參考文獻(xiàn)參考文獻(xiàn)膠質(zhì)瘤研究進(jìn)展文獻(xiàn)綜述1.1膠質(zhì)瘤簡介中樞神經(jīng)系統(tǒng)細(xì)胞主要分為神經(jīng)元和為神經(jīng)系統(tǒng)提供支持和保護(hù)的膠質(zhì)細(xì)胞，膠質(zhì)細(xì)胞維持體內(nèi)穩(wěn)態(tài)并在神經(jīng)元周圍形成髓鞘ADDINEN.CITE<EndNote><Cite><Author>Jessen</Author><Year>1980</Year><RecNum>1429</RecNum><DisplayText><styleface="superscript">[24]</style></DisplayText><record><rec-number>1429</rec-number><foreign-keys><keyapp="EN"db-id="we95a2ppjztw2ler5pzv5vfkdetsataxd5fs"timestamp="1619490290">1429</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Jessen,KristjanR.</author><author>Mirsky,Rhona</author></authors></contributors><titles><title>Glialcellsintheentericnervoussystemcontainglialfibrillaryacidicprotein</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>736-737</pages><volume>286</volume><number>5774</number><dates><year>1980</year></dates><publisher>SpringerScienceandBusinessMediaLLC</publisher><isbn>0028-0836</isbn><urls><related-urls><url>/10.1038/286736a0</url></related-urls><pdf-urls><url>file://E:\0-文獻(xiàn)\Endnoteclick\Jessen-1980-Glial-cells-in-the-enteric-nervous-.pdf</url></pdf-urls></urls><electronic-resource-num>10.1038/286736a0</electronic-resource-num></record></Cite></EndNote>[24]。在中樞神經(jīng)系統(tǒng)中，膠質(zhì)細(xì)胞包括少突膠質(zhì)細(xì)胞、星形膠質(zhì)細(xì)胞、室管膜細(xì)胞和小膠質(zhì)細(xì)胞。腫瘤由具備分裂能力的細(xì)胞發(fā)展而來，由神經(jīng)膠質(zhì)細(xì)胞或其前體產(chǎn)生的腫瘤成為神經(jīng)膠質(zhì)瘤ADDINEN.CITE<EndNote><Cite><Author>Kleihues</Author><Year>2002</Year><RecNum>1454</RecNum><DisplayText><styleface="superscript">[25]</style></DisplayText><record><rec-number>1454</rec-number><foreign-keys><keyapp="EN"db-id="we95a2ppjztw2ler5pzv5vfkdetsataxd5fs"timestamp="1619957232">1454</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Kleihues,Paul</author><author>Louis,DavidN.</author><author>Scheithauer,BerndW.</author><author>Rorke,LucyB.</author><author>Reifenberger,Guido</author><author>Burger,PeterC.</author><author>Cavenee,WebsterK.</author></authors></contributors><titles><title>TheWHOClassificationofTumorsoftheNervousSystem</title><secondary-title>JournalofNeuropathology&ExperimentalNeurology</secondary-title></titles><periodical><full-title>JournalofNeuropathology&ExperimentalNeurology</full-title></periodical><pages>215-225</pages><volume>61</volume><number>3</number><dates><year>2002</year></dates><publisher>OxfordUniversityPress(OUP)</publisher><isbn>0022-3069</isbn><urls><related-urls><url>/10.1093/jnen/61.3.215</url></related-urls><pdf-urls><url>/c9da2859-4971-4f85-a9ab-459eccec2016.pdf?X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIAUROH2NUQSIQZIEG4%2F20210502%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Date=20210502T120704Z&X-Amz-Expires=600&X-Amz-SignedHeaders=host&X-Amz-Signature=34ff83b0ce5241623c1f04932482588d19788c93a508f12c5e6230c19f759eb1</url></pdf-urls></urls><electronic-resource-num>10.1093/jnen/61.3.215</electronic-resource-num></record></Cite></EndNote>[25]。