Diagnostic and therapeutic methods for use with ROR1 antagonists

Abstract

The invention is a method of determining a likelihood that a patient with a ROR1-expressing tumor will respond to a ROR1-targeting therapy. Methods of treatment with ROR1-targeting therapy are also disclosed.

Description

[0001] orneoceo: . - , e ons aunceaon. camsroro..rovsona acaon sera no. one. eecroncanensane aormcaa aonn csonearens anceorueonraceesn ree wrenccenasse een sume co, creae ona, ,s name __.xm ans, nersen. szea. recson mecneenvenon reaesoee o oncoo an more secca,o a meo o eneca enneerencuumnor- aar coemnanmonmunaen coess.cesor use w ceeraancues manancesncnu esnma meane, ce-,mommearcans are,acnoesrer eaancsoear wemaooc memocacm.uormrean sana,r ou csearea rmaon , smaeu rnceu cees cmemoomeara, sem c,e anra cnsronanc anmocc era.eseeraes are no aeonuce remssonn aaens an m aree rease aer a remsso an exerence ovaran,un,ancreasn c e. ,x anressern a we rane oumorsncunemaooc manances, manances aners eas cancers. s aromsn newarenemaooca nown as crmuzumas cnuvrersenaonn can mcoanocraonsan a vnaroous aemaansooc maznoavnecraems,a an a ason auooous an- - ce comoson -ornesnoc cenco: . reasereracor aressve ce manancesnc arasn aens.eresa as neeeeno rerorreecsona m eexrcensseo an oun ro vare asnnem.aooca cancer exressn . acoemaooca an soumors -exressn one emomen,envenons a meoenn aaen suernrom areamen,e mneoum coorm asrsneeo seoss oveee rremsnonno ar aenameenne wnsne- caerse on aen’sumor anenneaen aseo resono -arener a eaen’sumoras or moerae- anenens.n a remen e anenenss measure ow comer. some emomens, anenenss exressen moecues n some emomens,e eaen’sumo er cemoce.n some emomens,e ces o exres r are casse asavn exresson, or moerae- eson, or mo exerarees-soowns exr aenssoenn, orenoswreae erxreasson.n some emomens, moce,e moerae- exressons a n, moecueser ce e moerae-ow exressons ane nenens, –, moce, exressons anenensewenens, –, moce, aneow n some emomens,e ces oreana,en’s muomcoer. aove, oreow areso o exre are casse asan a, orarenera.n so sson assocae w aosve resonseo - osve resonseome- eamreonmenesr,aesrnesoe ra one o exre asnsonen asseoncsaee wween a w, a anos,ve r mesoocnese.on some e-maroemnense,raesres caocua oe exresson assocae eermnn a cu-o vaue o anenensa s a meo comrsn: -arenreamenrom a earaes aouaon o resonerso sasca sncan manner, wereonu saaosnc oa n sonn-rescaonnceersseoermen seamereamenn a rom arou conssn oeuen's-es,e2-e aes seece rusa-as-es, anecoxon-es. s,eann-ne-es,e n some emomens,eaen’sumors a soorunmeoceo: . cancer,re neavereas cancer or seecerom ovaran aenocarcnoma,ancreac cancer,as,r cco caonreccera, m ceaanncoemr,a non-sma ceun cancer,un emaoocaumor seecer , an enomera carcnoma, ors a ,ocuarmomaom c,roancmocceuema , mane-cemoma , an marna-zonemomra-ce,mcomearr,use cemoma moma ,moasmacomoma, ce non-ansormaonmoma,ur moeuema , acue meoeuema , meoosnasmcoma , acue cemoma, anaens snrome , n one e rom macroounema. suernrom a m-exoremsesnn,uemonrv,eneo mneso a m coemors onreaem seens o o: aa canceeerrmanen anenensne ces o aaen’s n reson umor enneaen aseo ano aen-arenera remeneaen’sumoras or moerae-arenerae rnesmen oreaenneaen as noeo resono a - anc amnsern en’sumoras moerae-ow orow anenens osve resono a a --aarenera remenoeaenene aseo remen comrses a c renera remen, werene -arenera receor comrsmese ar sc anna seen rueecnece,o arn an-.n som sen eme-coamne vnarsa,ee cmerc anen aransmemraneoman aneoman, an a coasm ramenscv comrses a sna seuence, a coman.n some emomens,e - oman,e ransmemran coasmcoman comrsn oman ane emomens,e an- scv oeeom coan, ane neoman.n some , ane comrses a seuence s mrses a canLan aeav can comHrses a seuLence seece eecerom s:,, an, aneHscv oe comrsreosm a s:,, an.n some emomens,e an- essena o a seuence canL an aeav canH, aneL consss o a seuence seecerom s:,, an, aneHconsss essena oe co smeecerom s:,, an.n some emomens,e an- scv comrses aormursaes axnyne,r wnerensecn cea annLs a senrne.ene saovm ce eamnoHm,e anns,eener comrsese seuence seecerom s:,,, anor.nen sooceo: . consss essena oe seuence seecerom s:,,me emomens,e n some emomens,e sres , an. m enn anmmune ce seecerom a eacroae, a ce, a nauraer ce an annuce nauraer ce.n some emmoommeennss,,ee armmomrnuneen ceomc co mmorsecsao ann co armmorrsnesnaecnovmacon m oo ocaon.n some ceconene, or one or more reuaorene se ne or moremmune -, ,m eceromerou conssn o , an .n some emo,men, , , , , , , , ene annse s,e armornenomc mocaon comrsesnacvaon oe n somreon em oo anmens-,-emuson consrucnoe eneocus. cone-receor mune ces enneereo exress a memrane-oun n soumseon emrooenm,e wnserene cones seecerom- an-. armaceuca acceae ,emmune cesresenn a comosonncun a amoun oenw seoemne e×m6o ex anmcene ×sn,. 8e cemsm.unne s coemesn emeo commenoss,one armemune- ce cessne comoson are - cesne am8 9ne e oun oeween× an× ces.n some cmesoremseenns a,emmune cesne comoson are a mxure o - ces an - n a s roamoe o em aoromxemnas,ee:armace-uo -. more o caroraes,noran ca acceae excen comrses one or acs,as c sas, anmcroa aens, anoxans, suracans,uers, ervazees s,u waaresr,, a acooos,s m,anonoos,, xcoer,n m,a veoe,aace oos,, xoso, soos, suracans, suars, monoso, aonc ac, esere suars, suarom ro,ranos soro, aacose,ucose,-m ers, monosaccares,rucose, maose, osaccares, ranosaen,no msee,e szorosoes,e, masaoccexarrnse,s,eaxcroase, sucrose,reaose, ceoose, core,oassum core, soum suae ns, sarces, crc ac, soum emomens,e anmcroa a ,oassum nrae, an soumosae.n some core,enz enne comoson comrses one or more oenzaonum ene eonum core,enz acoo, cernum core, corouano,eno, comoson aucroeor, comenrsmeserc anurc an noxraea,n an seecemerroosma. asncor somea emmoae,menus,aee roxansoe,uae roxouene,oosorousorneoceo: . aae, soumsue, soumormaee su ac, monoocero,ro emomens,e comosonurer comrses a suorxacaane, s aenec seourmom meoasosruaees., snor somae esers,ecn,osacones,osaeanoamnes,a acs,a n coesero.n some emomens,e comosonu ac esers an rom o mesuoxe anrer coomrsesu areezn aen seece emomens,e comosonurer comrses man aumn.n some mearaen,roaraen, soumenzoae, aenzraeseornvaumve c seoercee, anroomx onanes o,r c meore o aens,araens, c cancer,re neamoero ve emu an n so a rono easm,e cne ansn c,o, er,e an coa s oeo renr c’sc a auc cmano. crs a soumor seecerom ovaran aenocarcnoma,anc er, non-sma ceun cancer,un emaoocaumor sreeaecce canrcoemr, carsorncc canmcer,o mceanoma, an enomera carcnoma, ors a ,ocuarmoma ,ar-cemcomeuaema,, mane-cemoma , an marna-zonemoma ,cerransormauose cemoma moma ,moasmacomoma, ce non-onmnommaoma,,ur moeuema , acue meoeuema , meosasc snrome acu,e cemoma,n a snomea emenosrmomen macroounema. ssemcever s,e amnserns seeceromerou conssn o ever,nraven,rcaureanreeravere,v seurc,unanraemouusscuarever,nravenousever,nraeca n some emomens,e comeosveor, annraermaever. comonena enaesme-ree nurer comrses aever-mn ever-mn comonens seeacsee,eroame m roeneoasseea,r oare s,useaanen, r aeease oe comoson,e so roo semermeae marx, an a cone seecne scormo ome emmer. -o,m-en,s,-e m,e-o anurer- co.mrses amnsernoeaen a euema cesrom seven c sroonwcs vmaraoceceue amnaenensaen ons.e surace ormar s ara sown anen-seccorneoceo: . es anoweseve o exress ss o aen ces w w moerae- eve os ara ex sreoswo sonn. anen-seccss oaen ces an cenes w -moeraeeve os ara ex sreoswsonn. n anen-seccss oaen ces an cenes wow-moeraeeve os ara ex sreoswson. anen-seccss oaen ces an cenes woweseve o s ara sownn. anen-seccss oaen ces an cenes s exoresson. or - ce acv. wse use o oeermne areso anenens - ce acv an sow exsreassone ussen o o conrmae reaonseween sowse reaoneenen o oerarameers. amma secreon. seween anenens annereron exressn soumor s ceowsn ceso anoxc acv o ex arnes-sn soum-or c ceesn