysilecysmetilevalasnileserglncystyrleualatyrasp

450455460

gluthrleuasnvalleulyspheseralailealaglnlysvalcys

465470475480

valproaspthrleuasnserserglnglulysleupheglyproval

485490495

lysserserglnaspvalserleuaspserasnserasnserlysile

500505510

leuasnvallysargalathrilesertrpgluasnserleugluasp

515520525

leumetgluaspgluaspleuvalglugluleugluasnalagluglu

530535540

thrglnasnvalgluthrlysleuleuaspgluaspleuasplysthr

545550555560

leuglugluasnlysalapheileserhisgluglulysarglysleu

565570575

leuaspleuilegluaspleulyslyslysleuileasnglulyslys

580585590

glulysleuthrleugluphelysileargglugluvalthrglnglu

595600605

phethrglntyrtrpalaglnargglualaaspphelysgluthrleu

610615620

leuglngluarggluileleuglugluasnalagluargargleuala

625630635640

ilephelysaspleuvalglylyscysaspthrarggluglualaala

645650655

lysaspilecysalathrlysvalgluthrglugluthrhisasntyr

660665670

valglyphegluaspileileaspserleuglnaspasnvalalaasp

675680685

ilelyslysglnalagluilealahisleutyrilealaserleupro

690695700

aspproglnglualathralacysleugluleulyspheasnglnile

705710715720

lysalagluleualalysthrlysglygluleuilelysthrlysglu

725730735

gluleulyslysarggluasngluseraspserleuileglngluleu

740745750

gluthrserasnlyslysileilethrglnasnglnargilelysglu

755760765

leuileasnileileaspglnlysgluaspthrileasngluphegln

770775780

asnleulysserhismetgluasnthrphelyscysasnasplysala

785790795800

aspthrserserleuileileasnasnlysleuilecysasngluthr

805810815

valgluvalprolysaspserlysserlysilecyssergluarglys

820825830

argvalasngluasngluleuglnglnaspgluproproalalyslys

835840845

glyserilehisvalserseralailethrgluaspglnlyslysser

850855860

glugluvalargproasnilealagluilegluaspileargvalleu

865870875880

glngluasnasngluglyleuargalapheleuleuthrilegluasn

885890895

gluleulysasnglulysgluglulysalagluleuasnlysglnile

900905910

valhispheglnglngluleuserleuserglulyslysasnleuthr

915920925

leuserlysgluvalglnglnileglnserasntyraspilealaile

930935940

alagluleuhisvalglnlysserlysasnglngluglngluglulys

945950955960

ilemetlysleuserasngluilegluthralathrargserilethr

965970975

asnasnvalserglnilelysleumethisthrlysileaspgluleu

980985990

argthrleuaspservalserglnileserasnileaspleuleuasn

99510001005

leuargaspleuserasnglyserglugluaspasnleuproasnthr

101010151020

glnleuaspleuleuglyasnasptyrleuvalserlysglnvallys

1025103010351040

glutyrargileglngluproasnarggluasnserphehisserser

104510501055

ileglualailetrpgluglucyslysgluilevallysalaserser

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130013051310

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133013351340

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138013851390

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224522502255

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227522802285

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229022952300

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234023452350

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2865287028752880

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290029052910

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299530003005

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357035753580

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405410415

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450455460

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530535540

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565570575

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595600605

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645650655

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740745750

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755760765

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805810815

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850855860

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885890895

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900905910

glyglulysthrlysargvalserserarglyslysproserleuglu

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930935940

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945950955960

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980985990

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99510001005

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101010151020

lysproprothrleulysalathrseraspglugluaspservalleu

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226022652270

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227522802285

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285028552860

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2865287028752880

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275280285

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151015

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202530

lysglualaphethrprogluglnleuhisleuglulysgluleugly

354045

glumetargleuargprothrvalleuhisserglnthrasphisgln

505560

glypheargproileprometmetgln

6570

<210>139

<211>72

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<400>139

metasntyrtyrglyasntyrtyrglyglyleuglytyrglytyrgly

151015

glypheaspaspleuglytyrglytyrglycysglycysglyserphe

202530

argargleuglytyrglyglyglytyrglyglytyrglytyrglyser

354045

glypheglyglytyrglytyrargsercysargprosercystyrgly

505560

glytyrglypheserglyphetyr

6570

<210>140

<211>321

<212>prt

<213>人(human)