世界衛(wèi)生組織根據(jù)膠質(zhì)瘤病理特征將腦膠質(zhì)瘤分為4個(gè)級(jí)別，其中I，II級(jí)為低級(jí)別膠質(zhì)瘤，III，IV級(jí)為高級(jí)別膠質(zhì)瘤。分級(jí)基于以下特征：細(xì)胞形態(tài)不典型、核不典型、壞死組織及新生血管的存在。IV級(jí)膠質(zhì)瘤通常被稱為膠質(zhì)母細(xì)胞瘤（glioblastoma,GBM），在老年人中更為常見。膠質(zhì)母細(xì)胞瘤（如圖1-1所示）缺乏統(tǒng)一性和邊界以及加速的有絲分裂，腫瘤組織內(nèi)部可能含有囊腫、鈣化、微血管增生和壞死等。膠質(zhì)瘤增殖速度增加，使腫瘤迅速擴(kuò)張，但由于顱骨內(nèi)體積有限，膠質(zhì)瘤缺乏生長空間，因此膠質(zhì)瘤生長時(shí)破壞周圍的神經(jīng)組織換取生長空間ADDINEN.CITE<EndNote><Cite><Author>Filbin</Author><Year>2015</Year><RecNum>1457</RecNum><DisplayText><styleface="superscript">[26]</style></DisplayText><record><rec-number>1457</rec-number><foreign-keys><keyapp="EN"db-id="we95a2ppjztw2ler5pzv5vfkdetsataxd5fs"timestamp="1620026872">1457</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Filbin,MariellaG.</author><author>Segal,RosalindA.</author></authors></contributors><titles><title>Howneuronalactivityregulatesgliomacellproliferation</title><secondary-title>Neuro-Oncology</secondary-title></titles><periodical><full-title>Neuro-Oncology</full-title></periodical><pages>1543-1544</pages><volume>17</volume><number>12</number><dates><year>2015</year></dates><publisher>OxfordUniversityPress(OUP)</publisher><isbn>1522-8517</isbn><urls><related-urls><url>/10.1093/neuonc/nov188</url></related-urls><pdf-urls><url>/986e2b70-c866-419f-8efe-739bdd6312c0.pdf?X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIAUROH2NUQSIQZIEG4%2F20210503%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Date=20210503T072631Z&X-Amz-Expires=600&X-Amz-SignedHeaders=host&X-Amz-Signature=a7167aeb387e63b4084eb4df81d73fe7167f442fd5ab31b05cabc82f7c66de03</url></pdf-urls></urls><electronic-resource-num>10.1093/neuonc/nov188</electronic-resource-num></record></Cite></EndNote>[26]。腫瘤細(xì)胞的增殖也受到附近血管中氧氣和營養(yǎng)物質(zhì)的限制，膠質(zhì)瘤細(xì)胞位于距離血管10細(xì)胞層以上的位置時(shí)，缺氧會(huì)導(dǎo)致細(xì)胞死亡，限制腫瘤的生長。因此高級(jí)別膠質(zhì)瘤（III級(jí)和IV級(jí)）通過微血管再生，形成新的血管ADDINEN.CITE<EndNote><Cite><Author>Onishi</Author><Year>2011</Year><RecNum>1458</RecNum><DisplayText><styleface="superscript">[27]</style></DisplayText><record><rec-number>1458</rec-number><foreign-keys><keyapp="EN"db-id="we95a2ppjztw2ler5pzv5vfkdetsataxd5fs"timestamp="1620027643">1458</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Onishi,Manabu</author><author>Ichikawa,Tomotsugu</author><author>Kurozumi,Kazuhiko</author><author>Date,Isao</author></authors></contributors><titles><title>Angiogenesisandinvasioninglioma</title><secondary-title>BrainTumorPathology</secondary-title></titles><periodical><full-title>BrainTumorPathology</full-title></periodical><pages>13-24</pages><volume>28</volume><number>1</number><dates><year>2011</year><pub-dates><date>2011/02/01</date></pub-dates></dates><isbn>1861-387X</isbn><urls><related-urls><url>/10.1007/s10014-010-0007-z</url></related-urls></urls><electronic-resource-num>10.1007/s10014-010-0007-z</electronic-resource-num></record></Cite></EndNote>[27]。