aesa.nsow e nessenenenoo son sws ecnon,eencnoncas a arenr soveo an unersann oescosure. meann common unersoo aerson o ocrennarc serms usensscosureavee oecuaronn,aoraoranua,th.ornnaer aorr.eae,. e.r.,amroo e a., eerm “acvaon” reersoe sae o ess . roeraon an c a ceancues one oro o ce eerom “naen secoreo”n reere ce. o so anmmunooun moecue wc seccans o aenr aonrmsen.eerm aso reerso anoramensncunndv,a ana2, scv an rnaroerscar.ere es.s,.,n..noe.s:aoraoranua, .reene,., e.,o eerm “co-smuaoroman” reerso aar oorn ae cmoceo: . wcs annarnera seccans a co-smuaorane,rc ce receor a co-smuaor resonse oe ce,roeraon, an cone ere mean smua secreon.xames o co- -oransncue,- ,- ,-,-,- , , co-smu,aor,omans,ncue, ,, ,,--,,,,,, an .xames o ,, , , ,-, ,-, amoun o aereaeerumcs “ ceome acn osveo a- nmo suu.n”c aenn “oerraeuca eecve amoun” reero an amnsereo a ouce aeraeucene uonen aen recevn aeaeere rmn. a “eraeucene” reerso aene oserven aaen uone smom euc comoson.enera,eraeucene maness as aevan n connecs oone wsea msae, snoawncnesroncreussonn oemeaosoeascea or m reaversnanne course oesease. manessse asecreasenumoruren,rev ces,eraeucene cncaes resu oserve enon o measases, ormrovemenn an crerasenauer e a.neaen.eraeucene mae assesse usn ueneve, ew resonse evauaon creran soumours: revse comee resonrson.urancer.:– oeermne weer aaenas roress se ,ara resonse , overa resonse , saesease or ,sevaesesreeaese survv.aerae,ucene mae exresse asroonaon o overa survva e orroresson-ree survva . o moecuar enese arnms c “omaromsacoenuscaao ac ncoearoeu”c aen an “ avaerrmsea,c aooeca acceae” reer reaconn aaen.or exame,earmaceu rc, or oereeerous rearaons sou meee sanars seo ca anarmacooca acceae eerm “armaceuca arcceaee carrer”ce ooocaanars. sovense.., waer, aueous so an “excen” reero aueous souon, ec., non-aueous soveunsones. o., arcoooesn,e sanceo s,ouooens, seoneumc co,or veee,aner's annecae oranc esers, as we asserson mea, coans, e o, reservavese.., anacera or suracans,es, anoxans, ases,soonc aens, asoron aneaunna a aeenns,s, s aan-ozxersa,nsn, ceres,ansn aeernas,on an aennesr, urcans, sweeenn aens,avorn aens, orneoceo: . comonensn aarma anes.e concenraon an oe varous eac comonen. ceuca comoson are ause accorno we-nownarameersor arcuar srucureenermee "noemnan" o re oeresr roe onoens reonn aoee wcsoeno a suc as a ce.eerm “eecoruncon” reers.o a secazeuncon o aerenae ce, a ceerareaemeremn. “axoamvees ce o” a reoersveo c a cea caneeneca moeor usen er ces. esncue ces, macroaes, an naura enec eerm “ceera” reersoereamen o asease orsorera uzes ea moe ces.eerm “aove ceera ” reerso aeraa uses enreaceas, na muorae aove ces.xames o ncue ceeraes, ce eeerrms “e ceecveera ameso an ceeraes. comoson suc as a c un” an “eraeuca eecve amoun” o a roveeesre reseonseernae coamenosoo wn,o remereo c ao smuocsenon amso aumn onseere comosono eerm “cnca sncaneve o . coo cooxc” reersoeeve o corxc eece eneca moe aovemmune ces oserven vroa eerne aaems wnser ae.esrencaera seunccaenne amonuna oen csooo wxcom cane aeovemmune cesave e resonse o aouaon oaensreae we s eermne oservn or eacaen, correaneae ame amoun o aove ceera, an cooxc acv oe ao n’s resonseoe aove ceeraoen vro eerms “evee c,”e “s aoanesee,”a anen “’sro ces. omers o amno acs,ncu en” arenercaneae an reero acs n naura an snecunnaura amno acs, as we as amno oe noeou mnane naruarnace oc ocrurnrenar arnoeens,n ee.rr.u,eeom nomn-eacs, an ocasomers. aso encomass amno acomers mno ac resues.eerms ormaon,cosaon,a aaveeen moerou aceaon,sueonae.eoee nee noonn,cuoesoerua-oenn, cros asm-nnon ac, or se counenucea oonee. r.e,e wrenc ae moecueu canncue on so muc oe reerence moeorneoceo: . oeeo reansesre acv.or exam cue as necessarn orerore roens,ramensereo,oees w amno ace,oees comrsnu-en are encomasse eerms “roen” a eeons, aons, an susuons reane.or exame,oees wn, “o,e,e,” ason aseesre acvs reerenceoee arencue asoneesre oress o seuenceen we eerm “reerence anenens ac”v reerss reoanee aeoees. aseeneermneoven a sasca sncan mannere maornenensa a anaonserarome maor o non-resonerso a a o resonerso a reerenceouaon o suecs.n some emomens,e naonseran avee samee oumor aseaenenes suecsne reerenceouaon cu-o orreso vaue o anenense moar aesoevee o anenens. ouaon o resonersoreamenrom aouao eermne as searan an a sasca sncan manner n o non-resonersoe samereamen suc aseuen's-es,2.asca sncance maeeermne a suaees ecoxon-es.so ase-es,eann-ne-es,erusa-as-es, an anenens aa useeren,eerm “reerence anenens” reerso aen’sumors comarens wc anoer anenense..,a o annvua oreraeuceermnaon.no orr eexramo mea,e oene or mo arne oe anaennsoscn, are recerevnec,er soamnose,c a, r aenereennceenosua meoans,u orer anre-assne cu-o orreso vaue cane comareoe eerm “res aonaeen’sumor. comee reso rs” reerso suecs wo aceve aara resonse or a resonse evauansoe as measure . crerasenauer e a., ew :-.en creran soumors: revse ueneverson.,ur.ancer . c erm “non-resoners” reerso suecs woave no aceve an seasencraee re ssurvonvsae.eson osre o cvanerae a ssusrevssvea asro.onesaonon ororessonree survva , ara resonse, comee resonse , or o se mancue saesease , eerm “roressonree survvavera r”es aosnose reerre. roresson” reersoeuraon oeero weneumo o as “meoumor eros ome wen aaen exerences, an.roes norow anncuese eerm “seaseree survva ” reersoeournreoceo: . aen remansre aon oeero wen a eee orm “seoavseer. sar oreamen. a survva ” reerso ae execanc o aaenrome “as” -aessoecrmase “roen” “cusere- reas”u aanr “nersace s sseomr”a renerroomce reeas, enooerveromroaroc oransms an comrsn a nu enome a seuence-secc nucec ac-ue e cec acue moecue an sran a a se co nonucease caae o ceavn aare nucec ac ssems amre reemveenwaerno aa searuoevnace en a.,e nucecv aocuoun aen. croasesrecsa o varous -as ssems.aureev on oe receorreowscrooo.:-. neurorocro snenase-e oran receor, asonown as , s amsnnoe-acnasero reecen, wor-re aameno a,cs asn or-an c reocmerosrnrosene e-nase-e anen. s acosaee memraneroenaeonsoe sxraceuaroman. receors. nnoe seccan acvaeseuoawmn o ce surace awas resonse sreamaco sor ex cere mo annvason. cronc ssen a we rane oumorsncunemaooc manances ovaran,unm,oacncrecaecu, aenmare nea anve mraenase c caencer.mom eaxresson anrv man more, row, survva, an measass.ecca, aseen esumor ce cancer sem ces anromoe sownoe exresse on ovaran verexresson o asee mneraecoen,nnvaoson,em anao coanccear c saenmcer cse an s soerouormaon.oweves o exressonaveeeneecen normaum mors.n enocrnessues, aneasr anssues suc as aosessue,mmunoera aan onesnarac man aromsnareor ceuar xressonnumas cancer.eeaarsnan e a. nass o roen anooao nancer anormassues,ncaanceresearc, :- nc , e: a. rosnenase as aaren cancereraes,ronersnncun enne ceeres. a ann- ces exre-ss cnes an anao-nss ceavse, aesen werev aosus-sco csee-, conanneraeuc comosons, an - ces- orneoceo: . aveeenrevousscosen conanneraeuc comosons oneemer, , ,..ero ovsonaaen acaonser.os. , e , anaceoere onune,nece,meer,n-, , e oneruar, s, ces exressnes an reae me cmerc anen receors aveooewome- cexnrceassnra csensv.esora exn os ame,e a.n canocnass excueaens woseumors cesor croncmocceuema ,raenerrauooou esxc -- wumors wereeweran o ces exress .mar, uesaens moe-ceeranreanaens w avance me cncaraeneca reuresa or more oeumor exressanancesraener eresence o neumorsca assesse oorncusonnera. socemsr .en useuanave,ese a w comer ormmuno- ouaon o cesa exresses u ssas reorerooron oe or ce. o no aress asoue numers o moecueser o, e a.,araeas eexrerssaon o aseenoun amon an aens.eenaens w roncmo:rmuumans nan anemnessnaures e anoru conuaec-ceaurema,eem ce :, anan e a., moma,.emao.nco. en s eecven--ressan mane ceoumors ,. s exressen normassues aoweves reave an norm.aeessueasa,rsn.nan e a., nass o roen exressonnuman cancer urrsna,nceernves. :. eecve,e