簡介：CYTOKINEDRIVENREGULATIONOFNKCELLFUNCTIONSINTUMORIMMUNITYROLEOFTHEMICANKG2DSYSTEMNORBERTOWZWIRNER,MERCEDESBFUERTES,MARI′AVICTORIAGIRART,CAROLINAIDOMAICA,LUCASEROSSILABORATORIODEINMUNOGENE′TICA,HOSPITALDECLI′NICAS‘‘JOSE′DESANMARTI′N’’,ANDDEPARTAMENTODEMICROBIOLOGI′A,FACULTADDEMEDICINA,UNIVERSIDADDEBUENOSAIRES,BUENOSAIRES,ARGENTINAAVAILABLEONLINE26FEBRUARY2007ABSTRACTNATURALKILLERNKCELLSARECRITICALPLAYERSDURINGTUMORGROWTHCONTROLINIMMUNOCOMPETENTHOSTSTHESECELLSALSOESTABLISHACROSSTALKWITHDENDRITICCELLSDCSANDPROMOTEATH1MEDIATEDIMMUNITYNKG2DISAPIVOTALRECEPTORTHATDIRECTSTHETUMORICIDALACTIVITYOFNKCELLSTHROUGHTHERECOGNITIONOFAGROUPOFLIGANDSSUCHASMICAWIDELYEXPRESSEDONDIFFERENTTUMORSHEREWEWILLREVIEWTHEMOSTIMPORTANTTUMORIMMUNEESCAPEMECHANISMSTHATCOMPROMISETHEFUNCTIONALITYOFNKG2DANDITSCOGNATELIGANDS,INCLUDINGTGFBSECRETION,TUMORSHEDDINGOFSOLUBLEMICA,ANDADDITIONALMECHANISMSTHATCOMPROMISETHETUMORICIDALACTIVITYOFNKG2DEXPRESSINGCELLSSUCHMECHANISMSMAYALSODAMPENTHECROSSTALKBETWEENNKCELLSANDDCSDURINGTHEANTITUMORIMMUNERESPONSESRECENTKNOWLEDGEMAYLEADTOINNOVATIVEAPPROACHESTOPROMOTEEFFICIENTNKCELLMEDIATEDANTITUMORIMMUNERESPONSES2007ELSEVIERLTDALLRIGHTSRESERVEDKEYWORDSMHCNKG2DNKCELLSMICATUMOR1INTRODUCTIONTUMORTRANSFORMATIONANDGROWTHISAMULTISTEPPROCESSTHATINVOLVESTHEACCUMULATIONOFMUTATIONSANDRESULTSINAGENETICINSTABILITY,LOSSOFCELLCYCLECONTROL,RESISTANCETOAPOPTOSIS,UNLIMITEDSELFRENEWALCAPACITYANDTHESELECTIONOFTUMORVARIANTSWITHTHEABILITYTOINVADELOCALANDDISTANTTISSUESHOWEVER,INIMMUNOCOMPETENTHOSTSTUMORSAREFORCEDTOGROWUNDERTHEPERMANENTPRESSUREOFANIMMUNESYSTEMTHATIMPOSESANIMMUNOLOGICALPRESSURETHISOBSERVATIONHASLEDTOTHEPOSTULATIONOFTHEIMMUNOSURVEILLANCEHYPOTHESISCURRENTLY,WEKNOWTHATMANYIMMUNEMEDIATEDCELLDESTRUCTIONMECHANISMSAREACTIVATEDTOELIMINATETUMORCELLSTHEPROGRESSMADEDURINGTHELASTTWODECADESINTHEAREAOFCELLULARANDMOLECULARIMMUNOLOGYANDONCOLOGYHASGREATLYCONTRIBUTEDTOADEEPERKNOWLEDGEABOUTTHETUMORHOSTRELATIONSHIPNEWIDEASHAVEBEENPROPOSEDTOEXPLAINTHECOMPLEXNATUREOFTHEEFFECTOFTHEIMMUNESYSTEMONTHETUMORCELLSANDTHEMECHANISMSDEVELOPEDBYTUMORSTOESCAPEDIFFERENTIMMUNEEFFECTORMECHANISMSALTHOUGHNOTMUTUALLYEXCLUSIVE,TWOMAINLINESOFTHINKINGWEREPOSTULATED1,2INTHEFIRSTCASE,ITWASPROPOSEDTHATTUMORGROWTHISACONSEQUENCEOFANIMMUNOEDITINGPROCESSACHIEVEDBYTHEIMMUNESYSTEMONTUMORCELLS1ACCORDINGLY,TUMORGROWTHANDMETASTASISINIMMUNOCOMPETENTHOSTSISACONSEQUENCEOFTHREESTAGESTHE‘‘THREEES’’OFIMMUNOEDITINGFIRST,THEIMMUNESYSTEMACHIEVESELIMINATIONOFSUSCEPTIBLETUMORCELLSIMMUNOSURVEILLANCESECONDLY,EQUILIBRIUMBETWEENTHEIMMUNESYSTEMANDTHESURVIVINGRESISTANTTUMORCELLSISREACHED,THUSSCULPTINGTHETUMORPHENOTYPEFINALLY,SURVIVINGTUMORCELLSENTERTHETUMORESCAPEPHASETHATISOFTENACCOMPANIEDBYTHEESTABLISHMENTOFMETASTASISOTHERAUTHORSHAVEPROPOSEDTHATTUMORSGROWWWWELSEVIERCOM/LOCATE/CYTOGFRCYTOKINEFAX541159508758EMAILADDRESSNWZSINECTISCOMARNWZWIRNER13596101/–SEEFRONTMATTER2007ELSEVIERLTDALLRIGHTSRESERVEDDOI101016/JCYTOGFR200701013THEABILITYOFNKG2DENGAGEMENTALONETOTRIGGERIFNGSECRETIONHASBEENQUESTIONEDBYTHEOBSERVATIONTHATENGAGEMENTOFTHISRECEPTORBYSOMESOLIDPHASEIMMOBILIZEDNKG2DSPECIFICMABSCOULDELICITCYTOTOXICGRANULERELEASEANDTARGETCELLKILLINGBUTNOTIFNGSECRETION13,16,19,23INSOMECASES,THISDIFFERENTIALRESPONSEHASBEENATTRIBUTEDTOADIFFERENTIALSPLICINGOFNKG2DINMOUSEBUTNOTHUMANNKCELLSANDTOADIFFERENTIALASSOCIATIONWITHTHEDAP10ANDDAP12ADAPTERPROTEINS24,25HOWEVER,RECENTEXPERIMENTALEVIDENCEINDICATESTHATMOUSENKG2DASSOCIATESWITHBOTHADAPTERPROTEINSINNKCELLSTOTRIGGERANACTIVATIONSIGNAL26INSOMECASES,THEDISCREPANCYINTHEABILITYOFNKG2DTOPROMOTEIFNGSECRETIONMIGHTBEDUETOTHEUSEOFSOLIDPHASEIMMOBILIZEDMABSAGAINSTNKG2DSINCEINTHESEEXPERIMENTS,IFNGSECRETIONWASINDUCEDBYENGAGEMENTOFNKG2DWITHSOLIDPHASEIMMOBILIZEDCHIMERICMOLECULESTHATRESEMBLENKG2DLS,SUCHASMICAFCANDULBP1FC16INADDITION,ITISLIKELYTHATINORDERTOTRIGGERIFNGSECRETIONTHROUGHNKG2D,NKCELLSREQUIRETHECOENGAGEMENTOFOTHERRECEPTORS12,13,23THEREFORE,INTERPRETATIONOFTHERESULTSOBTAINEDUPONSTIMULATIONOFNKCELLSTHROUGHNKG2DDURINGTHEINITIATIONOFCYTOTOXICITYANDCYTOKINEPRODUCTIONSHOULDBECAUTIOUSCONSIDERINGTHATTHEDISTINCTOUTCOMESDEPENDONTHECELLTYPE,ACTIVATIONSTATEOFTHECELLS,SPECIESANALYZEDHUMANORMOUSEANDTHESPECIFICLIGANDBEINGTESTEDTWOPOPULATIONSOFHUMANNKCELLSHAVEBEENIDENTIFIEDTHEMAJORPOPULATIONABOUT90ISCYTOTOXICANDSHOWSACD56DIMCD16PHENOTYPE,WHEREASTHEREMAINING10OFTHENKCELLSAREASOURCEOFIMMUNOREGULATORYCYTOKINESANDPRESENTACD56BRIGHTCD16DIMORCD56BRIGHTCD16?PHENOTYPE27ALTHOUGHNKG2DEXPRESSIONSEEMSTOBESLIGHTLYHIGHERINCD56DIMTHANINCD56BRIGHTNKCELLS,THESEDIFFERENCESDONOTAPPEARTOBEINVOLVEDINTHEDIFFERENTIALIFNGPRODUCTIONANDPROLIFERATIONOFTHESENKCELLSUBSETSUPONACTIVATIONBYDENDRITICCELLSDCS28INHUMANSANDMICE,NKG2DISPROMISCUOUSINTERMSOFLIGANDRECOGNITIONHUMANNKG2DLIGANDSNKG2DLSARETHEMHCCLASSIRELATEDCHAINGENESAANDBMICAANDMICB15,ANDAGROUPOFGLYCOSYLPHOSPHATIDYLINOSITOLGPIBOUNDSURFACEMOLECULESCALLEDUL16BINDINGPROTEINULBP1,2,3AND418,29MICEHAVEADIFFERENTSETOFNKG2DLS,WHICHCOMPRISETHERETINOICACIDEARLYINDUCIBLEGENERAE1FAMILYAGROUPOFGPIANCHORED,CELLSURFACEGLYCOPROTEIN,THEMINORHISTOCOMPATIBILITYANTIGENH60ANINTEGRALTRANSMEMBRANEPROTEINS,ANDTHEMURINEUL16BINDINGPROTEINLIKETRANSCRIPT1MULT1,ALLOFWHICHEXHIBITLOWSEQUENCEHOMOLOGYWITHTHEIRHUMANCOUNTERPARTS18,29HOWEVER,HUMANNKG2DBINDSMOUSENKG2DLSANDMOUSENKG2DCANRECOGNIZESOMEHUMANNKG2DLS,MOSTLIKELYREFLECTINGASELECTIVEADVANTAGEOFPRESERVINGTHENKG2DRECEPTORINBOTHSPECIESTHEMICAANDMICBGENESWEREDESCRIBEDIN1994ASAGROUPOFGENESTHATMAPWITHINTHEMHCCLASSIREGION,BUTEXHIBITALOWHOMOLOGYWITHTHECLASSICALMHCCLASSIGENES30,31EXPRESSIONOFMICAHASBEENOBSERVEDINHUMANEPITHELIALANDFIBROBLASTCELLLINES32,33,INPRIMARYCULTURESOFENDOTHELIALCELLSANDFIBROBLASTS34,TUMORSOFDIFFERENTHISTOTYPES12,35,THYMICMEDULLA36,ANDGASTROINTESTINALEPITHELIUM32EXPRESSIONOFMICAWASALSOOBSERVEDINCULTUREDHUMANKERATINOCYTES37,BUTTHISEXPRESSIONWASNOTOBSERVEDONTHECELLSURFACE34ALSO,ACTIVATEDCD4ANDCD8TCELLSWERESHOWNTOEXPRESSMICA38–40,ALTHOUGHLOWLEVELSOFTHISNKG2DLAREEXPRESSEDONTHECELLSURFACE41THEGENERALIZEDEXPRESSIONOFMICAOBSERVEDINMANYTUMORS35,42–46SUGGESTSTHATITSEXPRESSIONISACONSEQUENCEOFTHEMALIGNANTNEOTRANSFORMATIONHOWEVER,RECENTEVIDENCEINDICATESTHATEXPRESSIONOFMICAANDOTHERNKG2DLSISINDUCEDBYTHEDNADAMAGEPATHWAYINRESPONSETOGENOTOXICINSULTS,WHICHISACRITICALSTEPDURINGTHENEOTRANSFORMATION47HOWEVER,ALTHOUGHTHETUMORSUPPRESSORP53ANTIONCOGENHASBEENINVOLVEDINTHEPROTECTIONAGAINSTMALIGNTRANSFORMATION48,P53DOESNOTAPPEARTOBEINVOLVEDINUPREGULATIONOFMICAANDSUBSEQUENTACQUISITIONOFSUSCEPTIBILITYTONKG2DMEDIATEDCYTOTOXICITYALSO,EXPRESSIONOFMICAINACTIVATEDTCELLSINDICATESTHATTHISNKG2DLCANALSOBEINDUCEDBYCELLACTIVATIONCOINCIDENTALLY,CELLACTIVATIONANDNEOTRANSFORMATIONARETWOCELLULARPROCESSESREGULATEDBYNFKB49EXPERIMENTALEVIDENCEACCUMULATEDDURINGTHELASTYEARSINDICATESTHATTHEMICANKG2DSYSTEMPARTICIPATESINDIFFERENTASPECTSOFTHEIMMUNERESPONSE15,32,50–56,BUTTHATTHISINTERACTIONISPARTICULARLYIMPORTANTDURINGTUMORIMMUNITY42,43,57–60THEANTITUMOREFFECTORMECHANISMSUSEDBYNKCELLSCOMPRISETHECYTOTOXICITYAGAINSTSUSCEPTIBLETARGETCELLSANDTHESECRETIONOFIFNGANDOTHERPROINFLAMMATORYCYTOKINESTHEMECHANISMSOFNKCELLMEDIATEDCYTOTOXICITYHAVEBEENREVIEWEDELSEWHERE61,62INMOSTCASES,NKCELLSLYSESUSCEPTIBLETARGETCELLSSECRETINGCYTOTOXICGRANULESTHATCONTAINGRANZYMESANDPERFORINHOWEVER,STUDIESINPERFORIN,GRANZYMESORNKCELLDEFICIENTMICEANDSTUDIESWITHHUMANCELLSREVEALEDTHATNKCELLSCANALSOLYSETARGETCELLSBYDEATHRECEPTORMEDIATEDCYTOTOXICITYSUCHASTHEFASFASLSYSTEMANDTHETNFRELATEDAPOPTOSISINDUCINGLIGANDTRAIL63INMICE,NKCELLPERFORINMEDIATEDCYTOTOXICITY,BUTNOTPRODUCTIONOFIFNGWASCRITICALFORTHEREJECTIONOFRAE1BEXPRESSINGTUMORCELLSINVIVO22ANDFORTHEESTABLISHMENTOFTUMORMETASTASIS64,SUGGESTINGTHATPERFORINGRANZYMESECRETIONISTHEMAJOREFFECTORMECHANISMSOFTHENKG2DDEPENDENT,NKCELLMEDIATEDANTITUMORRESPONSETHEREFORE,CURRENTEVIDENCEINDICATESTHATTHEMECHANISMSTHROUGHWHICHNKG2DTRIGGERSNKCELLMEDIATEDCYTOTOXICITYRELIESONTHEGRANULESECRETIONPATHWAY,BUTITREMAINSANOPENQUESTIONWHETHERNKG2DENGAGEMENTCANALSOELICITFASANDTRAILMEDIATEDAPOPTOSISOFSUSCEPTIBLETARGETSTHEMOLECULARDISSECTIONOFRECEPTORSANDEFFECTORMOLECULESINVOLVEDINNKCELLMEDIATEDTUMORCELLDESTRUCTIONMAYLEADTOTHENWZWIRNERETAL/CYTOKINEGROWTHFACTORREVIEWS182007159–170161

簡介：中文中文9169字出處出處ZWIRNERN,FUERTESM,GIRARTM,ETALCYTOKINEDRIVENREGULATIONOFNKCELLFUNCTIONSINTUMORIMMUNITYROLEOFTHEMICANKG2DSYSTEMJCYTOKINEGROWTHFACTORREVIEWS,2007,181215970腫瘤免疫中腫瘤免疫中NK細(xì)胞功能的細(xì)胞因子驅(qū)使調(diào)節(jié)細(xì)胞功能的細(xì)胞因子驅(qū)使調(diào)節(jié)MICANKG2D系統(tǒng)的作用系統(tǒng)的作用NZWIRNER，MFUERTES，MGIRART，CDOMAICA，LROSSI摘要NK細(xì)胞在免疫活性宿主的腫瘤生長調(diào)控中起著關(guān)鍵作用。NK細(xì)胞還和樹突細(xì)胞相互，并且促進(jìn)了TH1介導(dǎo)的免疫活動(dòng)。NKG2D是指導(dǎo)NK細(xì)胞殺滅腫瘤作用的樞紐受體，它通過識(shí)別如MICA這樣的廣泛表達(dá)于不同腫瘤內(nèi)的一組配體發(fā)揮作用。這里我們將論述最重要的腫瘤免疫逃逸機(jī)制，即NKG2D的功能和它的相關(guān)配體，包括TGFB分泌物，腫瘤的可溶性MICA脫落物，及其他機(jī)制即NKG2D表達(dá)細(xì)胞的殺滅腫瘤作用。這些機(jī)制可能緩解了NK細(xì)胞和樹突細(xì)胞在抗腫瘤免疫反應(yīng)中的相互作用。最近的研究可能產(chǎn)生一種新的方法來促進(jìn)有效的NK細(xì)胞介導(dǎo)的抗腫瘤免疫反應(yīng)。關(guān)鍵詞MHC；NKG2D；NK細(xì)胞；MICA；腫瘤11序論序論腫瘤轉(zhuǎn)化和生長是一個(gè)多步驟過程，包括突變的積累和導(dǎo)致遺傳不穩(wěn)定性，細(xì)胞周期調(diào)控的喪失，抗凋亡，無限自我增殖能力和具有入侵局部和遠(yuǎn)處組織能力的腫瘤突變體的選擇。盡管如此，在免疫活性宿主中，腫瘤一直在一個(gè)免疫系統(tǒng)給予的免疫壓力下生長。這種觀點(diǎn)已經(jīng)引出免疫監(jiān)視假說。如今，我們知道有許多免疫介導(dǎo)的細(xì)胞破壞機(jī)制被激活來消滅腫瘤細(xì)胞。在過去二十年中，細(xì)胞和分子免疫學(xué)及腫瘤學(xué)領(lǐng)域中的進(jìn)展已經(jīng)很大程度地促進(jìn)了腫瘤和宿主之間聯(lián)系的深入研究。已經(jīng)有新的觀點(diǎn)被提出來解釋免疫系統(tǒng)對(duì)腫瘤細(xì)胞的作用的復(fù)雜本質(zhì)以及腫瘤逃避不同免疫效應(yīng)機(jī)制的機(jī)理。盡管不是互相排斥，這種觀點(diǎn)的兩條主要思路依然是假說。第一種思路提出腫瘤生長是免疫系統(tǒng)對(duì)腫瘤細(xì)胞的一個(gè)免疫編輯過程的結(jié)果。而且，腫瘤在免疫活性宿主的生長和轉(zhuǎn)移是三個(gè)步驟的結(jié)果。第一步，免疫系統(tǒng)實(shí)現(xiàn)對(duì)敏感腫瘤細(xì)胞的消除（免疫監(jiān)視）。第二步，免疫系統(tǒng)和存活腫瘤細(xì)胞之間達(dá)到平衡，從而腫瘤表型出現(xiàn)。