血管增生是高級(jí)別膠質(zhì)瘤的特征之一，血管增生過程包括血管通透性增加、血漿蛋白外滲、現(xiàn)有基底膜破裂、促血管生成基質(zhì)分子沉積及隨后的內(nèi)皮細(xì)胞的增殖和遷移等ADDINEN.CITE<EndNote><Cite><Author>Tasi?</Author><Year>2020</Year><RecNum>1459</RecNum><DisplayText><styleface="superscript">[28]</style></DisplayText><record><rec-number>1459</rec-number><foreign-keys><keyapp="EN"db-id="we95a2ppjztw2ler5pzv5vfkdetsataxd5fs"timestamp="1620028243">1459</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Tasi?,Desanka</author><author>Dimov,Irena</author><author>Kostov,Milo?</author><author>Vidovi?,Nata?a</author><author>Dimov,Dragan</author></authors></contributors><titles><title>Angiogenesisinglioblastoma:Molecularandcellularmechanismsandclinicalapplications</title><secondary-title>ActaFacultatisMedicaeNaissensis</secondary-title></titles><periodical><full-title>ActaFacultatisMedicaeNaissensis</full-title></periodical><pages>211-230</pages><volume>37</volume><number>3</number><dates><year>2020</year></dates><publisher>CentreforEvaluationinEducationandScience(CEON/CEES)</publisher><isbn>0351-6083</isbn><urls><related-urls><url>/10.5937/afmnai2003211t</url></related-urls><pdf-urls><url>/944b4599-c2a8-4192-8082-f8120270f572.pdf?X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIAUROH2NUQSIQZIEG4%2F20210503%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Date=20210503T075034Z&X-Amz-Expires=600&X-Amz-SignedHeaders=host&X-Amz-Signature=9ea410c2b08330bc0b2ea01bc47a1302db99822afd6f7bcbc50ed5f479cb265b</url></pdf-urls></urls><electronic-resource-num>10.5937/afmnai2003211t</electronic-resource-num></record></Cite></EndNote>[28]。與其他部分的腫瘤不同，原發(fā)性腦瘤很少通過血管或淋巴管轉(zhuǎn)移。但是膠質(zhì)瘤細(xì)胞能夠浸潤正常的腦組織、沿血管基底膜或室管膜等遷移。組織壞死是膠質(zhì)母細(xì)胞瘤的特征之一，當(dāng)生長中的腫瘤的營養(yǎng)需求超過現(xiàn)有的血管系統(tǒng)營養(yǎng)供給時(shí)，腫瘤細(xì)胞發(fā)生死亡。圖1-1膠質(zhì)母細(xì)胞瘤的增強(qiáng)T1MRI圖像ADDINEN.CITE<EndNote><Cite><Author>Okamoto</Author><Year>2002</Year><RecNum>1456</RecNum><DisplayText><styleface="superscript">[29]</style></DisplayText><record><rec-number>1456</rec-number><foreign-keys><keyapp="EN"db-id="we95a2ppjztw2ler5pzv5vfkdetsataxd5fs"timestamp="1620022082">1456</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Okamoto,K.</author><author>Ito,J.</author><author>Takahashi,N.</author><author>Ishikawa,K.</author><author>Furusawa,T.</author><author>Tokiguchi,S.</author><author>Sakai,K.</author></authors></contributors><titles><title>MRIofhigh-gradeastrocytictumors:earlyappearanceandevolution</title><secondary-title>Neuroradiology</secondary-title></titles><periodical><full-title>Neuroradiology</full-title></periodical><pages>395-402</pages><volume>44</volume><number>5</number><dates><year>2002</year><pub-dates><date>2002/05/01</date></pub-dates></dates><isbn>1432-1920</isbn><urls><related-urls><url>/10.1007/s00234-001-0725-3</url></related-urls></urls><electronic-resource-num>10.1007/s00234-001-0725-3</electronic-resource-num></record></Cite></EndNote>[29]Fig.1-1Post-contrastT1-weightedMRIimageofaglioblastomaADDINEN.CITE<EndNote><Cite><Author>Okamoto</Author><Year>2002</Year><RecNum>1456</RecNum><DisplayText><styleface="superscript">[29]</style></DisplayText><record><rec-number>1456</rec-number><foreign-keys><keyapp="EN"db-id="we95a2ppjztw2ler5pzv5vfkdetsataxd5fs"timestamp="1620022082">1456</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Okamoto,K.