crcaarameerseen aomrsouanve oscovereroean oonre sur-aacree on eaceruamoro cee arae a wne ansseesnssn.e neumer o anen-eexnsress mneas cueresmennseoumeo usensea o, orn scovereaumors comrsnumor ce r.envenorsave or no susceeo eraca s wow anenens areess suscee ces, weumor on anaonsssuc asor exame, -aren - aace aness comrsnumor ces w anenens are eecve esennsnrocaeeaumo arn ceaso wnssosuwc asor a enxamenee,ns ar-eareses snusce-e c oer nso. susceeon anaonss, we ces w orneoc aneeno:ens. suscese a uoseun anaonss. are ens ennsurerncaea anen scroesecor o success o -areneran aaen. anaonsrea erens aanoscesoreeoo o eecveness o a amnsern amen, aenaeso cnosmrreasnmen m.easusronscose anereenns aensrecsnonumor cesroro orean -exressnumors,e meo comrsn me mecne meo aumor an e anenenss ors aovaesur anres anenensn comoson com o, amnsern a n ornse enm aom anaons. aumor exr en,envenons a meo oenn a canceraenavn envenoresssanveevse as a meeoo oos usvne reson anoe anreeanmsen o onr aearaen’asruemnor ce.neveernmornseo wuneearuemoarsenavnseoos exvreess roens oorn mooerae--aren exerrea.soe eecveesroe cooxc acv o an- - ces, weumosson are moerae-ow exresson orow exresson are on m rsavn cooxc acv o an- - ces.n some emome aece or no aeceesn aaen'sumor sameor exre ns,envenon comrses eraoeermne aaen ssonroro commencemen o -aren n some emomesns,eeon rveesnononos a meeeora o. rom a -exressnumor aseoosve res enn aaen suernreamen.e meo comrseseermnn ono areamen w -arenumor, anenneaen aseo re anenensne ces o aaen’s aen’sumoras or moerae- so anno -arenera remene exame suer-resou aonn mencrosecnos o cranowe c meoamsuereen r.n s ae onns m m.eo avaaene ar,or meo comrsn a se o measurne e emomens,envenons a eess somemes re numer o roen moecueser manan ce.ess anenensomererr veaoo aws c “oemer. ann somene emensomeesn.”s,ne soemse esm suoermens,e mcrosco.n oer meo ornsrumena canuan -resouon er ces conemae wnsnvenon. e numer oroen moecues n-uman anoes caneeneraeornemmuonczeo: . anmas accorno sanarecnues.n ao n exermena rom commerca sue n, an-uman anoes are avaae oec an oer rsncuncam,oeen,ermosercenc,en er s.n- anoesaveeenescrenenernaona caon en.neeor.e ces.n some ee ona, n- ano an -aren an- an momens, a caraon meos esase aownoreren no soemseo eme uosem wens,e meonercanea. conuae an eaen’s ces are sane w auorescene- conuae - ano.n some emomens,e anos acoerrn- cenc. ann so-me em aonmoens,rome s aa conmem ceercsa ar seu sueerc, e..,oeen orermoser some emomens,euoresce eoow comer anass.n a nce measuremenrome ano-sane cess comareo emo omaenese, ree reereenrecneceeaeass w arenownensTeMs ouorescene moecues.n some oruanum™m e®uanreeaseconcnson oruanum™ em uareasansaoraores,nc.,sers,n..n some n soomem eemnso,mens a,nen aennseens oennsaeesn’s ces are normazeo unsane conro ces. er cemoce. onaen’s ces are reore as moecues anoes anore- scuoneru-reaseou seocnon macrros acnoo, ceosm cmanercea avaaermar an- uoroores cane use:oecu use.or exame,eoown oecne. arroes ermosercenc oraneauor manances.nn so some emomens,e anenensess aeo ce emomens, ceramne e smuraocemernose,ne m maraersnano cees aresoaeromaen’soo.n some assessn exresson. n an searaee manan cesor seara non-exausves o marersa cane useoen an eroeene m exaresnsanon ceesn coomerss cesaracer,sc o, eac m,anan,c are,se,na,e an.. ae.roen exressonenoes o ma orneoceo: . ce mananc en nan ces roncmocce o+e+ + + + -oancue-acre uema mmomomaa++ ++ +- +- + +aarr-ncae-zonmeommaoma+n+ ++ -- -- +-moce.or co snovmenee enmce,oemense,ren an aneneennss exressen moecueser ce rous suc as exr enses canerouen a seres o exr esson, moerae- exresson, moerae-ow aneesnsone,n asnowreaer eaxnre,sson. mno seocmuees emeormens,e exressons exressons anenens, – cemoce,e moerae-s anenens, – , moce,e moerae-ow exresson enseweran , moce, aneow exressons anen ces vares ameonn,ven m eoro asc oae vvee. roscoverea resonseo a co-cuure w an- - eerm us.s a resu,envenorsaveevse a meo o weernne w ceese or aeaeanens’seumoor r aerseono e-xarreessnors, mera eermnn exressors, moerae-ow exressor oerae-nvenorsa s, orow exressors.ore secca,e oeaenv’esusmcoovre arreea aaen exsresseors oor r mesooenraeo -arenera e ces n some emomens,envenon co - exressors. anenens.s v mrses a se oeermnn a reerence mannere reerenceaenaoueu oaon o r aensoenneresnso averaesrnom a sasca sncan era.n some emomens,e r non-resonersoe resoner eerence anenens searaese maor o eranso a a reerenc aenaoonusaoenra oroamenes maavorn o non-resonerso a -aren emomens, aeaenssuecsne reerenceouea saomneaveee o samuemorse. onu smomore. n some emomens, some or ae suecsne re orneoceo: .umor aseaeneneseoree erenceouaonavee samee o n some emomens,evneve onon com anrseenseenes. vaue o anenens aove wceaen souermnn a cu-o orresoarenera an souoona receve a e-sanae a resonero - emomens,e cu-o orreso vaue o anenerenera.n some searan aouaon o resonersoreame ns maeeermne asreamenn a sasc nrom aouaon o non-resonersoe same reso n a sonmaeen em s eon nsmcaen anres m,an useene rre. oer menacee one or a mnorenens ane cu-o or ronosc, oreraeuceermnaon.o e o aanosc,recve, same, a reerenceou r exame,e anenensn a reerence e an aon, or are-assne cu-o orreso vaue cane comareo nen somenes em moeasmuerens,n aeaen’sumor. exermenaeermne.n s cu-o orreso vaue o anenenss enss exerme ome emomens,e cu-o orreso vaue o anen emomens,e renearenceeoermuaneon sna eraesc on ae orro mroaree rearearmeneceerouaon.n some arameeren seeceromumore,ee oren oe w aneaen,e reevanaen caracersce.., ae,ener, sa aons, or an n some emomens, aeas ,,e oesease, anreamensor. ouaon wave anenensas a, or o resonersne reerence ens, we aeas , , or o non-ovee seece reerence anen ave anenensaseowe s resonersne reerenceouaon w e sasca sncance maeecee reeeerrmence anenens. uen's-es,e2-es,eann-ne-esne a suaees suc ase coxon-es ,erusa-as-es, ane rom a -exn. sreosmsen emumoorm asens,envenons a meo oenn aaen suernreamen, measurn aeoosve resono areamen w -aren weere measur nenensne ces o aaen’sumor aneermnn exresson assocaee w ao asnveen resenosnseoas a, o-rar aeovne, oreraeow.n a somrees eomo omens, ereso o exresson assocae w aosve orneoceo: .sne rane o anenenseween, resonseo -arenera n some emomens,e reerence an, an menoceens. ensn a reerenceouaon.n some emomens s a anen onvuasavn a -exre ,e reerenceouaons aouaon ens.n so ssnumor, wereneumorsave varn anen avne sammee emeo omumenors,, e.or., e aacumore se oecuemorr,ome reerenceouaons aouaon mane-cemoma ,ocuarmoma, croncmocceuema , cemoma , meosasc snromear,-ce cemmoma ,use zonemoma oma, an marna- same anan soonmse e.momens, a suecsne reerenceouaon werereae wene reerenceoua aosn waereenrea ceons wereeo sarmeeaen a.nna soomnes e amomens, a suecs ose asaen mnsere ae samenvuas wonse s coo umn mes o ermere s exoomrene as,aeen re.eren acneoenuaenson co anmrasvees a resrso suouaon o w a anaons, an a secon suouaon onvu neoreamen anenens anave no resoneo as woseumors ex aow n one emomen,envenonresa am mene w a anaons. suernrom a -exressnu o oreamen o a canceraen e ces oeumor a morncun a se o measurn anenensn n somen emoenmenneaen aseo resono arenera.o resono a -arens,e meoncues a se oenneaen ase anenens oera remeneaen’sumoras or moerae- era remeneaerenneaen as noeo resono a -aren meourer comrses a sne’s ou ammornasse mrnoe arae--owar oernowera r aenmeennoensea.ene ene asen soomeosve resono a -arenera remen. comos emomens,e -arenera comrses amnsern a cmerc aonn coemn rercsenor aove a esnenscereree ann-reaeremamuneeo cwe.s comrsn an an- s seconescresn moreeasemmuneor cnees uosceo: .reamen o a canceraen suernrom a -exressn en a meo o anrearaon o suc cesaseenesc umorescreeren.esn , e oneemer, ,re,n..er oonvsonaaen acaonser.os. oneruar, , anaceoere onune, ,eceemenr-,, cme, e receors