<400>140

methisglyargalatyrleuleuleuhisargaspphecysaspleu

151015

lysgluasnasntyrlysglyilethralalysprovalsergluasp

202530

metmetglutrpgluvalgluilegluglyleuglnasnservaltrp

354045

glnglyleuvalpheglnleuthrilehisphethrserglutyrasn

505560

tyralaproprovalvallyspheilethrileprophehisproasn

65707580

valaspprohisthrglyglnprocysileasppheleuaspasnpro

859095

glulystrpasnthrasntyrthrleuserserileleuleualaleu

100105110

glnvalmetleuserasnprovalleugluasnprovalasnleuglu

115120125

alaalaargileleuvallysaspgluserleutyrargthrileleu

130135140

argleupheasnargproleuglnmetlysaspaspserglngluleu

145150155160

prolysaspproarglyscysileargproilelysthrthrserphe

165170175

serasptyrtyrglnthrtrpserargilealathrserlysalathr

180185190

glutyrtyrargthrproleuleulysvalproasnpheileglygln

195200205

tyrtyrlystrplyslysmetaspleuglnhisglnlysglutrpasn

210215220

leulystyrservalilelyscystrpleualaarglysargmetpro

225230235240

hisgluvalthrhissermetglugluilelysleucysprothrleu

245250255

ileprothrthraspgluilepheleugluserprothralaileasn

260265270

serilethraspiletyrgluthrgluglugluglytrplysserasp

275280285

thrserleutyrgluasnaspthraspgluproarggluglugluval

290295300

gluaspleuilesertrpthrasnthrleuasnthrasnthrserglu

305310315320

asp

<210>141

<211>62

<212>prt

<213>人(human)

<400>141

metglygluleualaalaseralaasnhisglyhisserprocystyr

151015

progluarglysglythrproglyaspleuserlysarglysmetleu

202530

valhisphetyrproargarghisserhisproargalathrglngln

354045

trpileleulysasnlysthrleucysargargilelysglu

505560

<210>142

<211>188

<212>prt

<213>人(human)

<400>142

metphesercyscyspheprothrserargglycyscyspheargasn

151015

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202530

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354045

glnaspserleuglyglnalaleualaglyglnalathrprogluile

505560

proleuglyleuglnleuhisthrvalleuvalglngluileglnglu

65707580

leuileglualaglnthrleualaproglyprocysalagluvalarg

859095

alaleuproalaproalaalagluprogluproalatrpglugluala

100105110

proprogluargalaleugluleugluglyalaproalalysaspgln

115120125

thrasnglugluleuprogluilethrgluvalprogluserilelys

130135140

argargleuglyargargvalproalaalathrproalaproarggly

145150155160

asnleuleuleuglnalatrpmetargvalhissertrpalaserarg

165170175

leuphealaproasnvalleuproglythrglypro

180185

<210>143

<211>262

<212>prt

<213>人(human)

<400>143

metthrglnprovalproargleuservalproalaalaleualaleu

151015

glyseralaalaleuglyalaalaphealathrglyleupheleugly

202530

argargcysproprotrpargglyargarggluglncysleuleupro

354045

progluaspserargleutrpglntyrleuleuserargsermetarg

505560

gluhisproalaleuargserleuargleuleuthrleugluglnpro

65707580

glnglyaspsermetmetthrcysgluglnalaglnleuleualaasn

859095

leualaargleuileglnalalyslysalaleuaspleuglythrphe

100105110

thrglytyrseralaleualaleualaleualaleuproalaaspgly

115120125

argvalvalthrcysgluvalaspalaglnproprogluleuglyarg

130135140

proleutrpargglnalaglualagluhislysileaspleuargleu

145150155160

lysproalaleugluthrleuaspgluleuleualaalaglygluala

165170175

glythrpheaspvalalavalvalaspalaasplysgluasncysser

180185190

alatyrtyrgluargcysleuglnleuleuargproglyglyileleu

195200205

alavalleuargvalleutrpargglylysvalleuglnproprolys

210215220

glyaspvalalaalaglucysvalargasnleuasngluargilearg

225230235240

argaspvalargvaltyrileserleuleuproleuglyaspglyleu

245250255

thrleualaphelysile

260

<210>144

<211>344

<212>prt

<213>人(human)