</author><author>Ito,J.</author><author>Takahashi,N.</author><author>Ishikawa,K.</author><author>Furusawa,T.</author><author>Tokiguchi,S.</author><author>Sakai,K.</author></authors></contributors><titles><title>MRIofhigh-gradeastrocytictumors:earlyappearanceandevolution</title><secondary-title>Neuroradiology</secondary-title></titles><periodical><full-title>Neuroradiology</full-title></periodical><pages>395-402</pages><volume>44</volume><number>5</number><dates><year>2002</year><pub-dates><date>2002/05/01</date></pub-dates></dates><isbn>1432-1920</isbn><urls><related-urls><url>/10.1007/s00234-001-0725-3</url></related-urls></urls><electronic-resource-num>10.1007/s00234-001-0725-3</electronic-resource-num></record></Cite></EndNote>[29]膠質(zhì)瘤的常見癥狀包括顱內(nèi)壓升高（如頭痛、嘔吐等）和局部或全身性腦功能障礙（如癲癇、意識(shí)改等）。膠質(zhì)瘤的常見病因包括一些家族遺傳性疾病（例如I型和II型神經(jīng)纖維瘤?。┘半婋x輻射等ADDINEN.CITE<EndNote><Cite><Author>Ernest</Author><Year>2009</Year><RecNum>1455</RecNum><DisplayText><styleface="superscript">[30]</style></DisplayText><record><rec-number>1455</rec-number><foreign-keys><keyapp="EN"db-id="we95a2ppjztw2ler5pzv5vfkdetsataxd5fs"timestamp="1619958890">1455</key></foreign-keys><ref-typename="BookSection">5</ref-type><contributors><authors><author>Ernest,N.J.</author><author>Sontheimer,H.</author></authors><secondary-authors><author>Squire,LarryR.</author></secondary-authors></contributors><titles><title>Glioma</title><secondary-title>EncyclopediaofNeuroscience</secondary-title></titles><pages>877-884</pages><keywords><keyword>Apoptosis</keyword><keyword>Astrocytoma</keyword><keyword>Ependymoma</keyword><keyword>Ganglioneuroma</keyword><keyword>Glioblastoma</keyword><keyword>Glioma</keyword><keyword>HypoxiainduciblefactorMigration</keyword><keyword>Necrosis</keyword><keyword>Oligodendroglioma</keyword><keyword>p53</keyword><keyword>SystemX</keyword><keyword>Vestibularschwannoma</keyword></keywords><dates><year>2009</year><pub-dates><date>2009/01/01/</date></pub-dates></dates><pub-location>Oxford</pub-location><publisher>AcademicPress</publisher><isbn>978-0-08-045046-9</isbn><urls><related-urls><url>/science/article/pii/B9780080450469010081</url></related-urls></urls><electronic-resource-num>/10.1016/B978-008045046-9.01008-1</electronic-resource-num></record></Cite></EndNote>[30]。膠質(zhì)瘤具有高度浸潤性，難以通過手術(shù)治愈。