s, ces exr rc anen re,eessnes an reae meos. noeaen, or aoene cec cse mas,.ee. a,u ceoossoousa,e.e.,r coems asoonaoernromv auaaenor renuson umanonor o eerener.e ces maesoae usn s , suc as aea moces canesoaeromoo,ncun anarecnues.or exame, mo orans suc asemus,one mereraoo an coroo, orrom mossues .ecnues arrow,m noes, an mucosa-assocaene ar, see, e orsoanmocesrom sucssues are wenown er.er..,m,.. eressecnues an ceuarmmunomouaon, reuenc an.:unc-on. or enerscoeaeor smecocc seuss meas oe ce cas,ra scucerz aesn ceersm osr o secc, exame,esoaemoceouaon cane enrceor secc ces.or as+,+,+, or+.ee, e..,an e a.,o.e suses o ces, suc : oror ces+enoe. ces cane acvaera us –nn socouecs acvaors, or maneceas coae w an-an- monocona anoes as emronc snem som cee emocm aenns,nuc cees cuarnoeenro suecme ceserensa.nee s e.em. ., ce.s suenc ee.s,,emao.oec-er-ena-on- o_,umearnmanusorn,o eenemes,rnerresnem es a a.,aer,umanuroenem cess aereenneaweaneoo aurceom ooeanueorausoeuraeons. oo na,u era a.,er cesum wan emorenonc sem anomuomeosr aucsavne,oo, ane n vvo r nman, e a., emrane-oun- exvoroeraon oumanauraeres,one,:e . ere erenaonrocessca comrseswo an oona,ree ses: nauranaen sem cesnoemaooecroenor ces ,erenan no exansonr m caes asoe, anese ooonra eexarensseonnce o o ces.enoeero suuccs a os-esreencaconenoer exressonaerns,ncun exresson o- orneoceo: . . secc ce surace marers, e.., an comrsesormnn som see ermoomens,e se oormnemaooecroenor ces cenruaon, a s aown ceso areaeoona assse ow-see , ,n,ncu,an, ane se.ron sosmne eresence o one or more cones seecerom an momens,e comnaon o , , s uses u.sne s.omne s eommeo emmoensm,ens, aree coormmenaonnc ouaon,nere,sence, oe,ee, an suc asone marrow s r ces n some erommao cmeesn. neresence s,e se oormn ces comrsesncuan seros some e o one or more cones seecerom-,-,-,, an .n emommomens,e comnaon o-,-,-,, an s use.n some are use aesnes,eeeers.ern ce sosmes erommao cmees are use.n some emomens,eaver s+roma cesonane-erenaon snes,e racons enrceore cesror erenaon sae,e cer .n some emomens, ae comeon oe as an aconseseor surace exresson o-secc marers suc cesneresenn sco. em oe c emoonemse anns, anee snere osenn ce ce esxansosn comrsesncuan s are enneereo exress cones o .n some emomens,e overexress an m ne ce surace.n some emomens, s memr emraneoun-.n some emomens, s overexress some eamneoomunens,-.sn o sovmereex emresos amnens-,--s overexress cone-receorusons.n overexress an--- uson uson.n some emomens, s n so .n some emomens, exoenous cones are aso ae. evaumaee emnon vmreon asn,n- vs ae.n some emomens,ena exane rouc was esoae cvouncona assas. or - ces or -es a creesen.enca moeoare an- - ces eren comrse some emomens,eeraeuc comoson use useeren coms anrse-s an-- ces-.n so cmees. emno sommeen esm,oemeernase,uce comeraoseuonc comoson useeren comrses a mxure o a orneoceo: . ces. n- - ces an an- - comrsn an anecna cnmner rce aonn, aenra renceor comrses an exraceuaroman acvaonc smemraneoman, an one or morenraceuar oman.n soom-se emmuaoormenosm,aens.n a sosmoe co emmrosesm aeneas,ereee arso comrses ane ce memrane.esn anrearaon o an an- aseenecne oe caone escrennernaonaare r.o. e ona, n- ano an - en enneere ces, an..rovsona caonser.os. , e on anemaceero,er,e o, e onecemer,, , e oneruar,, ces exressnesnune, ,en- cmerc anen receors s, anennnr reeo,nare a e annn- reae meo .n som cs eo. emmrosesm aenns e,xreac aeuaroman comrsn an rom an ano.n some emomens,e an nennn reonserve ann soome. enm soomem emenos,meen asn,een annennn renen o rnen coonn m co r rme sesrons aess au mer mov aue nser semoumr ane mo senouceonncae. emomens,e anennn reon comrses au uence.n some n some emomens,e an manze mousemurne seuence. varaeramenscv.n s ennn reon comrses a sne-can neoHa var aaee r cv comrses a varae reon o an ano canLoe va eon o an anoeav canH.n some emomens,eLsne ner cane a naee uraen oner cce. urrrnene sreauen cocem orrs aens enromn aouo aou amno acs.e emomens,enerse eere seuence.or exame,n some , rverom aumanroen, e.., anmmunooun seecerom e,,,, or, orom.ann s oom aen emmmounmoenos,uneenaver c coman.rsnes som-e e ammnoo amcesrom ners acne an serne rcneravne seuence . ona ns,e an seuences arescosene..aeno.xynner exames aeno.,, oeenersorrouco,, erne-rceeners,.. mroveoeesrece aanns oo.snecroens, an aucaon n some emomens,e seuence oe scv orneoceo: . anen.n some emomens,e om surer omzeornnoe ceeav canHane canLozea sconv.roceasss ceoemn rreseosr vearaneenneerr seeuweenecne sannen-cueannceraem aenne vna-rscavesncvn anavoa, a ea an.s, αesn:nn ann omaon o a su,ranascec:..ecca,aseen sow sco ann vro amno ac seuence wne conex nan scoesn oener’s canener seuencesamare oere annoewnn a crnsa soruceu srce ov.ea ssc avs-oaneeo comex cmerc anen receors s conann an scv ca n sowna sm varneen oener, wereenne omzeornnoe anen oe same seuence.n e a. nen-neeenr ceonm arcsevsa ao vnar enaaenc neusmeer e oc reacea os xya cno-smeunae ces,a.e. :.n some emomens,e seue n seormeas emeoeneraormuaxyn. nces acaoner. mens,e comrses an scvescrene..rovsona n soo.me em,oe ona,,- ano an --- ces. an esc mens,e comrsese scv seecerom cones, e rene acaon , sura.n some emomens,e comrses som sec emv coommresnns, a seeuence co semecresesrome scv conss:n, o a seuen:ce, an :.n :, :, an :.n some emomens,e scv c soemecerom o :surer omzeo comrse : conannersn a seuence emomens, ner4.n some ne so omem emzeo scmevn cso,nses ssc ovs encoe: a. nucec ac seuenc cvs: enc,o oer a nucec: ac, o sreuence cons:sn, o e comrsn s or ::,. onr some emo:m,e ons,e :, or r comrsn a senu seonmcee s eem: eco. emreonms,e anen:,nn reon: c,o amrses aeav canHemomens,e anennn reon comrses ae n :.n some seecerom :, :, an av c:an.Hconssn o a seuence n some emomens,e anennn reon coorneoceo: . comrsn a seuence seecerom :, :, amrses a canLemomens,e anennn reon comrses aea n :.n some seecerom v canHconssn o a seuence n :, :, an :. emomens,e somnee eommaonmseners,veerome aso croomern.sens so amen emeoomman.n some oman comrses :.n some emomens,eneo ens,ene :.n some emomens,eneomans enco man consss o :.n some emomens,eneoman e a nucec ac comrsn :. s encoe a nucec ac conssn o enaesracnn som oe emeomeons,e comrses a snaeea sna seuencea co e ce memrane.n some emomens,e sna seuence om arses a sna s senuaen scee.unen scoem.en e smomoe emomens,e sna seuence consss essena seuence.n some emomens,e snmaen ses,uenec se cnoans sessue enscseen coamr oses a a s sna seuence. na memrane-ounn so omrera enmsmoemmreannes,eransmemraneoman oe serverom a erverome sameroen ase croo-esnm.una soomre eommaonsmeenscs,reeraensmemraneomansransmemraneoman oe maeerans ow.or exame,e can orea-can, a memraneoman o a ce receor aa- , , , ,-zea can, ,-eson can, ,,,,, , , , , , , , , , , , or .,n some, emom,ens,e,ransmem,r, , , , , , oman.n some emomens aneomanse ransmemrane emomen ,eransmemraneoman comrses :.n someransmemrasn,eeomraansnmesm enracnoeeoman a c nouncsessc o ac comr:.n some emomens,e emomens,eransmemraneomans enc sn :.n some . oe a nucec ac conssn o : smuaoromaen c oo aasmcs r oersonnrsaceeuoarr ac svnaaonn o oonmea onr m aosroe e reeecrroerunoc asons oe coe- mmune ce exressne .n some emo orneoceo: . comrses aar o ore mens,e co-smuaoroman oe can enre seuence oe zea can, zea can, eson a,a,,,, ,,- , ,-ea ,- , , , , or a, com, , , , , , , coasmcoman o naonereo.n some emomens,e emom e comrsese zea co-smuaoroman.n some n some eemnso,mee cnso,aesm ccooamsmanc oomean o coemrse csonse- co-smuaoroman. co-smuaor ss oe zea an- .n someno smomaen es.momens,e zea co-smuaoroman comrses : some emo emmenos,meens, zeea co- zsemau coa-sormuoamoarnso emnacon consss o :.n :.n some emomens,e zea e a nucec ac comrsn nucec ac conssn o : co-smuaoromans encoe a .n some emno sommeen ems,oem-ens, coe. -s-muao