<400>144

metglualaalaargprophealaargglutrpargalaglnserleu

151015

proleualavalglyglyvalleulysleuargleucysgluleutrp

202530

leuleuleuleuglyserserleuasnalaargpheleuproaspglu

354045

gluaspvalasppheileasnglutyrvalasnleuhisasngluleu

505560

argglyaspvalileproargglyserasnleuargphemetthrtrp

65707580

aspvalalaleuserargthralaargalatrpglylyslyscysleu

859095

phethrhisasniletyrleuglnaspvalglnmetvalhisprolys

100105110

phetyrglyileglygluasnmettrpvalglyprogluasngluphe

115120125

thralaserilealaileargsertrphisalaglulyslysmettyr

130135140

asnphegluasnglysercysserglyaspcysserasntyrilegln

145150155160

leuvaltrpasphissertyrlysvalglycysalavalthrprocys

165170175

serlysileglyhisileilehisalaalailepheilecysasntyr

180185190

alaproglyglythrleuthrargargprotyrgluproglyilephe

195200205

cysthrargcysglyargargasplyscysthrasppheleucysser

210215220

asnalaaspargaspglnalathrtyrtyrargphetrptyrprolys

225230235240

trpglumetproargprovalvalcysaspproleucysthrpheile

245250255

leuleuleuargileleucyspheileleucysvalilethrvalleu

260265270

ilevalglnserglnpheproasnileleuleugluglnglnmetile

275280285

phethrproglugluserglualaglyasngluglugluglulysglu

290295300

gluglulyslysglulysgluglumetglumetgluilemetglumet

305310315320

glugluglulysglugluargglugluglugluglugluthrglnlys

325330335

glulysmetgluglugluglulys

340

<210>145

<211>2896

<212>prt

<213>人(human)

<400>145

metserglulysserglyglnserthrlysalalysaspglylyslys

151015

tyralathrleuserleupheasnthrtyrlysglylysserleuglu

202530

thrglnlysthrthralaarghisglyleuglnserleuglylysval

354045

glyileserargargmetproproproalaasnleuproserleulys

505560

alagluasnlysglyasnaspproasnvalasnilevalprolysasp

65707580

glythrglytrpalaserlysglngluglnhisglugluglulysthr

859095

progluvalproproalaglnprolysproglyvalalaalapropro

100105110

gluvalalaproalaprolyssertrpalaserasnlysglnglygly

115120125

glnglyaspglyileglnvalasnserglnpheglnglngluphepro

130135140

serleuglnalaalaglyaspglnglulyslysglulysgluthrasn

145150155160

aspaspasntyrglyproglyproserleuargproproasnvalala

165170175

cystrpargaspglyglylysalaalaglyserproserserserasp

180185190

glnaspglulysleuproglyglnaspgluserthralaglythrser

195200205

gluglnasnaspileleulysvalvalglulysargilealacysgly

210215220

proproglnalalysleuasnglyglnglnalaalaleualasergln

225230235240

tyrargalametmetproprotyrmetpheglnglntyrproargmet

245250255

thrtyrproproleuhisglyprometargpheproproserleuser

260265270

gluthrasnlysglyleuargglyargglyproproprosertrpala

275280285

sergluprogluargproserileleuseralasergluleulysglu

290295300

leuasplyspheaspasnleuaspalaglualaaspgluglytrpala

305310315320

glyalaglnmetgluvalasptyrthrgluglnleuasnpheserasp

325330335

aspaspgluglnglyserasnserprolysgluasnasnsergluasp

340345350

glnglyserlysalasergluasnasngluasnlyslysgluthrasp

355360365

gluvalserasnthrlysserserserglnileproalaglnproser

370375380

valalalysvalprotyrglylysglyproserpheasnglngluarg

385390395400

glythrserserhisleuproproproprolysleuleualaglngln

405410415

hisproproproaspargglnalavalproglyargproglyprophe

420425430

proserlysglnglnvalalaaspgluaspgluiletrplysglnarg

435440445

argargglnglnsergluileseralaalavalgluargalaarglys

450455460

argargglugluglugluargargmetglugluglnarglysalaala

465470475480

cysalaglulysleulysargleuaspglulysleuglyileleuglu

485490495

lysglnproserproglugluilearggluarggluargglulysglu

500505510

arggluargglulysgluleuglulysgluglngluglngluargglu

515520525

lysgluargglulysasparggluargglnglnglulysglulysglu

530535540

leuglulysgluglnglulysglnargglumetglulysgluarglys

545550555560

glnglulysglulysgluleugluargglnlysglulysglulysglu

565570575

leuglnlysmetlysgluglnglulysglucysgluleuglulysglu

580585590

argglulysleugluglulysilegluproarggluproasnleuglu

595600605

prometvalglulysglnglusergluasnsercysasnlysgluglu

610615620

gluprovalphethrargglnaspserasnargserglulysgluala

625630635640

thrprovalvalhisgluthrgluprogluserglyserglnproarg

645650655

proalavalleuserglytyrphelysglnpheglnlysserleupro

660665670

proargpheglnargglnglngluglnmetlysglnglnglntrpgln

675680685

glnglnglnglnglnglyvalleuproglnthrvalproserglnpro

690695700

serserserthrvalproproproprohisargproleutyrglnpro

705710715720

metglnprohisproglnhisleualasermetglypheaspproarg

725730735

trpleumetmetglnsertyrmetaspproargmetmetserglyarg

740745750

proalametaspileproproilehisproglymetileproprolys

755760765

proleumetargargaspglnmetgluglyserproasnserserglu

770775780

serphegluhisilealaargseralaargasphisalaileserleu

785790795800

sergluproargmetleutrpglyseraspprotyrprohisalaglu

805810815

proglnglnalathrthrprolysalathrglugluprogluaspval

820825830

argserglualaalaleuaspglngluglnilethralaalatyrser

835840845

valgluhisasnglnleuglualahisprolysalaasppheilearg

850855860

gluserserglualaglnvalglnlyspheleuserargservalglu

865870875880

aspvalargprohishisthraspalaasnasnglnseralacysphe

885890895

glualaproaspglnlysthrleuseralaproglnglugluargile

900905910

seralavalgluserglnproserarglysargservalserhisgly

915920925

serasnhisthrglnlysproaspgluglnargsergluproserala

930935940

glyileprolysvalthrserargcysileaspserlysgluproile

945950955960

gluargprogluglulysprolyslysgluglypheileargserser

965970975

gluglyprolysproglulysvaltyrlysserlyssergluthrarg

980985990

trpglyproargproserserasnargargglugluvalasnasparg

99510001005

provalargargserglyproilelyslysprovalleuargaspmet

101010151020

lysglugluarggluglnarglysglulysgluglyglulysalaglu

1025103010351040

lysvalthrglulysvalvalvallysproglulysthrglulyslys

104510501055

aspleuproproproproproproproglnproproalaproilegln

106010651070

proglnservalproproproileglnproglualaglulysphepro

107510801085

serthrgluthralathrleualaglnlysproserglnaspthrglu

109010951100

lysproleugluprovalserthrvalglnvalgluproalavallys