1.2膠質(zhì)瘤的治療研究進(jìn)展在過去的30年中，高級(jí)別膠質(zhì)瘤治療的主要方案一直沒有變更，包括最大程度的手術(shù)切除、放射治療和化療ADDINEN.CITE<EndNote><Cite><Author>Bush</Author><Year>2017</Year><RecNum>1422</RecNum><DisplayText><styleface="superscript">[31]</style></DisplayText><record><rec-number>1422</rec-number><foreign-keys><keyapp="EN"db-id="we95a2ppjztw2ler5pzv5vfkdetsataxd5fs"timestamp="1619356397">1422</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Bush,NancyAnnOberheim</author><author>Chang,SusanM.</author><author>Berger,MitchelS.</author></authors></contributors><titles><title>Currentandfuturestrategiesfortreatmentofglioma</title><secondary-title>NeurosurgicalReview</secondary-title></titles><periodical><full-title>NeurosurgicalReview</full-title></periodical><pages>1-14</pages><volume>40</volume><number>1</number><dates><year>2017</year></dates><publisher>SpringerScienceandBusinessMediaLLC</publisher><isbn>0344-5607</isbn><urls><related-urls><url>/10.1007/s10143-016-0709-8</url></related-urls><pdf-urls><url>file://E:\0-文獻(xiàn)\Endnoteclick\Bush-2017-Current-and-future-strategies-for-t.pdf</url></pdf-urls></urls><electronic-resource-num>10.1007/s10143-016-0709-8</electronic-resource-num></record></Cite></EndNote>[31]。手術(shù)切除作為高級(jí)別膠質(zhì)瘤的最初治療方案，全切除對(duì)于膠質(zhì)瘤的治療十分重要，膠質(zhì)瘤的主要治療方法是手術(shù)治療，手術(shù)切除率與無進(jìn)展生存期和總生存期的長度相關(guān)ADDINEN.CITEADDINEN.CITE.DATA[32-34]。但是由于膠質(zhì)瘤自身的浸潤性，難以完全切除，需要術(shù)后放化療作為輔助治療ADDINEN.CITE<EndNote><Cite><Author>Dea</Author><Year>2012</Year><RecNum>1453</RecNum><DisplayText><styleface="superscript">[35]</style></DisplayText><record><rec-number>1453</rec-number><foreign-keys><keyapp="EN"db-id="we95a2ppjztw2ler5pzv5vfkdetsataxd5fs"timestamp="1619790036">1453</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Dea,Nicolas</author><author>Fournier-Gosselin,Marie-Pierre</author><author>Mathieu,David</author><author>Goffaux,Philippe</author><author>Fortin,David</author></authors></contributors><titles><title>DoesExtentofResectionImpactSurvivalinPatientsBearingGlioblastoma?</title><secondary-title>CanadianJournalofNeurologicalSciences/JournalCanadiendesSciencesNeurologiques</secondary-title></titles><periodical><full-title>CanadianJournalofNeurologicalSciences/JournalCanadiendesSciencesNeurologiques</full-title></periodical><pages>632-637</pages><volume>39</volume><number>5</number><edition>2014/12/02</edition><dates><year>2012</year></dates><publisher>CambridgeUniversityPress</publisher><isbn>0317-1671</isbn><urls><related-urls><url>/core/article/does-extent-of-resection-impact-survival-in-patients-bearing-glioblastoma/5355854B82F9EC1A8A0B2D2566FC6C8E</url></related-urls></urls><electronic-resource-num>10.1017/S0317167100015377</electronic-resource-num><remote-database-name>CambridgeCore</remote-database-name><remote-database-provider>CambridgeUniversityPress</remote-database-provider></record></Cite></EndNote>[35]。局部放射性治療是針對(duì)膠質(zhì)母細(xì)胞瘤的主要治療手段，標(biāo)準(zhǔn)劑量為60Gy，每次1.8-2.0Gy，總劑量分為30-33次照射，主要照射腫瘤靶區(qū)及腫瘤邊緣1-3cm，以消滅浸潤性膠質(zhì)瘤細(xì)胞。