cro-sommuaano cronsoman comrses : emomens,e- co-smuaoromans ss o :.n some :.n some emomens,e encoe a nucec ac comrsn conssn o - co-smuaoromans encoe a nucec ac seeceromn some em: .o. :m,e,ns,,e, c anmerc. ann soemne receor comrses a seuence seuence seecerom .:, emomens,e consss o a encoe a nucec ac c ,,, an.n some emomens,e s .n some e omrsn a seuence seecerom :,,,, an rom mo:m,ens,,e,, as encoe a nucec ac conssn o a seuence seecemmun uosaenecn s nunomuem eamnoaemenns,.e suuman orsumanzeo reuce coon ns.n some emomens,e seuences omzeor :,,em , nuacn oe ce rc asc. ma encoennrouec aenn-o a ce ae.., nucec acs comrsn seuence.e c seuence comrses an oen reans araemnoemocrera snesuaenocne o or a ce an- ann some emomens,e c urer comrsoersn uenoceo: .mroveor exame,e sa ore rae oransa ransae eemensa n some emomens,e an- on o coen an se-uencesns me. ceuarenome o a ce or an ce ae enoenous ce rece renoeocus.n some emomens,e ocussaree a enoorn aa can asa or an aueonuceoe.n some emoumceeasee..,as, onuceoes a r - onu ns,eue n some emomens,en ceoec . enoenousomooous reco seron oe an- s rean one ce’s con seuence mae mnaon ssems.n suc emomens,e an- n nroucenoe ce va cemca or eecrocemca meanssuc asnroucaenonarocee c oer e usecnro veocraoron.e an- con seuence can asoe a vra vecore.n. s,o am reer eomvroa vmecens ors. ,, aeen voevcroar v uesecoro, aeenvoe-rasseocae- venrcao venc nucec acs vecor.uae vecors are non-recannear or, orenvras seecerom oresneas e ces.n some emomens,e vecor roen exresson seuences.en s oonme em,om,ens,, oer exre.ssone v seecuoerncnecsor aroera ceose omzeor exressonn mammaan ces.n some emomen on- reuaor seuencesncunran s,e vecor asoncororaes reressornn seuences, enancerssc,rnroonnas, a ancvaeore.nnn som see eumencoes,meranscrona vecor sues a consuve or annuceromoer.n s ns,e vra seeceromα, , ,c, ,a a,om ane em-ocmens,eromoers emomens,eromoers seecerome ea nromoer.n some comeaovrus mmeae earromoer, an r anaeromoers,e reea - romoer, mouse m eous sarcoma vrusonermna romoer,e-nereron ammarumor vrusonermna reea - emomens,e romoer,es romoer an -αromoer.n some nn s soomro mem e eo emer mos om an meennss,,ee vro verm cao o ve rerc. so ar suases aranscronermnaor. a euarocasm, an a sueasm. m seecerom aroarocasm, usenenvnen somone e amreo enmneenerse,eo a enx-resse- o arorne nur-oc er coomreo:- ce.s mocaon resunn armorn oe ces aans an rse aenome recen oe aoenecmmune ces.n aac emmune ssem o a comrsesroeco some emomens,e armorn mocaon reconz nrom reconon e cooxc ces oeos.ooxc ces oea-e mcrooasusn anens. assnocae wasse mavoe ccuaenss o a ce su-racreo meonsecuse comrse oe- a,oene-c, ces- re,conz-e, c-o aonxc-+. cees an, -- coms receox oe nnec zeee surraocme se,e aoenec cese e ces.n some emomens, as non- - ces oenvenon comrse an armornenomce an- - or sruon oe ene anereore,sruon o mocaon comrsn a comex.ssruon emnaese ass e ass ce surace-oun a cooxc ce anen reconona norma smuaes reconon one s a aonmace- e.momen-s, cees a ormrorn-eno cmees moec naauorna comerrsess creus oon o os. ces reconze ces wou -roen as “mssn se” an s e ces arene -roens,ncun -, a mnmaomorcuc- ces. n some emomens,e an- - ces or - ces oenven roen. rs armornenomc mocaon comrsn asru on comrse a sruon oe ass ce surace-oun on oe ene anereore, reconona smuaes a coo comex,sruon oe ass anen enomc m xc ce aac, anurer comrse a secon armorn mcroouoncaone cnoem, anrsnere anore,ns eexrroensso on o ane--ene-u cosensruoceeea-- coae cesrom an aac ces.ee, e..,ornausse sneo uroen sem ces escae aoenec res e a., --exressn :-. onses anss ces,a.oecno. sencn orsrun some emomens,e armorn mocaon comrsesranscrona e ceconenens on seee ocr meorerommmune ceneccooen or reeuaoreneense.,n some e,momens,, , , -, ,m, orneoceo: . an . , , , , , ,, roen some emomens,e sence orsruemmune ceconenes . nsnos a ancmvamnune cowecnsroeanm c eonercoorns o acv ce os an ceos.wnonsosoraon, roeasome-meaeeraaon. neav reuaesemrou roucon anerssence, a e aecs ce cooxc, cone uncon o n suressn acvn ces enancese anumor cvaeu ces.eeu e a., -sreuae anas aeaveoen senceummanan cees rse,somnmu snroon.ero c:o–ne smuamaeosnc,wamnmnuenro e a., - u.: uo, e a., aaon w as enanceser c. oancer, umanacena sem ce-erve cesor cancer ooxc o :e . mmunoera.mmunoer. oancer cone-nn some emomens,e sence orsrue reuaorenes . or aseen suocweno enarnoceenes ao neenca ove reu ceaosr a oan cse cesr aann can ces.non o ..aeno. cers annecons moce acnv sao,me e,mo.mens,e sence orsruemmune ceconenes . exresse on acvaeon ore enxeause c,e ass.onownn aseracs ws anm cmausne cecon receor ceuncon an conrueso ce exauso s moecueson o exress an secree wc n.roncmocceuema ces romron cec amac.a souo conrueo umorrow an escaen c ro e a., moce acvaonene: a noveeraeucare no scomce eemueomma,eaemaooca, :. cemm ns,e sence orsruemmune ceconenesm. s receorunaoeconu-n o mnucen suracem os c ae nse aanven reusaoer ounc ceuncon.mnsoncun+ces,+ces,res an ee on o varoses o cesncun croncmocceu r ces.nemaooc manancesnorre ces,n eerem ceaunco,n an coevrreesa oe w exreossoronro onosms. uanre eu aa.e, cvaeaecn-mromoesre an suresseorneoceo: . mocceu s eecorunconn cronc ne smoma,e e .:e . cemmunoreceor wmommmeunnos,oeu snen acne orsruomeanmmune cse ecxroesnseene ascvae. ee+r ce ans.+eve ces os, naura exreerssonn ces,- re cueaso arre ass coecsaere ws, anocuar - ceera.acson e a., euenane-er oor resonseo arerroneveas as aarer o -easnuscrona anroen on-onmom nconnaens w n some eam,oancmerenss,c movu.e:mmun.e ceconenes arenacvaen an- enes aren-ac cvease orne- same ce ces..nn so smomee em emoommenens,wo or moremmune ceconncue a comnaon seecerom an s,e mue ceconenes an . m, an , an , anm sruen ann- some emo-m ceenss, oremm-une ce cesc usonnene ore reuaorenes ceaves nucec ac srans wn an enonuceasea secca ceavae e seuence-secc en aonaruceea sseeu reesnuces on nueceecne aco seransrue.e sran reare non-omooous enonn . s anmere reasa mae resunrec re-aonu more oen, r c rearrocessa ma more nuceoesneare seuence.ucesuesenonse,ensoenr,onnsse,r oro snu, or susuon o one or nuceoesneare seuence ma r suons o one or more con se esun mssense or nonsense muaonsneroen roen.uence an emnaeroucon o anroen or causeroucon o a non-uncona - ces orn som-e em ceosmen cosn,acenmmeun cee c wec aonenessruen an-rerne rocess wne seuence-secc enonucease an exresson o ce resunnene muaon an emnaon oroen cun resrcone n sm eonmm zeun m eme c e, aoecmeonns,e , aene s. nec-uennceer-s nuecceasce enonuc aneas aes seece enroonmuc ae raarsee-. n some emomens,e seuence-secc eonrnoeoceo: . enonucease seeceromas anasa.n som nuceases asar o a nuceoroen comex e emomens,e enonucease nucec acaren nucec ac comrsne enonucease an ue one or more nuceoe or .n some emomens,e comrses emomens,e ss s aeneces arome emorm- or c .n some ,,.n some emomens,e s seeceensescren..aeno. nernaona caonu.o. -croonmae emomensescreneor e ssems, an meos o man an usnnnonuceoes anues escreerenn seo.m.e, eemneonamcenvas,onnr ooruncsenro onne or moree s oame.eenec mocaons enome o an an- - ces or - ce ose w-con seuencesnoe enonucease. e a o a seuence-secc enec mon some emomens,e enonucease useonrouce one or more oe euarnecrsaaocnesescorreanereronmsc enceoeaesenoemcocusoscuos.unen manrouasreorec ceansosmecsa anon oroves ressocan acreeo renvason ooren nucec acs.rucure, nomencaure, an -as ssem vewenaarova e a.,vouon an casscaon oe n sosm.ea emureoemveenwss,ecr eonoo. une:-. enec mocaon onucease useonrouce one or more oe s sescreerene..,enenacvaon ornseron oe -con eenuoennucceseasen.oeenome o a ces a resrcon enonucease, e.., ae resrcon enec mocna soome emomens,e enonucease useonrouce one or more oe ca nsescreerens a caacanacve enonuceasee.., enaonuccaeasenaocv.eseeas e.. o,ruasnear, c.on.,u