最后，存活腫瘤細(xì)胞進(jìn)入腫瘤逃逸階段，該階段經(jīng)常伴隨有腫瘤轉(zhuǎn)移。其他專家也有提出腫瘤在活性免疫系統(tǒng)不斷給予的固定選擇壓力下生長。這種觀點(diǎn)認(rèn)為，只有那些對(duì)免疫系統(tǒng)的免疫破壞和攻擊耐受的腫瘤細(xì)胞才會(huì)成為過度生長的腫瘤細(xì)胞。這些特性共同賦予腫瘤不受控制生長和轉(zhuǎn)移的潛力。盡管如此，腫瘤生長其實(shí)是一個(gè)更為復(fù)雜的過程，因?yàn)樵谀[瘤生長中，一系列血管生成和抗血管生成因子也參與形成腫瘤表型。；另外，細(xì)胞外基質(zhì)在腫瘤生長中的重要作用最近也已經(jīng)被認(rèn)識(shí)到。不管有多少作用因素，無可爭議的是，免疫系統(tǒng)對(duì)腫瘤生長的調(diào)控很關(guān)鍵。細(xì)胞毒性細(xì)胞，特別是NK細(xì)胞及致炎細(xì)胞因子促進(jìn)了免疫抗腫瘤作用。在這篇綜述中，我們將集中于腫瘤免疫中NK細(xì)胞功能的細(xì)胞因子驅(qū)使調(diào)節(jié)研究的新方面，特別是MICANKG2D系統(tǒng)在腫瘤逃逸中的作用。關(guān)于T淋巴細(xì)胞在腫瘤免疫中的作用以及細(xì)胞因子如何參與形成這些機(jī)制，將在另一篇優(yōu)秀的綜述中論述。2NK細(xì)胞，受體和配體細(xì)胞，受體和配體在過去幾十年的研究中已經(jīng)明確NK細(xì)胞呈現(xiàn)細(xì)胞毒性，分泌致炎細(xì)胞因子如IFNG,TNFA,TNFB,IL13,IL10ANDGMCSF與敏感腫瘤靶細(xì)胞接觸。例如，活體內(nèi)NK細(xì)胞缺失會(huì)導(dǎo)致腫瘤生長的不受控制。而且，化學(xué)方法誘發(fā)的腫瘤在NK細(xì)胞缺陷的小鼠體內(nèi)被迅速排斥，而移植入NK細(xì)胞充分的小鼠體內(nèi)則腫瘤發(fā)展平衡。最近，NK細(xì)胞還被證明參與形成小鼠和人類的適應(yīng)性免疫反應(yīng)。NK細(xì)胞對(duì)靶細(xì)胞的識(shí)別是通過種系密碼，細(xì)胞表面抑制和活化受體實(shí)現(xiàn)的。我們知和MICB，以及一組叫UL16結(jié)合蛋白1，2，3，4的糖基磷脂酰肌醇錨定表面分子。小鼠有一組不同的NKG2D配體，其中包含了維甲酸早期誘導(dǎo)基因I家族，次要組織相容性抗原H60，及小鼠UL16結(jié)合蛋白類轉(zhuǎn)錄子。盡管如此，人類NKG2D能結(jié)合小鼠的NKG2DLS，而小鼠的NKG2D也能識(shí)別一些人類NKG2DLS，這一現(xiàn)象最有可能反映的是NKG2D受體在人類和小鼠中的選擇性保存優(yōu)勢，MICA和MICB基因在1994年被描述為一組基因，定位于MHC類別I區(qū)域，但和經(jīng)典MHC類別I基因呈現(xiàn)低同源性。MICA的表達(dá)已經(jīng)在人類上皮和成纖維細(xì)胞系中發(fā)現(xiàn)，首先是在上皮細(xì)胞和成纖維細(xì)胞，不同組織分型的腫瘤，胸腺髓質(zhì)，胃腸上皮組織的培養(yǎng)系中發(fā)現(xiàn)的。MICA的表達(dá)也在人工培養(yǎng)的人類角質(zhì)化細(xì)胞中發(fā)現(xiàn)，但是這種表達(dá)不是發(fā)生在細(xì)胞表面。而且，活化的CD4和CD8T細(xì)胞也被證明表達(dá)MICA，盡管低水平的這種NKG2DL是表達(dá)在細(xì)胞表面。MICA在許多腫瘤上發(fā)現(xiàn)有表達(dá)，這表明它的表達(dá)是腫瘤惡性轉(zhuǎn)化的結(jié)果。盡管如此，最近的證據(jù)表明MICA和其他NKG2DLS的表達(dá)是適應(yīng)遺傳毒性損傷的DNA破壞途徑導(dǎo)致的，這是轉(zhuǎn)化中的關(guān)鍵步驟。雖然抑癌基因P53參與保護(hù)對(duì)抗惡性轉(zhuǎn)化，P53并不涉及MICA的上調(diào)及隨后NKG2D介導(dǎo)的細(xì)胞毒性敏感性的獲得。另外，MICA在活化T細(xì)胞的表達(dá)表明NKG2DL也能由細(xì)胞活化導(dǎo)致。同時(shí)，細(xì)胞活化和轉(zhuǎn)化是兩個(gè)受NFKB調(diào)控的細(xì)胞過程。去年的實(shí)驗(yàn)證據(jù)表明MICANKG2D系統(tǒng)參與免疫反應(yīng)的不同方面，但是這種相互作用在腫瘤免疫中尤其重要。NK細(xì)胞的抗腫瘤效應(yīng)物機(jī)制包含對(duì)可疑靶細(xì)胞的細(xì)胞毒性，IFN的分泌和其他致炎細(xì)胞因子。NK細(xì)胞介導(dǎo)的細(xì)胞毒性機(jī)制已經(jīng)在別處進(jìn)行了綜述。在大多數(shù)實(shí)驗(yàn)中，NK細(xì)胞溶解敏感靶細(xì)胞分泌細(xì)胞毒性顆粒，其中包含粒酶和穿孔素。盡管如此，對(duì)于穿孔素，粒酶或者NK細(xì)胞缺陷小鼠和人類細(xì)胞的研究表明NK細(xì)胞也能通過死亡受體介導(dǎo)（TRAIL）的細(xì)胞毒性溶解靶細(xì)胞。在小鼠體內(nèi)，NK細(xì)胞穿孔素介導(dǎo)的細(xì)胞毒性，但不是IFN的產(chǎn)生對(duì)于體內(nèi)RAE1B表達(dá)的腫瘤細(xì)胞的排斥和腫瘤轉(zhuǎn)移的建議是置關(guān)重要的，這表明穿孔素粒酶分泌是NKG2D依賴性的，NK細(xì)胞介導(dǎo)的抗腫瘤反應(yīng)的主要效應(yīng)物機(jī)制。因此，當(dāng)前證據(jù)表明，NKG2D啟動(dòng)NK細(xì)胞介導(dǎo)的細(xì)胞毒性機(jī)制依賴于顆粒分泌途徑，但關(guān)于NKG2D配對(duì)是否也能引起FAS和TRAIL介導(dǎo)的可疑靶細(xì)胞的凋亡依然是個(gè)疑問。對(duì)于受體和效應(yīng)分子的分子解析涉及NK細(xì)胞介導(dǎo)的腫瘤細(xì)胞破壞，可能促進(jìn)抑制腫瘤生長和轉(zhuǎn)移的新方法的發(fā)展。3NK3NK細(xì)胞的細(xì)胞因子刺激及和樹突細(xì)胞的相互細(xì)胞的細(xì)胞因子刺激及和樹突細(xì)胞的相互NK細(xì)胞的分化和刺激是受巨噬細(xì)胞和樹突細(xì)胞如IL2，IL12，IL15，IL18，IL21，IL23和IFNA/B分泌的不同細(xì)胞因子的控制的。這些致炎細(xì)胞因子有差別地促進(jìn)NK細(xì)胞活化標(biāo)記的表達(dá)，IFN的分泌和/或啟動(dòng)NK細(xì)胞介導(dǎo)的細(xì)胞毒性，促進(jìn)他們的腫瘤殺傷功能。特別是，樹突細(xì)胞通過依賴于可溶性因子和細(xì)胞細(xì)胞連接的相互作用的建立，在活化NK細(xì)胞中發(fā)揮了關(guān)鍵的作用，在小鼠體內(nèi)引出了強(qiáng)烈的抗腫瘤免疫反應(yīng)。盡管一種類似的相互作用也被證明發(fā)生在人類DC和NK細(xì)胞之間，但可以觀察到的是不同的樹突細(xì)胞亞群促進(jìn)NK細(xì)胞活化，增殖，發(fā)揮細(xì)胞毒性的能力也不同。DC刺激NK細(xì)胞的能力不僅依賴于IL12，還依賴于其他細(xì)胞因子比如IFNA/BANDIL18,ANDCELL–CELL相互作用在人類中，涉及DCNK細(xì)胞相互作用的主要的NK細(xì)胞受體是NKP30，該受體導(dǎo)致了不成熟DC的殺傷而不是成熟DC。這種差別抵抗的潛在機(jī)制并沒有被完全弄清楚，但它可能和成熟DC比非成熟DC表達(dá)更高水平的MHCI型分子有關(guān)。而且，一些證據(jù)表明NKP46和NKP44，NKG2D在DC和NK細(xì)胞相互作用中有少量參與，盡管其他也可能無法證明NKP46和NKG2D的涉及。NKG2D確實(shí)可能涉及這種相互作用，因?yàn)橐恍┛蒲腥藛T報(bào)道，MICA在DC的表達(dá)上調(diào)導(dǎo)致IL15或者IFN或者微生物組成的成熟。而且，因?yàn)镈C能被相關(guān)的有害復(fù)合物如TOLL類受體或TLRS促效藥刺激，以及考慮到最近出現(xiàn)的證據(jù)表明甚至連NK細(xì)胞也表達(dá)功能性TLRS。在DC和NK細(xì)

簡介：REVIEWARTICLETHEIMPACTOFGLYCAEMICCONTROLONOUTCOMESINPATIENTSWITHENDSTAGERENALDISEASEANDTYPE2DIABETESSOPHIAZOUNGAS,1,2PETERGKERR,3MICHELLELUI1ANDHELENAJTEEDE1,21DIABETESCLINICALSERVICESANDRESEARCHUNITAND3DEPARTMENTOFNEPHROLOGY,MONASHUNIVERSITY,MONASHMEDICALCENTRE,AND2JEANHAILESRESEARCHGROUP,MONASHINSTITUTEOFHEALTHSERVICESRESEARCH,MONASHMEDICALCENTRE,CLAYTON,VICTORIA,AUSTRALIASUMMARYINAUSTRALIAANDNEWZEALANDTHEPREVALENCEANDINCIDENCEOFENDSTAGERENALDISEASEESRDHASINCREASEDINAUSTRALIAALONETHEFINANCIALBURDENISESTIMATEDTOREACH500MILLIONBY2007DATAFROMTHENATIONALCHRONICKIDNEYDISEASESTRATEGYWORKSHOPREPORT2005THELEADINGCAUSEOFESRDINAUSTRALIAANDNEWZEALAND,ANDTHROUGHOUTTHEDEVELOPEDWORLD,ISTYPE2DIABETES,HAVINGOVERTAKENGLOMERULONEPHRITISIN20041TODATE,MANAGEMENTOFPATIENTSWITHDIABETESANDESRDHASBEEN,ACCORDINGTOGUIDELINES,GIVENFORPATIENTSWITHOUTESRDTHISCOMMENTARYRAISESTHREEIMPORTANTEMERGINGCONCERNSINTHECLINICALCAREOFTHESEPATIENTSITHELACKOFRELIABLETOOLSTOMEASUREGLYCAEMICCONTROLIILIMITATIONSOFTHECURRENTDATASETSUPPORTINGARELATIONSHIPBETWEENOUTCOMEANDGLYCAEMICCONTROLINESRDANDIIILACKOFSTUDIESEXAMININGTHEEFFECTOFINTENSIVEDIABETESCAREANDGLUCOSECONTROLINPATIENTSWITHESRDKEYWORDSENDSTAGERENALDISEASE,GLYCAEMICCONTROL,OUTCOMES,TYPE2DIABETESTHEEMERGINGPROBLEMOFTYPE2DIABETESANDESRDINAUSTRALIAANDNEWZEALAND,APPROXIMATELY740PEOPLEPERMILLIONPOPULATIONRECEIVERENALREPLACEMENTTHERAPYANDOFTHESE420PEOPLEPERMILLIONREQUIREDIALYSISTHERAPY2OVERTIMEASTEADYINCREASEINTHESEPREVALENCERATESHASBEENOBSERVEDFIG12OFTHOSEREQUIRINGRENALREPLACEMENTTHERAPY,ABOUTONETHIRDARENEWPATIENTSENTERINGADIALYSISPROGRAMMETHEMOSTCOMMONCAUSEOFESRDINAUSTRALIAANDNEWZEALANDISDIABETESIN2005,DIABETICNEPHROPATHYACCOUNTEDFOR32–41OFALLNEWPATIENTSENTERINGADIALYSISPROGRAMME1SIMILARLY,OFALLPATIENTSREQUIRINGRENALREPLACEMENTTHERAPY,42AND46HADDIABETES,RESPECTIVELYTHEMAJORITYOFTHESEPATIENTSAPPROXIMATELY90HAVETYPE2DIABETESFIG21OFTHOSEABOUTHALFARERECEIVINGINSULINTHERAPYSURVIVALOFTHEAVERAGEDIALYSISPATIENTISPOORTHEANNUALMORTALITYRATEFORTHEAUSTRALIANANDNEWZEALANDDIALYSISPOPULATIONIS145AND164DEATHSPER100PATIENTYEARS,RESPECTIVELY3ALARGEPROPORTIONOFTHIS,APPROXIMATELY65,ISATTRIBUTEDTOCARDIOVASCULARDISEASECVDANDINFECTIONANZDATAREGISTRYREPORTOF2005CAUSEOFDEATH,AUSTRALIA49CVDAND13INFECTIONNEWZEALAND49CVDAND15INFECTION3FURTHERMORE,THEDEATHRATEDUETOCVDIS10TO100FOLDGREATERTHANTHATFORAGEMATCHEDPOPULATIONSFIG33,4OVERTHELASTFIVEDECADES,MORTALITYDUETOCVDINTHEGENERALPOPULATIONHASDECLINEDBY505ANDINCIDENTCARDIOVASCULAREVENTSHAVEALSODECLINEDINPEOPLEWITHDIABETESNOTCOMPLICATEDBYESRD6ASREPORTEDBYANZDATA,3,7INTHEESRDPOPULATION,MORTALITYDUETOCVDREMAINSUNCHANGEDANDUNAFFECTEDBYMAJORADVANCESINMEDICALTHERAPYCVDMORTALITY1993AND2005485AND49,RESPECTIVELYINOUROWN5YEARPROSPECTIVESTUDYOFINCIDENTCARDIOVASCULAREVENTSINPATIENTSWITHESRD,THOSEWITHDIABETESHADATWOFOLDGREATERRISKOFEVENTSANDTHISRISKWASNOTABROGATEDBYADJUSTMENTFORAGE,GENDER,BLOODPRESSURE,PASTHISTORYOFCVD,SMOKINGSTATUSANDTREATMENTWITHLIPIDLOWERINGTHERAPYORASPIRINUNADJUSTEDHAZARDRATIO241,P0001,95CI183–318ADJUSTEDHAZARDRATIO186,P0001,95CI138–252UNPUBLISHEDDATA,FIG4CORRESPONDENCEDRSOPHIAZOUNGAS,DIABETESCLINICALSERVICESANDRESEARCHUNIT,SOUTHERNHEALTH,MONASHMEDICALCENTRE,246CLAYTONROAD,CLAYTON,VIC3168,AUSTRALIAEMAILSOPHIAZOUNGASMEDMONASHEDUAUACCEPTEDFORPUBLICATION15OCTOBER2007?2007THEAUTHORSJOURNALCOMPILATION?2007ASIANPACIFICSOCIETYOFNEPHROLOGYNEPHROLOGY200813,124–127DOI101111/J14401797200700901XANAEMIA,BLOODTRANSFUSIONANDRECOMBINANTERYTHROPOIETINUSEMAYALLIMPACTONTHEACCURACYOFTHEHBA1CMEASUREMENTTOTHISEND,AJAPANESESTUDYHASRECENTLYREPORTEDTHATGLYCATEDALBUMINMAYPROVIDEASIGNIFICANTLYBETTERMEASUREOFGLYCAEMICCONTROLINDIABETICHDPATIENTSCOMPAREDWITHHBA1CBECAUSEOFTHEEFFECTSOFANAEMIAANDERYTHROPOIETINUSE22MOREOVER,ITISUNCLEARASTOATWHATPOINTACROSSTHEVARIOUSSTAGESOFCHRONICKIDNEYDISEASETHESEMETHODOLOGICALISSUESBECOMECLINICALLYRELEVANTASMOSTOFTHEEFFECTSOFURAEMIAWOULDBEEXPECTEDTOLOWERHBA1CESTIMATIONS,ITMAYALSOBENECESSARYTODEFINEADIFFERENT‘NORMALRANGE’FORESRDULTIMATELY,AVAILABLE000025050075100KAPLAN–MEIERSURVIVALPROBABILITY7255280DIABETES2431711060NODIABETESNUMBERATRISK0246FOLLOWUPTIMEYEARSFIG4KAPLAN–MEIERCARDIOVASCULARDISEASEFREESURVIVALINPATIENTSWITHENDSTAGERENALDISEASEESRDASCOMPAREDWITHTHOSEWITHESRDANDDIABETESUNPUBLISHEDDATAP0001NODIABETES––––––DIABETES?ANZDATAREGISTRYCOMORBIDCONDITIONSATENTRYTOPROGRAM2005NUMBEROFPATIENTSPATIENTSCOUNTRYCHRONICLUNGDISEASECORONARYARTERYDISEASEPERIPHERALVASCULARDISEASECEREBROVASCULARDISEASESMOKINGAUSTRALIA2210YES27612731333921824011CURRENT25411TYPEI864SUSPECTED7313315671346603FORMER90241IIINSREQ37017NO187385132360168476191086NEVER105448IINONINS46421NO129058NEWZEALAND436YES6114111256415399CURRENT7016TYPEI143SUSPECTED2465112256123FORMER17841IIINSREQ9923NO35180274633477938588NEVER18843IINONINS8620NO23754DIABETESINCLUDINGDIABETICNEPHROPATHYNNFIG2COMORBIDCONDITIONSATENTRYTODIALYSISPROGRAMME1000120406080100AGEYEARS0010102040620406080100MORTALITYPERYEARFIG3AGESPECIFICMORTALITYRATESOFPATIENTSREQUIRINGRENALREPLACEMENTTHERAPYASCOMPAREDWITHTHEGENERALPOPULATION32004MORTALITYRATESDIALYSISTRANSPLANT–––––AUSTPOPULATIONSZOUNGASETAL126?2007THEAUTHORSJOURNALCOMPILATION?2007ASIANPACIFICSOCIETYOFNEPHROLOGY