1105111011151120

thrvalasnglnglnthrmetalaalaprovalvallysgluglulys

112511301135

glnproglulysvalileserlysaspleuvalilegluargproarg

114011451150

proaspserargproalavallyslysgluserthrleuproproarg

115511601165

thrtyrtrplysglualaarggluargasptrppheproaspglngly

117011751180

tyrargglyargglyargglyglutyrtyrserargglyargsertyr

1185119011951200

argglysertyrglyglyargglyargglyglyargglyhisthrarg

120512101215

asptyrproglntyrargaspasnlysproargalagluhisilepro

122012251230

serglyproleuargglnarggluglusergluthrargsergluser

123512401245

seraspphegluvalvalprolysargargargglnargglyserglu

125012551260

thraspthraspsergluilehisgluseralaserasplysaspser

1265127012751280

leuserlysglylysleuprolysargglugluargprogluasnlys

128512901295

lysprovallysprohisserserphelysproaspasnhisvalarg

130013051310

ileaspasnargleuleuglulysprotyrvalargaspaspasplys

131513201325

alalysproglypheleuprolysglygluprothrargargglyarg

133013351340

glyglythrpheargargglyglyargaspproglyglyargproser

1345135013551360

argproserthrleuargargproalatyrargaspasnglntrpasn

136513701375

proargglnsergluvalprolysprogluaspglygluproproarg

138013851390

arghisgluglnpheileproilealaalaasplysargproprolys

139514001405

phegluarglyspheaspproalaarggluargproargargglnarg

141014151420

prothrargproproargglnasplysproproargpheargargleu

1425143014351440

arggluargglualaalaserlysserasngluvalvalalavalpro

144514501455

thrasnglythrvalasnasnvalalaglngluprovalasnthrleu

146014651470

glyaspileserglyasnlysthrproaspleuserasnglnasnser

147514801485

seraspglnalaasngluglutrpgluthralasergluserserasp

149014951500

pheasngluargarggluargaspglulyslysasnalaaspleuasn

1505151015151520

alaglnthrvalvallysvalglygluasnvalleuproprolysarg

152515301535

gluilealalysargserpheserserglnargprovalasparggln

154015451550

asnargargglyasnasnglyproprolysserglyargasnpheser

155515601565

glyproargasngluargargserglyproproserlysserglylys

157015751580

argglypropheaspaspglnproalaglythrthrglyvalaspleu

1585159015951600

ileasnglyserseralahishisglngluglyvalproasnglythr

160516101615

glyglnlysasnserlysaspserthrglylyslysarggluasppro

162016251630

lysproglyprolyslysprolysglulysvalaspalaleusergln

163516401645

pheaspleuasnasntyralaservalvalileileaspasphispro

165016551660

gluvalthrvalilegluaspproglnserasnleuasnaspaspgly

1665167016751680

phethrgluvalvalserlyslysglnglnlysargleuglnaspglu

168516901695

gluargarglyslysglugluglnvalileglnvaltrpasnlyslys

170017051710

asnalaasnglulysglyargserglnthrserlysleuproproarg

171517201725

phealalyslysglnalathrglyileglnglnalaglnserserala

173017351740

servalproproleualaseralaproleuproproserthrserala

1745175017551760

servalproalaserthrseralaproleuproalathrleuthrpro

176517701775

valproalaserthrseralaprovalproalaserthrleualapro

178017851790

valleualaserthrseralaprovalproalaserproleualapro

179518001805

valseralaseralaservalseralaservalproalaserthrser

181018151820

alaalaalailethrserserseralaproalaseralaproalapro

1825183018351840

thrproileleualaservalserthrproalaservalthrileleu

184518501855

alaseralaserileproileleualaseralaleualaserthrser

186018651870

alaprothrproalaproalaalaserserproalaalaprovalile

187518801885

thralaprothrileproalaseralaprothralaservalproleu

189018951900

alaproalaseralaseralaproalaproalaprothrprovalser

1905191019151920

alaproasnproalaproproalaproalaglnthrglnalaglnthr

192519301935

hislysprovalglnasnproleuglnthrthrserglnserserlys

194019451950

glnproproproserileargleuproseralaglnthrproasngly

195519601965

thrasptyrvalalaserglylysserileglnthrproglnserhis

197019751980

glythrleuthralagluleutrpaspasnlysvalalaproproala

1985199019952000

valleuasnaspileserlyslysleuglyproileserproprogln

200520102015

proproservalseralatrpasnlysproleuthrserpheglyser

202020252030

alaprosersergluglyalalysasnglyglngluserglyleuglu

203520402045

ileglythraspthrileglnpheglyalaproalaserasnglyasn

205020552060

gluasngluvalvalprovalleuserglulysseralaasplysile

2065207020752080

progluprolysgluglnargglnlysglnproargalaglyproile

208520902095

lysalaglnlysleuproaspleuserprovalgluasnlysgluhis

210021052110

lysproglyproileglylysgluargserleulysasnarglysval

211521202125

lysaspalaglnglnvalgluprogluglyglnglulysproserpro

213021352140

alathrvalargserthraspprovalthrthrlysgluthrlysala

2145215021552160

valserglumetserthrgluileglythrmetileservalserser

216521702175

alaglutyrglythrasnalalysgluservalthrasptyrthrthr

218021852190

proserserserleuproasnthrvalalathrasnasnthrlysmet

219522002205

gluaspthrleuvalasnasnvalproleuproasnthrleuproleu

221022152220

prolysarggluthrileglnglnserserserleuthrservalpro

2225223022352240

prothrthrpheserleuthrphelysmetgluseralaarglysala

224522502255

trpgluasnserproasnvalargglulysglyserprovalthrser

226022652270

thralaproproilealathrglyvalserserseralaserglypro

227522802285

serthralaasntyrasnserpheserseralasermetproglnile

229022952300

provalalaservalthrprothralaserleuserglyalaglythr

2305231023152320

tyrthrthrserserleuserthrlysserthrthrthrserasppro

232523302335

proasnilecyslysvallysproglnglnleuglnthrserserleu

234023452350

proseralaserhispheserglnleusercysmetproserleuile

235523602365

alaglnglnglnglnasnproglnvaltyrvalserglnseralaala

237023752380

alaglnileproalaphetyrmetaspthrserhisleupheasnthr

2385239023952400

glnhisalaargleualaproproserleualaglnglnglnglyphe

240524102415

glnproglyleuserglnprothrservalglnglnileproilepro

242024252430

iletyralaproleuglnglyglnhisglnalaglnleuserleugly

243524402445

alaglyproalavalserglnalaglngluleupheserserserleu

245024552460

glnprotyrargserglnproalaphemetglnserserleusergln

2465247024752480

proservalvalleuserglythralailehisasnpheprothrval

248524902495

glnhisglngluleualalysalaglnserglyleualapheglngln

250025052510

thrserasnthrglnproileproileleutyrgluhisglnleugly

251525202525

glnalaserglyleuglyglyserglnleuileaspthrhisleuleu

253025352540

glnalaargalaasnleuthrglnalaserasnleutyrserglygln

2545255025552560

valglnglnproglyglnthrasnphetyrasnthralaglnserpro

256525702575

seralaleuglnglnvalthrvalproleuproalaserglnleuser

258025852590

leuproasnpheglyserthrglyglnproleuilealaleuprogln

259526002605

thrleuglnproproleuglnhisthrthrproglnalaglnalagln

261026152620

serleuserargproalaglnvalserglnpropheargglyleuile

2625263026352640

proalaglythrglnhissermetilealathrthrglylysmetser

264526502655

glumetgluleulysalapheglyserglyileaspilelysprogly

266026652670

thrproproilealaglyargserthrthrprothrserserprophe

267526802685

argalathrserthrserproasnserglnserserlysmetasnser

269026952700

ilevaltyrglnlysglnpheglnseralaproalathrvalargmet

2705271027152720

thrglnpropheprothrglnphealaproglnileleuserglnpro

272527302735

asnleuvalproproleuvalargalaprohisthrasnthrphepro

274027452750

alaprovalglnargproprometalaleualaserglnmetpropro

275527602765

proleuthrthrglyleumetserhisalaargleuprohisvalala

277027752780

argglyprocysglyserleuserglyvalargglyasnglnalagln

2785279027952800

alaalaleulysalagluglnaspmetlysalalysglnargalaglu

280528102815

valleuglnserthrglnargphephesergluglnglnglnserlys

282028252830

glnileglyglyglylysalaglnlysvalaspseraspserserlys

283528402845

proprogluthrleuthraspproproglyvalcysglnglulysval

285028552860

gluglulysproproproalaproserilealathrlysprovalarg

2865287028752880

thrglyproilelysproglnalailelysthrglugluthrlysser

288528902895

<210>146

<211>108

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<400>146

aspileglnmetthrglnserproserproleuseralaservalgly

151015

aspservalthrilethrcysglnalaserglnaspileargasnser

202530

leuiletrptyrglnglnlysproglylysalaprolyspheleuile

354045

tyraspalagluasnleugluileglyvalproserargphearggly

505560

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859095

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354045

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505560

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65707580

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859095

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100105110

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115120125

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130135140

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145150155160

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165170175

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151015

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202530

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354045

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505560

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65707580

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859095

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100