ea ae.,oe. cuesavoaneoman oe resrconoo nuceasemrovese secc oenome o caacanacveas –. mocaon,aureoecnoo, , more oeenen scom meo emcaoomnsenesscre eenoenruecneass ae znec ennoneurc nuecaseea useseon, oror auce on-eo or uson.n suc emomens,eare seuences a orneoceo: . o reconon seuences, ea ou-aseson an comrses aar nuceoeson.e c- nuceoeson, searae a sacer, wcs-usonsoo e e...,m.., e a., .r resrcon enmes:ncner n c seoamvae eemoomamne,nrso,cea enocnac . : –. more oeen uceasee enonucease useonrouce one or nucease e,c or m aocao-nosesucsrone.ne sruecn ems aormanesncrs,oena arcev saeoru-ence eecor - nuceoeson an comrses aar o reconon seuen es aouon, searae a sacer, wcs-aseson.e ces, eac-ases aren oue-sranreas w eecor nucee e..,rsan. e a., n some emomens, aua conro measuarses,enecs. :–. oe enneere an- - ces a e assessn one or moreroeres amnserne ceso aaen woaseenn - cess aeoe cesroro ens. seeceorreamen assessn anen - cesns someer eemsenocem oense, ane assesseroer oe an- - ces an resence oe ne ceuaren- nucec acne ceuarenome.e ac rzaon, nu ome mae assesse a meo seecerom nucec reacon cec ac seuencn, an secc amcaonncunomerase can .n som,eu eamnoamveens,e , rea-me r anroe a assesse w amcaonrersence oe an- ne ceuarenomes n some emomens,emers seccor one oro nseron ses. - cess surace exresso assesseroer oe an- - ces an mae assesse uorescen oe an- .e surace exresson oe , ores nce-acvae ce sorn , mcroucs-ase screenn, a erno.n some emomens,e surace exresson oe an- s esmsesosemens,owe s curoamcee erx wresso ann o ane- aan- ano orsa aseseesseureow an ceon.n some .nur soacmee e exmreossomne ons,e aen a mer w es s n-- s- se ceece oror am-ns creaonoou aaoane wn.e nne someneo emme,o ormeenrasc,oen orac ceons on cees cenoe cueaoonu exaroesnsnaroren an-e an- one ce suraces useoeermneeoa numerorneoceo: . consun a o ces oe ceouaon ner saomeueca eecveose. ces are assessen emomens,eroeres oe an- - ces or - ex vro an are seecerom ce va, anen-eenenss o anen- exrreessssnnaarree ce cessna an serean- reeceaneenne c woo axncen,-exncreussn reeaess o anen- eresence o anen-exressnare ce nare cesroeraonn secreonneresence o sanen-eenenroeraon an cone memor cee anen-exressnare ces, ce exauson, aneresence o a - ces unn soozmesee. eamreo cemesn osr,areen c veron aesss.esnsm soemne o eme an- - ces orumor ces seeceromrmarumor ce omens,eare ces are emomens,eumor ces ar s an esaseumor cenes.n some - ce,.e.,eumenowno exresse secc anenore - ce ore - ces.n some emoro ces exress reconze e an- - ces an no,- aneo-.nmens,eumor ces areromumor cenes , , exresson. some emomens,eare ces arers assesseor - cesn some emomens,e assesseroer oe an- - ces or cess maes a asnsesseen-e ceon-ceunursns oe anouena-oanr coormnrsarne en cense.eree an--eenen ces or - ceseecor ces or eecors w -exressnare ces - n some emomens,eare ces are -exressnumor c ares. emomens,e -exressnumor cenes are se enes.n some , mane cemoma, ,-cronecce ceromeueemoa cemoma, .n some emomens,eare ces arermar cesroma, , annoumorsnowno exress .n some emomens, ens suernrom aen, e.., a cemomaaen.e coermar ces arerom amoma eecor:are raos: raos.n so -cuure mae esase a eren . an aou.n some emomens,mweo em or moormeen:s, raeos:n rae soese acreen ranee ra anree ev oau aaoeu n some emomens,e -exressnare ces areaee w a cera . erace™oee n avance an co-cuure w an- -cn ore-e.., eecor ces a a rane o: raos.er a cer orneoceo: . -amnoacnomcn s ae a anme, e..,ours,roumoe or ueanare ceea eav seaanree. c.e,ss n+. or-e num m oarze a+er onvea orre ces us caouense ev aasuaee num vaero ow cracoem searnnoo ans-e ce nusm reemra onnve.anr seom ce emomens,e numer o e an- - or - ces oravn moc - oesn a conro cuureacn ces. r - ces, e.., anen-arornn soamree em ceos.mens,e assesseroers reeae anen-eenenss o caen e anen-eenen cess mae assesse successve -es cesesr wa recwao oenr meosre oree sameouaon o enneere an- - ces or n some e s auos oare ces. eercenae o -exmresosnmeanrse, ceess-s o sreece-or c aemnosuraaoonn eo aecanen.en somese emxroessmnensa,ree ce-s osru-avn ceowo nuoan-sonec ececanre a ceesrcsensa see oeceo- amnsraono aaen.n some emomens,e - or - ceour eecneesercenae o reeae -exressnare cess aon amnsraono aa s seeceor cess ann seonm-ee e enm. enoenmernos,erae assesseroer oe an- e - or - cuurn aouao on oe ces.roeraon mae assesse co- w -exren comrsn enneere an-- - or - ceseecors, o aou.n somssen emaorem ceenss, caererso,e.ran soonmes emeeocemensa,e co-cuures a: rao ces w ceermean saeuorescenese..,er en - or - uon wn ace™oe an measurne ne som- or - ceouaon. exneese ra eem oormoenesr,e an- - or - ceouaon seeceor amn aonneresence o -exressnare cess e an- n sosmra -e eomn oroo amae-nesn,. cee ass.sesnse somroee ermos cone or cemone secreon cones or cemoness assesse.e one or more conemse anres s,e seeccreeornom o one-, or mo-rαe, -,-,-, an- an cemones suc as-α,orne-,oceo: . one or cemone secreon mae assesse co-cu -, an . enneere an- - or - ceseecorsurn aouaon comrsn cesares,.n some emomens,e co , w a -exressnare emomens,e cones or -cuures a: rao o aou.n some uana cemonesne co-cuure suernaan caneeece or on ovreeec ane sm anar a snecoonar-a asne oor an-asoe m ceonousa we-as ceoo arssa suc asesern eecon meo merc oruorescen exnens. soemsee evmeo om cenos,nee or an ce-mone sec- or - ceouaon exressnare cess seeceor am reonneresence o - are assessenn v sovome an em aorem seeencse,en romrsora aero een cso n o aa cea aenn.- - or - ces carrnareumor ces.n racerscs o exermena anmas an exermena an smomaes e amreo mmceen esn,raeaere w ces areeuummoorr c ceessnorwono exress amnsere aose oe an- - or - ces.n some emormeoen exermena anmas are mce enrae weo-umor ces ns,e assessmen o an- - or - ces com .n some emomens,e survva, anumoruren oe m rses monorno we, overa e an- - or -ce enrae weumor ces an amnsere aose o cene anunm soormeu ermenosm aesn. sess,see anm maesas aurern enrna vev w auorescenaeeumor measuremens.n some e ouorescencean oer mouse enrae weo--moucmuecnse,rasee- eexxerresmsennau amnomra cse asre.mnm soumnoee ecen mce resus are exrreesse as canenuorescen momens,e as area une ce oeumorsor anmas overme an evauae exne mn cu os sorvme reeuc emono. nmeunmso,ruer aenn-n exermena- an ormas en-rae ceouaon exressnumors annece w e an- - or - cess w seece- amnsraono aaen.n some emomens,e an- - or - ceor ouaon exne smaes area unere curve sorneoceo: . aen. seeceor amnsraono a or - cens sonmee e cmrcouamoenn os, ane e axssesseroerserssence o an- -umor annece we an- ermena anma enrae w a -exressn erssence o an- - ces - or - ces.n some emomen+s,en a voume oe s assesse aseresence anor numer o ces cess assesse as anemare’ssencoeo an.nor so nmume eemr oomen+s c,esene ars vsoeunmcee o o ane- - n some emomens,euaave anoruanave a anma’soo. or - cesnoo samesserorme ow cssessmen o an- - ces w an- anoes resecve.n some emo omer w an- anoes or ano ane an mens,e anoes aree an-uman n -uman ano. exne seosmeer esmseoncmens,e an- - or - ceouaon exressnumo en crcuaon o exermena anmas enrae w - amnsraonor as aanenece w e an- - or - cess seeceor nne some- enm. orome-ns, cee asssnessee crcrouaeron os c aonn exnueerm eexnraes asnomn oe an- w s a -exressnumor annece we an- - or -a en ceras.en noomrmea emzeoomeen esx,reess eoxnr oess aon oonae-rease asseesnsees.ow comer an comare or s seconescresn moreeasen some emomens,e aona. usene meo oreamen o a c comosons comrsnmmune ces escreeren.n anceraen suernrom a -exressnumor cesor amn some emomens,e comosonsncue an- - or - orreamens aesrsenssno aaen an sueenrnensrom aneum-eoxr.rens ssonmeu emmoro woaseen seece comrses comosonsncuno an- - an - cmens,envenonumorroer.n some emomens,envenon c es exn an an- - ces or an- - ces assessomrses comosonsncun an- sasacoreve o aarameer