浸潤性膠質(zhì)瘤細(xì)胞能夠隱藏在血腦屏障的完整部分后，因此想要通過抗癌藥物有效治療浸潤性膠質(zhì)瘤，抗癌藥物必須具備血腦屏障滲透能力ADDINEN.CITE<EndNote><Cite><Author>Taylor</Author><Year>2019</Year><RecNum>1450</RecNum><DisplayText><styleface="superscript">[36]</style></DisplayText><record><rec-number>1450</rec-number><foreign-keys><keyapp="EN"db-id="we95a2ppjztw2ler5pzv5vfkdetsataxd5fs"timestamp="1619787756">1450</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Taylor,OliviaG.</author><author>Brzozowski,JoshuaS.</author><author>Skelding,KathrynA.</author></authors></contributors><titles><title>GlioblastomaMultiforme:AnOverviewofEmergingTherapeuticTargets</title><secondary-title>FrontiersinOncology</secondary-title></titles><periodical><full-title>FrontiersinOncology</full-title></periodical><volume>9</volume><dates><year>2019</year></dates><publisher>FrontiersMediaSA</publisher><isbn>2234-943X</isbn><urls><related-urls><url>/10.3389/fonc.2019.00963</url></related-urls><pdf-urls><url>/04b2619e-24e5-423d-a130-dcb9fe0a1075.pdf?X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIAUROH2NUQSIQZIEG4%2F20210430%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Date=20210430T130102Z&X-Amz-Expires=600&X-Amz-SignedHeaders=host&X-Amz-Signature=262dfaa51d753fc3891a708f61edf8ef81a05e654b405f0426d7986066d7e847</url></pdf-urls></urls><electronic-resource-num>10.3389/fonc.2019.00963</electronic-resource-num></record></Cite></EndNote>[36]。替莫唑胺是腦膠質(zhì)瘤的一線化療藥物，是一種烷基化劑，通過烷基化腫瘤細(xì)胞DNA造成腫瘤細(xì)胞死亡，同時(shí)具有較好的血腦屏障滲透能力，腦脊液中替莫唑胺濃度約為血漿中的30%，是目前主要應(yīng)用的針對(duì)膠質(zhì)瘤的化療藥物。但仍存在一些問題，例如替莫唑胺早期實(shí)驗(yàn)中造成的腫瘤體積減小，但該反應(yīng)持續(xù)時(shí)間短，幾乎沒有影響整體生存ADDINEN.CITE<EndNote><Cite><Author>Batchelor</Author><Year>2000</Year><RecNum>1435</RecNum><DisplayText><styleface="superscript">[8]</style></DisplayText><record><rec-number>1435</rec-number><foreign-keys><keyapp="EN"db-id="we95a2ppjztw2ler5pzv5vfkdetsataxd5fs"timestamp="1619578928">1435</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Batchelor,Tracy</author></authors></contributors><titles><title>Temozolomideformalignantbraintumours</title><secondary-title>TheLancet</secondary-title></titles><periodical><full-title>TheLancet</full-title></periodical><pages>1115-1116</pages><volume>355</volume><number>9210</number><dates><year>2000</year></dates><publisher>ElsevierBV</publisher><isbn>0140-6736</isbn><urls><related-urls><url>/10.1016/s0140-6736(00)02055-9</url></related-urls><pdf-urls><url>file://E:\0-文獻(xiàn)\Endnoteclick\Batchelor-2000-Temozolomide-for-malignant-brain-tu.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/s0140-6736(00)02055-9</electronic-resource-num></record></Cite></EndNote>[8]。目前用于治療膠質(zhì)瘤的化療方案仍然存在許多局限性。全身遞送的藥物由于血腦屏障阻礙，通常在難以在中樞神經(jīng)系統(tǒng)內(nèi)及腫瘤部位達(dá)到高濃度，同時(shí)具有明顯的全身性副作用，例如骨髓抑制。將藥物直接遞送至中樞神經(jīng)系統(tǒng)及腫瘤內(nèi)部是未來膠質(zhì)瘤化療的發(fā)展方向。參考文獻(xiàn)] Kheirollahi,M.,Dashti,S.,Khalaj,Z.,etal.,BrainTumors:SpecialCharactersforResearchandBanking[J].Advancedbiomedicalresearch,2015.4:4.[2]