簡介：THEEXPRESSIONOFCSRCGENEINTHECARCINOGENESISPROCESSOFHUMANCARDIAADENOCARCINOMAWANGXIUJIA,YUANSHULAN,XIAOLIN,WANGXUHUAANDWANGCHAOJUNPOBOX2345,BEIJING100023,CHINAWJG,1999DECEMBER56488491FAX861085381893WORLDJOURNALOFGASTROENTEROLOGYEMAILWJGWJGNETCOMWWWWJGNETCOMCOPYRIGHT?1999BYTHEWJGPRESSISSN10079327SUBJECTHEADINGSCSRCGENEEXPRESSIONPRODUCTPP60CSRCCARDIAADENOCARCINOMACARCINOGENESISNEOPLASMMETASTASISIMMUNOHISTOCHEMISTRYABSTRACTAIMTOINVESTIGATETHEACTIVATION,EXPRESSIONOFCSRCGENEANDITSROLEINTHECARCINOGENETICPROCESSOFHUMANCARDIAADENOCARCINOMACAMETHODSFIFTYSIXCASESOFCA,34CASESOFNORMAL,36CASESOFPROTIFERATIVEEPITHELIAADJACENTTOCARCINOMA,AND20CASESOFLYMPHNODEMETASTASESOFCAWERESTUDIEDFORPP60CSRC,THEEXPRESSIONPRODUCTOFCSRCGENEIMMUNOHISTOCHEMICALLYBYUSINGTHESPECIFICMONOCLONALANTIBODY,MAB327RESULTSTHEPOSITIVERATESOFPP60CSRCINTHENORMALEPITHELIA,PROTIFERATIVEEPITHELIA,CAANDLYMPHNODEMETASTASESWERE29410/34,94434/36,71440/56AND60012/20,RESPECTIVELY,AMONGTHEM,THEDIFFERENCESOFTHEPOSITIVERATESWERESTATISTICALLYSIGNIFICANTP001THEEXPRESSIONLEVELSOFPP60CSRCINCAANDPROLIFERATIVEEPITHELIAWERESIGNIFICANTLYHIGHERTHANTHATINTHENORMALEPITHELIAP001THEPP60CSRCPOSITIVERATESINTHEPAPILLARY,TUBULAR,POORLYDIFFERENTIATEDANDMUCOUSADENOCARCINOMAWERE7506/8,81818/22,50010/20AND10006/6,RESPECTIVELY,WHEREASTHOSEOFTUBULARANDMUCOUSADENOCARCINOMASWERESIGNIFICANTLYHIGHERTHANTHOSEOFPAPILLARYANDPOORLYDIFFERENTIATEDADENOCARCINOMASP005,ANDTHEPP60CSRCEXPRESSIONLEVELSOFTUBULARANDMUCOUSADENOCARCINOMASWEREALSOSIGNIFICANTLYHIGHERTHANTHOSEOFPAPILLARYANDPOORLYDIFFERENTIATEDADENOCARCINOMASP001CONCLUSIONTHEACTIVATIONANDEXPRESSIONOFCSRCGENEAREASSOCIATEDWITHTHEINITIATIONANDDEVELOPMENTOFHUMANCATHEPROTEINAMOUNTOFPP60CSRCINCREASEDDURINGTHEPROCESSOFCARCINOGENESISANDPP60CSRCEXPRESSIONISALSORELATEDTOLYMPHNODEMETASTASESINTRODUCTIONTHEREISAGENERALTENDENCYINGASTRICCANCERTHATTHEINCIDENCERATEOFCARDIAADENOCARCINOMACAISINCREASINGSTEADLY,ANDCANCEROFTHEDISTALSTOMACHISDECREASINGPROPORTIONATELYTHEBIOLOGICALANDEPIDEMIOLOGICALFEATURESOFCAAREDISTINCTFROMTHOSEOFTHEDISTALSTOMACH,ANDTHEUNDERLYINGCAUSEREMAINEDUNELUCIDATED13PP60CSRCISTHEPRODUCTOFCSRCGENEPOSSESSINGTHEACTIVITYOFTYROSINEKINASEINCREASEDEXPRESSIONOFCSRCGENEHADBEENREPORTEDINSOMEHUMANSARCOMAANDCANCERSOFBREAST4,ESOPHAGUS5,STOMACH6ANDCOLON7,ANDTHEACTIVATIONANDEXPRESSIONOFCSRCGENEMIGHTBEASSOCIATEDWITHTHEINITIATIONANDDEVELOPMENTOFSOMECANCERSOURPREVIOUSSTUDYSHOWEDTHEACTIVATIONANDEXPRESSIONOFCSRCGENEWASASSOCIATEDWITHTHEDEVELOPMENTANDDIFFERENTIATIONOFESOPHAGEALSQUAMOUSCELLCARCINOMAS8,WEBELIEVEDTHATSIMILARCHANGESMIGHTOCCURINCANCEROFCARDIA,THEREFORE,THEFOLLOWINGSTUDYWASCARRIEDOUTMATERIALSANDMETHODSSAMPLECOLLECTIONANDPROCESSINGALL56CASESOFCASAMPLESWERECOLLECTEDFROMTHECAPATIENTSSURGICALLYTREATEDINYANTINGINSTITUTEOFCANCERPREVENTIONOFSICHUANPROVINCEALLTISSUESPECIMENSWEREROUTINELYPROCESSED,FORMALINFIXEDANDPARAFFINEMBEDDED,ATLEAST2SERIALPARAFFINSECTIONSOF4ΜM6ΜMTHICKNESSWEREMADE,ONEWASSTAINEDWITHHEMATOXYLINANDEOSINHEANDTHEOTHERWASUSEDFORPP60CSRCPROTEINDETECTIONBYIMMUNOHISTOCHEMICALSTAININGREAGENTSTHEMONOCLONALANTIBODYMAB327MOUSEIGGWASKINDLYGIVENBYTHEMOLECULARPATHOLOGYINSTITUTEOFCANCERRESEARCH,CANCERCENTER,THEFIRSTUNIVERSITYHOSPITALOFWESTCHINAUNIVERSITYOFMEDICALSCIENCES,CHENGDU610041,SICHUANPROVINCE,CHINAWANGXIUJIE,MALE,BORNON19570215INZIYANG,SICHUANPROVINCEANDGRADUATEDFROMWESTCHINAUNIVERSITYOFMEDICALSCIENCESIN1982,NOWASSOCIATEPROFESSOROFONCOLOGY,ENGAGEDINTHERESEARCHESOFETIOLOGYANDMECHANISMSOFCARCINOGENESISOFCANCERS,SCREENINGANDDEVELOPINGANTICANCERDRUGS,HAVING20PAPERSPUBLISHEDPROJECTSUPPORTEDBYTHEGRANTOFWESTCHINAUNIVERSITYOFMEDICALSCIENCES,NOL293015CORRESPONDENCETOWANGXIUJIE,INSTITUTEOFCANCERRESEARCH,CANCERCENTER,THEFIRSTUNIVERSITYHOSPITALOFWESTCHINAUNIVERSITYOFMEDICALSCIENCES,CHENGDU610041,SICHUANPROVINCE,CHINATEL86285501218,FAX86285583252RECEIVED19990721ACCEPTED19990922FIGURE1THEEXPRESSIONOFPP60CSRCINTHEPROLIFERATIVEEPITHELIAADJACENTTOCARCINOMALSAB200FIGURE2THEEXPRESSIONOFPP60CSRCINTUBULARADENOCARCINOMALSAB200FIGURE3THEEXPRESSIONOFPP60CSRCINTHEPOORLYDIFFERENTIATEDADENOCARCINOMALSAB200FIGURE4THEEXPRESSIONOFPP60CSRCINTHELYMPHNODEMETASTASISOFCALSAB200TABLE1THEEXPRESSIONOFPP60CSRCINCAANDRELATEDLESIONSSTAININGINTENSITYLESIONCASEPOSITIVERATENORMALEPITHELIA3424705102940010294PROLIFERATIVEEPITHELIA36256616728778D34944BCARDIAADENOCARCINOMA56162862035720357D40714BLYMPHNODEMETASTASES2084008400420012600BP001,INCOMPARISONOFTHEPOSITIVERATESINDIFFERENTLESIONSΧ23419VSNORMALEPITHELIADP001,INCOMPARISONOFTHEPOSITIVEINTENSITYINDIFFERENTLESIONSΧ22508VSNORMALEPITHELIATABLE2THEEXPRESSIONOFPP60CSRCINCAOFDIFFERENTHISTOLOGICALTYPESSTAININGINTENSITYLESIONCASEPOSITIVERATE0/10PAPILLARY822506750006750TUBULAR224182418214636B18818APOORLYDIFFERENTIATED2010500105000010500MUCOUS6000061000B61000ATOTAL5616286203572035740714AP005,INCOMPARISONOFTHEPOSITIVERATESOFTUBULARANDMUCOUSADENOCARCINOMASVSTHOSEOFPAPILLARYANDPOORLYDIFFERENTIATEDADENOCARCINOMASΧ2811BP001,INCOMPARISONOFTHEPOSITIVERATESOFTUBULARANDMUCOUSADENOCARCINOMASVSTHOSEOFPAPILLARYANDPOORLYDIFFERENTIATEDADENOCARCINOMASΧ22756DISCUSSIONPP60CSRCISAPHOSPHORYLATEDCYTOPLASMICPROTEINENCODEDBYCSRCGENE,HAVINGTHEACTIVITYOFTYROSINEKINASETHEEXPRESSIONOFPP60CSRCCANBEFOUNDINMANYNORMALCELLS,WHICHPLAYSIMPORTANTROLESINTHEREGULATIONOFCELLPROLIFERATION,DIFFERENTIATIONANDTRANSFORMATION4RECENTSTUDIESINDICATEDTHATTHEINCREASEINTHEAMOUNTOFPP60CSRCPROTEINANDKINASEACTIVITYWASASSOCIATEDWITHINITIATIONANDDEVELOPMENTOFSOMEHUMANNEOPLASMS,ANDTHEACTIVATIONANDINCREASEOFEXPRESSIONWEREONEOFTHEFACTORSFORCANCERINITIATION48INTHISSTUDY,THEEXPRESSIONSOFPP60CSRCINCA,PROLIFERATIVEEPITHELIAANDNORMALEPITHELIAWERE71440/56,94434/36AND29410/34,RESPECTIVELYANDTHEPOSITIVERATESOFPP60CSRCINCAANDPROLIFERATIVEEPITHELIAWEREMUCHHIGHERTHANTHATINTHENORMALEPITHELIAP001JANKOWISKIETALANALYZEDTHEEXPRESSIONPRODUCTOFCSRCGENEIN15CASESOFESOPHAGEALADENOCARCINOMAAND15CASESOFBARRETT’SESOPHAGEALEPITHELIAIMMUNOHISTOCHEMICALLY,THEPOSITIVERATESWERE203/15,SUGGESTINTHATTHEEXPRESSIONOFCSRCGENEISRELATEDTOTHEDEVELOPMENTOFESOPHAGEALADENOCARCINOMATHEREFORE,THERESULTSOFTHISSTUDYINDICATEDTHATTHEACTIVATIONANDEXPRESSIONOFCSRCGENEMIGHTBEASSOCIATEDWITHTHEINITIATIONANDDEVELOPMENTOFCAHOWEVER,THEHIGHEXPRESSIONOFPP60CSRCINTHEPROLIFERATIVEEPITHELIAMIGHTBEASSOCIATEDWITHTHEPROLIFERATIONOFGLANDULAREPITHELIALCELLS,OCCURRINGINTHEAGEDRATS9THELOWPP60CSRCEXPRESSIONINSOMENORMALEPITHELIAADJACENTTOCANCERMIGHTBEEXPLAINEDBYTHEFACTTHATTHEREHAD490ISSN10079327CN141219/RWJGDECEMBER1999VOLUME5NUMBER6

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簡介：ORIGINALARTICLEALIMENTARYTRACTDOWNREGULATIONOFMIR141INGASTRICCANCERANDITSINVOLVEMENTINCELLGROWTHYINGDU?YANJUNXU?LINGDING?HAOMIYAO?HONGYU?TIANHUAZHOU?JIANMINSIRECEIVED18AUGUST2008/ACCEPTED28JANUARY2009/PUBLISHEDONLINE11APRIL2009?SPRINGER2009ABSTRACTPURPOSEHUMANMICRORNA141MIR141,AMEMBEROFTHEMIR200FAMILY,HASBEENREPORTEDTOBEASSOCIATEDWITHVARIOUSHUMANMALIGNANCIESHOWEVER,ITREMAINSUNKNOWNWHETHERMIR141ISINVOLVEDINTHEPATHOGENESISOFGASTRICCANCERTHEREFORE,WEEXAMINEDTHEEXPRESSIONOFMIR141INGASTRICCANCERTISSUESANDTHEEFFECTOFMIR141OVEREXPRESSIONONCANCERCELLPROLIFERATIONMETHODSTHEEXPRESSIONLEVELOFMIR141IN35PAIRMATCHEDGASTRICNEOPLASTICANDADJACENTNONNEOPLASTICTISSUES,ANDIN5GASTRICCANCERCELLLINESWEREEXAMINEDBYQUANTITATIVEREALTIMEPCRTHEGROWTHOFMGC803CELLSTRANSFECTEDWITHMIRNAPRECURSORWASEXAMINEDBYMTT34,5DIMETHYLTHIAZOL2YL2,5DIPHENYLTETRAZOLIUMBROMIDEASSAYRESULTSMIR141WASSIGNIFICANTLYDOWNREGULATEDIN8028/35OFPRIMARYGASTRICCANCERTISSUESCOMPAREDWITHPAIRMATCHEDADJACENTNONTUMORTISSUESP\001THEEXPRESSIONOFMIR141WASALSOFOUNDTOBESUBSTANTIALLYREDUCEDINSEVERALHUMANGASTRICCANCERCELLLINESSUCHASMGC803,HGC27,SGC7901ANDBGC823CELLSOVEREXPRESSIONOFMIR141WITHITSPRECURSORSSIGNIFICANTLYINHIBITEDTHEPROLIFERATIONOFGASTRICCANCERCELLSCONCLUSIONSTHESERESULTSSUGGESTTHATMIR141MAYBEINVOLVEDINTHEDEVELOPMENTOFGASTRICCANCERTHROUGHITSINHIBITORYEFFECTONCELLPROLIFERATIONKEYWORDSMIR141?GASTRICCANCER?MGC803CELL?CELLPROLIFERATIONINTRODUCTIONMICRORNASMIRNAS,ANEWCLASSOFENDOGENOUS,NONCODINGANDSINGLESTRANDEDRNAS,WERERECENTLYDISCOVEREDINBOTHANIMALSANDPLANTSTHEYTRIGGERTRANSLATIONALREPRESSIONAND/ORMRNADEGRADATIONMOSTLYTHROUGHCOMPLEMENTARYBINDINGTOTHE30UNTRANSLATEDREGIONSOFTARGETMRNASSTUDIESHAVESHOWNTHATMIRNASCANREGULATEAWIDEARRAYOFBIOLOGICALPROCESSESSUCHASCELLPROLIFERATION,DIFFERENTIATION,ANDAPOPTOSIS1ACCUMULATINGEVIDENCESUGGESTSTHATALTERATIONSOFMIRNASEXPRESSIONMAYPLAYVARIOUSROLESINTHEPATHOGENESISOFMANYHUMANCANCERS2,3SOMEMIRNASHASBEENSHOWNTOPOSSESSONCOGENICORTUMORSUPPRESSORACTIVITY4HIGHTHROUGHPUTTECHNIQUESHAVEBEENUSEDTOSCREENMIRNASDIFFERENTIALLYEXPRESSEDBETWEENHUMANNONMALIGNANTANDMALIGNANTSAMPLES,ANDANUMBEROFMIRNASDEREGULATEDINNUMEROUSHUMANTUMORSWEREFOUND,INCLUDINGLUNG,BREAST,LIVER,ESOPHAGEALANDPROSTATECANCERS5–9AMONGTHESEMIRNAS,MIR141,AMEMBEROFTHEMIR200FAMILY,ISOVEREXPRESSEDINOVARIANANDCOLORECTALCANCERS10,11ANDDOWNREGULATEDINPROSTATE,HEPATOCELLULAR,ANDRENALCELLCARCINOMA5,9,12,RAISINGACONTROVERSIALISSUEABOUTTHEROLEOFMIR141INCANCERPROGRESSIONELECTRONICSUPPLEMENTARYMATERIALTHEONLINEVERSIONOFTHISARTICLEDOI101007/S0053500900377CONTAINSSUPPLEMENTARYMATERIAL,WHICHISAVAILABLETOAUTHORIZEDUSERSYDU?HYU?JSIP\001SUBSTANTIALLYREDUCEDEXPRESSIONSOFMIR141WEREFOUNDINBOTHINTESTINALTYPE17FOLDN23FIG1BP\005ANDDIFFUSETYPEGASTRICCANCERS30FOLDN9FIG1CP\001THEEXPRESSIONOFMIR141INCELLLINESDERIVEDFROMGASTRICCANCERTOCONFIRMTHEASSOCIATIONBETWEENMIR141EXPRESSIONANDGASTRICCANCER,WEDETECTEDMIR141EXPRESSIONINFIG1THEEXPRESSIONOFMIR141INGASTRICCANCERQUANTIFICATIONOFMIR141WASMEASUREDBYTAQMANREALTIMEPCRALLDATAOFFOLDCHANGEWERETRANSFORMEDTOLOG2VALUESARELATIVEEXPRESSIONOFMIR141IN35PRIMARYGASTRICCANCERTISSUESCOMPAREDWITHTHEIRPAIRMATCHEDADJACENTNONTUMORTISSUESBRELATIVEEXPRESSIONOFMIR141IN23TISSUESWITHINTESTINALTYPEADENOCARCINOMARELATIVETOTHEIRPAIRMATCHEDADJACENTNONMALIGNANTTISSUESCRELATIVEEXPRESSIONOFMIR141IN9DIFFUSETYPEADENOCARCINOMATISSUESCOMPAREDWITHTHEIRPAIRMATCHEDADJACENTNONTUMORTISSUESTHEPATHOLOGICALFEATURESOFREPRESENTATIVEINTESTINALTYPEANDDIFFUSETYPEGASTRICCANCERWERESHOWNWITHHESTAININGSCALEBARS200LM558JGASTROENTEROL200944556–561123