eoravn a sasacorroer or ane ceuarenome, surace e sxereecsseonr oom oene an or- more o:e, arensenecne- oeeen anen- cooxc n vro, an-umor acvn vvo, anen-eenenroe orneoceo: . secreonn vvo raonn vvo orn vro, an cone n ocrenr voro. ces ca uce anoona assesseoreesreroeres,e enneere coneormuaeno comosonsorevero auman suecoereae.e exmcoesnso.nsxnemcuaere ex ecnneenesrencmue,o wceso,u anm onea oorn m,o craeroarmraaceuca acceae anmcroa aens, anoxans, suracans,ue es,noranc sas, xcens suaeornecae c rs, acs,ases, an comnaonsereo. veeae os,osos omosonsncue waer, acoos,oos,cern, suc , an suracans. carorae suc as a suar, aervaze suar exc aesn a.n aeco,c a caornoc acra, aen e exscerenes suncaru, aen,oorr a ex suamare,o mmer maeresen as an rucose, maose,aacose,ucose, onosaccares, suc asacose, sucr -mannose, sorose, aneesaccares, suc as maoexrnoss,e,erxeraanoss,e s,a crecoes,o asne, aneee aeno asaoccs,a sruces, suc as ranose, meezose,aco, xo, sorouco,ranos soro, mon as manno, xo, mao, asoncue annoranc sa oruer suc a oso, anee.e excen can soum suae,oassum n s crc ac, soum core,oassum core, ee, an comna rae, soumosae monoasc, soumosaeasc, an orrevenn onr soemeeo rr en nms moere cmo roe.nas,roew com.nos somone eumroer cmoemnrses an anmcroa aen seeceromenzaonum core,enzeonum c s,e anmcroa aens core, corouano,eno,ene acoo,ore,enz acoo, cernum e, an comn enmercurc nrae,merosa, ane na sonsereo. rev ome emomens,e comosonurer comrses an anoxan aeo romen ascoreeearomraaoen, oueaemorocxeasn.sno seo,mue emaeomernoxs,oeu aenne,oxaonoss seoerce ac, monoocero,ro aae, soumsue, soumormaee suoous soum measue, anee, an xae, n some emom comnaonsereo. emomens,e suracanse snese,cee corommosoosnoruarees,r c soomrranses es ae srus,racans,. snuc som aes ososecn an oerosacones,osaorneeanoceo: . ana esers seros, suc as coesero oamnes,a acs o men somse emomens,e co,m anoseonue.rer comrses areezn aen suc as e nuuoxe oro uman aumn. vareenn on sevmeraera oco anrs-u w om-a an coomrrse a-er caeesuncae c eomecovse aomno wun aomsenserar voan. oncereraasenu acmaoun ese ocvee aonse- caneeer-m ane exermena reeae comosonn oreroeermne wc amo nor - ce-conann n some emomens,e numunerouces aeraeucene. e comosonseermne assessn r o an- - anor - cesn vro co-cuures wareum eeve o cooxc exe sa cesnn cuures areaen’sumor ces.onr s coemes. emn soommee enms,oem nuemns,ereareumor cesn co- - cesne comosonsse smaes numer o s o an- - anor cnca sncaneve o cooxc sa ces aaa ces suceno ex a cocuures. nsaen’sumor cesnn vro - cesern some emomens, were7e suecs auman,e numer o an- erosesewerosaen asoeuwer×an8c aeosu.n× some ce ems aonmeen nus,meer oose an co- -7ce7s .×8or a suae numerne rane o×6 -×8a mrses×,×, emomens,eose comrses×8,×8,9n- - ces.n some ×7 -×9an- - ces.n so .× or a suae numerne rane o o an- - ces a me emomens,eose comrses a comnaon - ces ane an-n an-- - ces.n some emomens,e an- rao:. cesne comnaon areresen aroxmae a a ercenae orn som-eex emresosnme cness, aemoona n aumeer o ce cessnnee ceose cosm aousease one emomens,eoa numer o ces amnseres son.n some ercenae o -exressn cesne ce comoso mue werese numer o cesa muse amnsereoe n.e mucaoneseoa o -exressn ces. aenn orero amnsereesre numer orneoceo: . ameoran an ma somnean emsoeasmeenns, aaeennve wneornese a mseeao orean aaen or exressne anen,e meo comrsn ses assocae w aumor anenensne ces oeaen’ assessneeve or exresson enssoun, amnsernoeaen a cosumor an sucen anen suc as an- - ces or an- moson comrsn an- mmune ces n some emomens, a same o- ces, or a comnaonereo. racon oeaen’soo aen’sumors oane e.., asoo or a roenensomer.re,e.anen so’mse ce ems aore smaennes, w a anuoreesncenense-cson asusesase an- rmar ano, e.., acoerrn-conuae an- ano, ane sane ces are assesse ow comer.o oan anenens ex e numer o moecueser ce,euorescen snas resse as a uorescenaeeeasavn anownens comareoe snarom n some emomens,eaen’s c oeuorescene moecues. seccss an- - ces or -s ce ares assesseor susce o - cesares ane -aren coo .n some emomens,eaen’s eecor:are: xc ceseecors are co-cuure a varous emomens,ouan rao cse, e..,n:,a rraeos cens aree raaneeee wwee anve. ce: sa anne.:.,.en some oeTMroro co-cuurn.ere co-cuurn, e.., ae races ae, e..,roumoe or-amnoacno rours, aea ce san ce cuures evauae vaow com mcn .n some emomens,e ve ceeu no san erouanveare ces, e.., ces sane we woue+-e weea cee.n some emomens,+eve-are ces n s.omn seom eme eommoenmens,eveare ces woue . exressor cooxcs s,eaen’sumors caracerze as a n some emom oesnersv,ee evean aeneowes: raos. exressor anear ’sumors caracerze as a moerae- .:o ncreasen cooxcs oserve wncrease o: raorom exres:so.rn c soomoex ecmo reamceenss a,oueaen a’s:um roaros o c aaraocuerz:e. as a moerae- n some emomens,eaen’sumors caroacrneoceo: . exressor some cooxcs oserve erze as a moerae-ow raoseween.: an:.n some e uoes no excee ne rane o: moerae-ow e momens,eaen’sumors caracerze as a rane o: ra xressor some cooxcs oserveuoes no excee ne exressor nonos c sooemw oxee c eemno. s om: seen a rvsn e,ne:. eaen’sumors caracerze as aow some emomens,eaen’s rane o: raoseween.: an:.n sascca con s umors caracerze as aow exressoreres no sec roncanerencen cooxc o -secc eecor ces an non- - n e seocmoer c eemsos omesenrvs,enee rane an o: raoseween.: an:. com enensneaen’s sames an-areo a u -res co anenens neeeonuce -secc cooxc meas es or - ces.n some emomens, area unere curve -re cmeens osr oan-er coems one or more exermens assessn cooxc acv o an- n so aans -exressnares. ens aove wcm ce enmcaom senns,c aa sna amsocuan a ona csososx ucse oocceuresr.mnne s areso anen a sasca anasss useoeermne areso an ome emomens, sncan amoun o cooxc occurs.n enenseow wc no cnca en e anenensreso a some emomens, cacuaons useo sars occurrn. wc anncreasen s occurs.e., cooxc anenens conn saonmne e amoresmoen as, wc an cnaccrueaaseonns uses ooccuresn.e., ce roanoxec o occurrn. sars anenensn ne seomeeo emnoucemens,-seecaecn c’so soamxces c aonm-areo a-res oo ces usn a surroaearameer.n some emomens,e su r - amma secreon measuren rroaearameersnereron- - ces.n some e suernaans o co-cuures o an- - ces or ensreso a wcm anoncmens, cacuaons useoen e anen n some emomens, r ceaasceuanons s uescereoon oecncurs.ee. r,a cneo ooxc sa arns oecncurernns. conann areso a wc anncreasen secr orneoceo: . occurrn. eon occurs.e., cooxc sars een assesseonr soamven em a saosmaecnosr,reooerua oro an s oasmamcuonre ceeves a om ansereo aaenas one or more o:eresence oe an arameer seecerom e an- , anen - ne ceuarenome, surace exresson o eenenro -eenen cooxcn vro, an-umor acvn vvo, anen- ner saomone, e amno cmoennes, secereon. rom soumorsncun ovaran cancer m,eroe nes aaveereoasa canencesr, caovonrecuamors seece sma ceun cancer,un aenocarcnom cancer, non- e a,ancreac cancer,asrc cancer, meanoma, anenuoemmeara carc, mnoamnae,- acse wem asomeamaooc,aoucmuoarrsnmcuomnarom croncmocc ,use cemoma , marna-zonemo,maar-ce,mcomearansormaonmoma,ur moma,moasmacomoma, ce nr onsmasco smnarome, acue,m ceomeuome on- meo ma, aana,e ancsureom m meacoroeouuemneama,n aaen.n some emomens,envenons a meo onnerow o a.umor suec oraenn s aomeera emeuocamen es,eceven nvuemnoenr o comrses a meo o amnserno a or a comnaon o an- ces an an- an c-e ces, an- ces, n some emomens,e comrses a sn s exressn an an- . ramenscv arans a seuence, an an- sne-can varae exame,e mamaveem araneo smanan s aeuenncee, aom caon,a asnmc a comoanas cmomcrosmnan,or exoemmana arnomea-ns oomean,e arescraonssememererann,eoorm eaxanm, ane,ee sneoman.encue a o s:, or, or, an a o s:c, ovr o, ore.n s moma emomenLs,e scv comrses anernneHcan aneeav e w aormua , werescne ans serne.n some emLo canHe seuence seecxeynrom s:,,, an. mens, comrses n some emomens,e usene an-orneeoraceso:res .mmune ce seecerom