簡介：ULTRASENSITIVEELECTRICALBIOSENSINGOFPROTEINSANDDNACARBONNANOTUBEDERIVEDAMPLIFICATIONOFTHERECOGNITIONANDTRANSDUCTIONEVENTSJOSEPHWANG,GUODONGLIU,ANDMRASULJAN?DEPARTMENTOFCHEMISTRYANDBIOCHEMISTRY,NEWMEXICOSTATEUNIVERSITY,LASCRUCES,NEWMEXICO88003RECEIVEDDECEMBER15,2003EMAILJOEWANGNMSUEDUTHEDETECTIONOFDNAANDPROTEINSISOFCENTRALIMPORTANCETOTHEDIAGNOSISANDTREATMENTOFGENETICDISEASES,TOTHEDETECTIONOFINFECTIOUSAGENTS,DRUGDISCOVERY,ORWARNINGAGAINSTBIOWARFAREAGENTS14SUCHBIODETECTIONCOMMONLYRELIESONHYBRIDIZATIONORANTIGENANTIBODYAGABINTERACTIONS,ANDREQUIRESPROPERATTENTIONTOTHEACHIEVEMENTOFULTRASENSITIVEMEASUREMENTSELECTROCHEMICALTRANSDUCERSAREVERYATTRACTIVEFORSUCHBIOASSAYS,OWINGTOTHEIRHIGHSENSITIVITY,INHERENTSIMPLICITYANDMINIATURIZATION,ANDLOWCOSTANDPOWERREQUIREMENTSTHEUSEOFENZYMELABELSTOGENERATEELECTRICALSIGNALSHASBEENEXTREMELYUSEFULFORULTRASENSITIVEELECTROCHEMICALBIOAFFINITYASSAYSOFPROTEINSANDDNAHELLER’SGROUP5,6DEMONSTRATEDTHATAHIGHLYSENSITIVEAMPEROMETRICMONITORINGOFDNAHYBRIDIZATIONDOWNTO5ZMOLCOULDBEACHIEVEDINCONNECTIONWITHAHORSERADISHPEROXIDASEHRPLABELEDTARGETANDANELECTRONCONDUCTINGREDOXPOLYMERHRPLABELHASBEENCOMBINEDBYWILLNER’SGROUP7,8WITHABIOCATALYTICPRECIPITATIVEACCUMULATIONOFTHEENZYMEGENERATINGPRODUCTTOACHIEVEMULTIPLEAMPLIFICATIONSANDVERYLOW25AMOLDETECTIONLIMITSEFFORTSTOAMPLIFYENZYMELINKEDELECTRICALPROTEINASSAYSINCLUDEDDUALENZYMESUBSTRATERECYCLING9ORIONEXCHANGEACCUMULATIONOFTHEPRODUCT10YET,AMPLIFIEDTRANSDUCTIONOFBIOLOGICALRECOGNITIONEVENTSREMAINSAMAJORCHALLENGETOELECTRICALBIOASSAYSNEWSCHEMESBASEDONCOUPLINGTHEBIOCATALYTICAMPLIFICATIONOFENZYMETAGSWITHADDITIONALAMPLIFICATIONUNITSANDPROCESSESAREHIGHLYDESIREDFORMEETINGTHEHIGHSENSITIVITYDEMANDSOFELECTROCHEMICALDETECTIONOFPROTEINSANDNUCLEICACIDSHEREWEDEMONSTRATETHEUSEOFCARBONNANOTUBESCNTSFORDRAMATICALLYAMPLIFYINGENZYMEBASEDBIOAFFINITYELECTRICALSENSINGOFPROTEINSANDDNATHEUNIQUEELECTRONIC,CHEMICAL,ANDMECHANICALPROPERTIESOFCNTSMAKETHEMEXTREMELYATTRACTIVEFORELECTROCHEMICALSENSORS11,12MOSTCNTSENSINGWORKHASFOCUSEDONTHEABILITYOFSURFACECONFINEDCNTSTOPROMOTEELECTRONTRANSFERREACTIONSINVOLVEDINBIOCATALYTICDEVICES13,14INOURNEWBIOAFFINITYASSAYSFIGURE1,CNTSPLAYADUALAMPLIFICATIONROLEINBOTHTHERECOGNITIONANDTRANSDUCTIONEVENTS,NAMELYASCARRIERSFORNUMEROUSENZYMETAGSANDFORACCUMULATINGTHEPRODUCTOFTHEENZYMATICREACTIONTHESENOVELSUPPORTANDPRECONCENTRATIONFUNCTIONSOFCNTSREFLECTTHEIRLARGESPECIFICSURFACEAREA15ANDAREILLUSTRATEDUSINGTHEALKALINEPHOSPHATASEALPENZYMETRACERSUCHCOUPLINGOFSEVERALCNTDERIVEDAMPLIFICATIONPROCESSESLEADSTOTHELOWESTDETECTIONLIMITREPORTEDTHUSFARFORELECTRICALDNADETECTIONTHENEWCNTBASEDAMPLIFIEDBIOELECTRONICPROTOCOLFIGURE1INVOLVESTHESANDWICHHYBRIDIZATIONAORANTIGENANTIBODYBBINDINGALONGWITHMAGNETICSEPARATIONOFTHEANALYTELINKEDMAGNETICBEAD/CNTASSEMBLYA,FOLLOWEDBYENZYMATICAMPLIFICATIONB,ANDCHRONOPOTENTIOMETRICSTRIPPINGDETECTIONOFTHEPRODUCTATTHECNTMODIFIEDELECTRODECOURTEMOBSERVATIONSEG,FIGURE2INDICATETHATTHEHYBRIDIZATIONEVENTLEADSTOCROSSLINKINGOFTHEALPLOADEDCNTSANDTHEMAGNETICBEADSWITHTHEDNADUPLEXACTINGAS“GLUE”TOOURKNOWLEDGE,THISISTHEFIRSTEXAMPLEOFUSINGDNAFORLINKINGPARTICLESTOCNTSNOSUCHAGGREGATIONWASOBSERVEDINTHEPRESENCEOFNONCOMPLEMENTARYOLIGONUCLEOTIDESBAPPARENTLY,WITHOUTTHERECOGNITIONEVENT,THEALPTAGGEDCNTSAREREMOVEDBYTHEMAGNETICSEPARATION,LEAVINGTHEMAGNETICBEADSBEHINDALPWASIMMOBILIZEDONCNTSUSINGA1ETHYL33DIMETHYLAMINOPROPYLCARBODIIMIDELINKERSEEFIGURE1INSUPPORTINGINFORMATIONACOVERAGEOFAROUND9600ENZYMEMOLECULESPERACNTIE,BINDINGEVENTWASESTIMATEDFROMASEPARATEELECTROCHEMICALEXPERIMENTCOMPARINGTHERNAPHTHOLRESPONSEOFKNOWNAMOUNTSOFALPLOADEDCNTSANDALPASSUMINGSIMILARACTIVITIESFORTHEFREEANDBOUNDALPTHEDRAMATICSIGNALENHANCEMENTASSOCIATEDWITHTHECNTBASEDDUALAMPLIFICATIONROUTEISDEMONSTRATEDINFIGURE3FORDNAHYBRIDIZATIONAANDAGABBBIOASSAYSTHECONVENTIONALPROTOCOLS,BASEDONTHESINGLEENZYMETAGANDAGLASSYCARBONTRANSDUCER,ARENOTRESPONDINGTOEITHER10PGML1DNATARGETA,AOR80PGML1IGGB,ATHEFIRSTAMPLIFICATIONSTEPBASEDONTHEALPLOADEDCNTSBOFFERSCONVENIENTDETECTIONOFTHESELOWANALYTECONCENTRATIONSTHESINGLEALPPROTOCOLSDISPLAYEDA?PERMANENTADDRESSDEPARTMENTOFCHEMISTRY,UNIVERSITYOFPESHAWAR,PAKISTANFIGURE1SCHEMATICREPRESENTATIONOFTHEANALYTICALPROTOCOLACAPTUREOFTHEALPLOADEDCNTTAGSTOTHESTREPTAVIDINMODIFIEDMAGNETICBEADSBYASANDWICHDNAHYBRIDIZATIONAORABAGABINTERACTIONBBENZYMATICREACTIONCELECTROCHEMICALDETECTIONOFTHEPRODUCTOFTHEENZYMATICREACTIONATTHECNTMODIFIEDGLASSYCARBONELECTRODEMB,MAGNETICBEADSP,DNAPROBE1T,DNATARGETP2,DNAPROBE2AB1,FIRSTANTIBODYAG,ANTIGENAB2,SECONDARYANTIBODYSANDP,SUBSTRATEANDPRODUCT,RESPECTIVELY,OFTHEENZYMATICREACTIONGC,GLASSYCARBONELECTRODECNT,CARBONNANOTUBELAYERFIGURE2TEMIMAGESOFTHEMAGNETICBEADSDNACNTASSEMBLYPRODUCEDFOLLOWINGA20MINHYBRIDIZATIONWITHTHE10AAND0BPGML1TARGETSAMPLETHEMICROGRAPHSWERETAKENWITHAHITACHIH7000INSTRUMENTOPERATEDAT75KVPUBLISHEDONWEB02/18/200430109JAMCHEMSOC2004,126,30103011101021/JA031723WCCC2750?2004AMERICANCHEMICALSOCIETYLOWERSIGNALFORASIGNIFICANTLY1000FOLDHIGHERTARGETCONCENTRATIONNOTSHOWNTHENEARLY104IMPROVEMENTINTHESENSITIVITYISINGOODAGREEMENTWITHTHEESTIMATEDALPLOADINGPERCNTONLY～50FOLDSENSITIVITYENHANCEMENTWASOBSERVEDBYUSINGASTREPTAVIDINCOATEDPOLYSTYRENECARRIERBEADINSTEADOFTHECNTSUPPORTFURTHERENHANCEMENTSOFTHEDNAANDPROTEINSIGNALSBY～30FOLDAREOBSERVEDINTHESECONDAMPLIFICATIONPATH,EMPLOYINGTHECNTMODIFIEDTRANSDUCERCTHELATTERREFLECTTHESTRONGADSORPTIVEACCUMULATIONOFTHELIBERATEDRNAPHTHOLONTHECNTLAYERTHEPRECONCENTRATIONFEATUREOFTHECNTLAYERWASINDICATEDFROMTHEUSEOFDIFFERENTACCUMULATIONTIMESTHATLEDTOASHARPINCREASEINTHERNAPHTHOLSIGNALCOMPAREDTOTHETIMEINDEPENDENTSIGNALOBSERVEDATTHEBAREELECTRODESEEFIGURE2INSUPPORTINGINFORMATIONFIGURE4ADISPLAYSTYPICALCHRONOPOTENTIOGRAMSFOREXTREMELYLOWTARGETDNACONCENTRATIONS001100PGML1AEWELLDEFINEDRNAPHTHOLSIGNALSAREOBSERVEDFORTHESELOWDNACONCENTRATIONSINCONNECTIONWITH20MINHYBRIDIZATIONTHERESULTINGPLOTOFRESPONSEVSLOGTARGETSHOWNASINSETISLINEARANDSUITABLEFORQUANTITATIVEWORKTHEFAVORABLERESPONSEOFTHE5FGML1DNATARGETBINDICATESAREMARKABLYLOWDETECTIONLIMITOFAROUND1FGML154AM,IE,820COPIESOR13ZMOLINTHE25ΜLSAMPLESUCHALOWDETECTIONLIMITCOMPARESFAVORABLYWITHTHELOWESTVALUESOF5ZMOL3000COPIESAND25AMOLREPORTEDFORELECTRICALDNADETECTION6,8SIMILARLY,IGGWASDETERMINEDWITHADETECTIONLIMITOF500FGML1160ZMOLIN25ΜLSAMPLESANDEXHIBITSAWELLDEFINEDLOGARITHMICCONCENTRATIONDEPENDENCETHESMALLERSIGNALOBSERVEDINACONTROLEXPERIMENTFORAHUGE～106EXCESSOFANONCOMPLEMENTARYOLIGONUCLEOTIDEFIGURE4,CVSBREFLECTSTHEHIGHSELECTIVITYASSOCIATEDWITHTHEEFFECTIVEMAGNETICSEPARATIONTHEAMPLIFIEDELECTRICALSIGNALISCOUPLEDTOAGOODREPRODUCIBILITYTWOSERIESOFSIXREPETITIVEMEASUREMENTSOF1PGML1DNATARGETOR08NGML1IGGYIELDEDREPRODUCIBLESIGNALSWITHRELATIVESTANDARDDEVIATIONSOF56AND89,RESPECTIVELYINCONCLUSION,WEHAVEDEMONSTRATEDACNTBASEDDUALAMPLIFICATIONROUTEFORULTRASENSITIVEELECTRICALBIOASSAYSOFPROTEINSANDDNATHEUSEOFCNTAMPLIFIERSLOADEDWITHNUMEROUSALPTAGSHASBEENCOMBINEDWITHTHEPRECONCENTRATIONFEATUREOFCNTTRANSDUCERSTOYIELDADRAMATICENHANCEMENTOFTHESENSITIVITYSUCHCOUPLINGOFSEVERALCNTDERIVEDAMPLIFICATIONPROCESSESRESULTSINHIGHLYSENSITIVEDETECTIONOFPROTEINSANDDNAANDHENCEINDICATESGREATPROMISEFORPCRFREEDNAASSAYSFURTHERIMPROVEMENTSINTHESENSITIVITYAREEXPECTEDEITHERTHROUGHREDUCINGTHEELECTRODESIZEANDSAMPLEVOLUME6ORBYSUBSTRATERECYCLING9THENEWCNTDERIVEDAMPLIFICATIONBIOASSAYSAREEXPECTEDTOOPENNEWOPPORTUNITIESFORMEDICALDIAGNOSTICSANDPROTEINANALYSISTHEFINDINGTHATDNAHYBRIDIZATIONCANBEUSEDFORLINKINGCNTSTOPARTICLESHOLDSPROMISEFORASSEMBLINGCONTROLLABLENANOSCALESYSTEMSACKNOWLEDGMENTFINANCIALSUPPORTFROMTHENATIONALSCIENCEFOUNDATIONGRANTCHE0209707ANDNATIONALINSTITUTESOFHEALTHAWARDR01A105604701ISGRATEFULLYACKNOWLEDGEDSUPPORTINGINFORMATIONAVAILABLERELATEDEXPERIMENTALCONDITIONSINSTRUMENTATION,REAGENTS,SEQUENCES,ANDPROCEDURESALONGWITHADDITIONALDATAPDFTHISMATERIALISAVAILABLEFREEOFCHARGEVIATHEINTERNETATHTTP//PUBSACSORGREFERENCES1PALECEK,EFOJTA,MANALCHEM2001,73,75A2DRUMMOND,TGHILL,MGBARTON,JKNATBIOTECHNOL2003,21,11923WANG,JCHEMEURJ1999,5,16814GOODING,JJELECTROANALYSIS2002,14,11495CARUANA,DJHELLER,AJAMCHEMSOC1999,121,7696ZHANG,YKIM,HHELLER,AANALCHEM2003,75,32677PATOLSKY,FKATZ,EBARDEA,AWILLNER,ILANGMUIR1996,12,37038PATOLSKY,FLITCHENSTEIN,AWILLNER,IANGEWCHEM,INTED2000,39,9409BAUER,CEREMENKO,AEHRENTREICHFOSTER,EBIER,FMAKOWER,AHALSALL,HBHEINEMAN,WRSCHELLER,FWANALCHEM1996,68,245310LIMOGES,BDEGRAND,CANALCHEM1996,68,414111BAUGHMAN,RHZAKHIDOV,ADEHEER,WASCIENCE2002,297,78712ZHAO,QGAN,ZZHUANG,QELECTROANALYSIS2002,14,160913WANG,JMUSAMEH,MLIN,YJAMCHEMSOC2003,125,240814RUBIANES,MDRIVAS,GAELECTROCHEMCOMMUN2003,5,68915PEIGNEY,ALAURENT,CFLAHAUT,EBASCA,RROUSSET,ACARBON2001,39,507JA031723WFIGURE3CHRONOPOTENTIOMETRICSIGNALSFOR10PGML1TARGETOLIGONUCLEOTIDEAAND80PGML1IGGBUSINGTHEGLASSYCARBONGCTRANSDUCERANDAASINGLEALPTAGANDBCNTLOADEDWITHMULTIPLEALPTAGSCSAMEASBBUTUSINGTHECNTMODIFIEDGCELECTRODEAMOUNTOFMAGNETICBEADS,50ΜGSANDWICHASSAYWITH20AND30MINFOREACHHYBRIDIZATIONEVENTANDAG/ABASSOCIATION,RESPECTIVELYSAMPLEVOLUME,50ΜLDETECTION,ADDITIONOF50ΜLRNAPHTHYLPHOSPHATE50MMSOLUTIONWITHA20MINENZYMATICREACTIONMEASUREMENTSOFTHERNAPHTHOLPRODUCTWEREPERFORMEDATTHEBAREORMODIFIEDGCELECTRODES,USINGA2MINACCUMULATIONAT02VINASTIRREDPHOSPHATEBUFFERSOLUTION005M,PH741ML,FOLLOWEDBYA10SRESTPERIODWITHOUTSTIRRINGANDAPPLICATIONOFANANODICCURRENTOF50ΜASEESUPPORTINGINFORMATIONFORTHECONCENTRATIONSOFTHEOLIGONUCLEOTIDEPROBESANDANTIBODY,ANDSEQUENCEOFOLIGONUCLEOTIDEPROBES,LEVELSANDPREPARATIONOFTHEALPDNACNTANDALPSTREPTAVIDINCNTCONJUGATESFIGURE4CHRONOPOTENTIOMETRICSIGNALSFORINCREASINGLEVELSOFTHEDNATARGETA001,B01,C1,D50,E100PGML1ALSOSHOWNINSETISTHERESULTINGCALIBRATIONPLOTA,ANDTHERESPONSEFOR5FGML1TARGETDNABAND10NGML1NONCOMPLEMENTARYNCOLIGONUCLEOTIDECSAMPLEVOLUME,25ΜLBAND50ΜLCOTHERCONDITIONS,ASINFIGURE3A,CBASEDONPROTOCOLOFFIGURE1AACCOMMUNICATIONSJAMCHEMSOC9VOL126,NO10,20043011

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