a macroae, a ce, a naura enn an er ce.n aonoe ,emmune ce maer ce an annuce naura enomc mocaons,or exa comrse one or more armorn one or more reuaorene seemcee,r aonmnacevraouon co ons onsen or o moremm,une ce-c,onene, or , , , , , , , , an , annac,m, oe ene wnseron o an - vaon ornausse e a., --exr - uson consrucnoe eneocus anss c essnuroen sem ces escae aoenec resonses ce exre es,a.oecno. :-.n some emomens,emmune seecerossmes a- me amnrane-oun cone-receorusonroen, werene cones - ces, or aarm coamce-unac.aon co om aons-on comrsn- a cnes- a - ces, an- exressne an- caneevere va varous roun an- - cesoca or s,senmcever,ncunare es anever meos suc as sucuaneous neraever,nramuscuar,nravenous, nr saomeeca,nravenrcuar, ornraermaever. res emomens,e meo comrses amnserne comoson oe menoenveennonoer aa su.ne scom we eomaosmeeenns,rerceocnononoenn ws w anmmmunooeene..,ncun comna aens aarma scoo emn een aens, nues o c eam c cooco mmoeo snsso,am n oer ce oormm an uoasu ooa nnra w orne co.rmerumasoneoro amnsernoe acvenreen an conans on non-oxc aona oca acv o an a ecxcceeanse, c saarrerzse.rsn, a snomer emomens,armaceuca com acocenenase su ccarr aesrsnacrmuaceeuucaers, n some emeoservmaeves. reserva ns, areservaves use.n some emomens,e enzaonvuem c comorrsee,s an onoex oran ms,o cree oan m aeens,araaren,roaraen, soumenzoae, ac.n some emomens aens, corouano,eno, an sorc oeoa comoson.,ereservavesresen a aou. o aou we n some emomens, a carrers use.n somoern eemooceo: . comrses auer, anoxansncun ascorc ac a mens,e carrer aumn,ean, ormmunoouns n meonneroens, suc as serum acs suc ascne,uamne, rocomers suc asovnrroone amno monosaccares,saccares, asucaorsae,n mea,nnsose,n oer, aerxnrnnse, c oreasnne a caernosraes suc as suars suc as sucrose, manno,reaose or soro sa suc as mea comexese..n-roen c -ormn couner-ons suc as soum co . omexes anor non-onc suracans suc asoeene uer n some emomens,e carrer comrses auer.n some emomens,e oer ac coms arnse ssa cs.rcn a scom,e s eomuomm cernase,,eosueorrcs acres,eno aas asuomosae, an varous we oeo u. o aou comoson comna s c roo smm neo esmo evon. erm sensse,mse su mceoa comrses amnsern aarmaceuca me.n suc emomensearma eever oe comoson occurs over n some em ceuca comoson comrsesme-reease comonens. ean.n soomeme enms,oemenasr,maceeucaarm coacmeuoscaon co cmomosrsoesn a cuommnrusm monosearae or marces o so roocomers.n some emomens, es semermeae ms or mcroca e marces areneorm o comoson comns su rosmes ne. a em seroemeuns, suce a mse anosoo cnomc aruseesou as smounsoner, snus aensoanr,m eamcueusocna, emseorsmonesn,s o,r vescouasrm caocmeuocsao cno,m woscon mas ae seureerenecoa ae se soecueon.n somencororane cesn a soven suc as sere waer,sooca reare ucose,exrose, oree.n some emomen sane, or souons or comrsessersn, or emusn s,earmaceuca comosonurer aves,reservaves aens, uern aens,en or vscos enancn amnsraon a ,avorn aens, coors, anee,eenn uone roue o exressne ann n so-mee ermeaoramon aerne ess c,re o-ae. amnn-sere w c-o cense os.r ann so-me emom-ens ces cones are seecerom-,-,-,-, an-.n some emomens,,ee cones are amnsere a aoseer oo we o auorneoceo: . nmouseor-,, unsmouseor-, an moumanas euvaeno cssnen an som-e emomense,scre seor-. exre aen-eren are e-n cneeesre or ano- consuve- ex creesss conosnuesv.en s eoxmree essmeo cmoennes,s aree c meomnraens areuman cones.n some emomens,e exresse memran e-oun.n some emomens,e consuve some emomens,e-oun cones seecerom-m- an-m-.n e coneos recee coonrscuovene e-xrecreessoer muesmonra.nen- sooumne e cmoone comrses auson o oun cone-receorusons seecero mens,e memrane- uson an--- receoruson--m---us- receoruson-- aso comrses a snaee.n s on.n some emomens,euson snaee an snaeeome emomens,eeaerees seecerom- . e a., mmxunrees cseosn e onne-ere.o or ex anress- co-nesavuesoenen onescre, c ee..s, moowee, aoveranserre ceunconn cs.ur..mmuno.: annr s acaonerao. , one-receorusonsormmun ovsona.. a, . e ce smuaone on are assesseorn su sormacee e emxoressmoenn os,ee a mnem-rane - ces or an- - ces e memrane-oun con -oun cone.e surace exresson o mcrouc e mae assesse uorescence-acvae ce sorn , exresson os-aese mem screraennen-o,un co, onrese assseersnseo.now so cmeo emomens,e surace ano.n some emomens,e an- - ces ormer w an an-cone ouaon wees surace exresson oe memrane-o an- - ce amnsraono aaen.n some emomens un cones seeceor exresson oe memrane-oun ,e ceouaon wees surace n some emomen cs,oen aes seeceorerenaonno ces. exressne memrane-oun conen a-r - ces or an- - ces emomens,e cooxcroeres are assessee assesnse co-couru crno woxcurmoaenruems.orn ce sso.mne some emomens,e memrane-oun cone-exressn oornreoc ceeoo: . ees cooxc acvs seeceor amnsraono aaen. uaon w xam-exere.ssnn- consrucs a creon ssoruwcns ae. consru nae. ame s cs acv z one a : * na : - z * -ronmo meor : z -mu – oman , – snaee, –ne, an – cosmuan romse ve acnor resecve,: –, snanoman.--mu – cone co-exresse . mu-:-erve muan snaroen : nxams eexe.rmareae anenensn aens o moecueser ce wans,eeorom snames were oanerom aens.e numer -conuae an- ano eo.ereen,,aarne ceeos, weare. sane w coerrn uancaon vaow comer, evensn snesae were c,oeocnee.e.orroen mean oeare ces were cTMeomerc ou omareoa uanreeas conannour moecaueosnse wa annownenses o2moecues.ne o wasenerae rean -ens vaeeoarmeer cce meaneome..e euaon oene was useo cacuaeo unsane conros an reore as morc mean. anenenses were normaze xame.ooxc acv o anecu-esce.-e r ceesuss a aaren ssoowwn ann . exressorsn v oeesnro -se exxreesrsmnenoneoro cweessonor-exnre asnsnn vorono cr coeosxcono arssa w.erree com,aarree ces wereaee weraceoeTM.n- orne- coecse weroe: . w -aeeare ces a varous eecor:are: raosnr co-cuure conro cesncue asruon oe ocus wou an ncaeorours.e enome . - ces were use as conro eecors ceronne ceuar s eveacuace v.aeorw coomuersr,roouaunmoaree ce weaas a.eveaor eeac ce wee cou annsac s we unae was an seccss − w !a "#s c ^&a 'cu!a *+e ,^r -e !!a ^-.v / e 0^"o 0^5:: 6^4:': ^+*c ".o.n ^xr^os us re exrace, !"#^&'!*+,^-!!^-. / 0^"0^1:3^4:'^+*"neormua: ns ex.ermen a coecon oonor samaesen ans an ce cenes anenens ow comer usnuanreTMear nes was assesseor cnson,anose,a.e vaues ranerom ~ oenensomerecon u resus are s moceo ~ moce. enoronoraowen or.nae a an.enoneonrs or one surnaceca o coes - ene n moce emeec-nooes oencor -- oo--o ronns - onor scovesece-nces oonnoorr oo--oonnss -- oonnoor o-ons - onorr - - orneoceo: . .-- ec- - enoo- anenexnasme.ooxc o -aren - ces aansares w varn .eses exresson cenesno,es eox-,ermece-n e , a ax nssersessesors -.ees-eoaurre sse ecxcress o es -exressn er cemoce, exce -, exressn mosscereaseereaxnam,e moecues o consrucs , , an escrenxame w .e cesno were use as a neav ere use. varous eecor:are: raos.e c:on –ro.:.e an-- - ces wereresen a eecor cesac ces were use as conro momcreroeresnusra anree s s s,oewcncn. neave. suares, ranes, , conrocrces.orees exressors . moaxemrauem- seccs es was oserve even aeowes: raoese. exressnrms exermen assessexreessors-our seccss o moerae - ens oeweaern aaouen, ces aromonors,,, an.eseares exress a a , , an n aeoscure,n moxamceesee wexream usee..e co cnessrucs r w:earree use as a neave conro.e a no eeco n- - ces wereresen a varous e:su rsa aorse s.ow: –:. mrroreranenn . suares, ranes, exressors, -, mosc,e secc nsesa wave conrocrces.ore moeraencreaseo reac maxmum ae: raos o:so os:er.ve aeowes: raoese an .o exressnrmaraxer eea orneoceo: . s enrem-o cew ens arsosemss eexres onoresors s- anour seccss o moeraeow -ares exress a aens oew an cenes an .ese .e cons een aou, an aou, moceseexame cesrnuocs , , an escrenxame were use. resen a varous eecor:ar weere: use ra aso as ne.av:e conro.e an- - ces were rroerseusr aarne seso,wnn –:. m nea.ve conrocsrcuaerses.,ore mranes, exressors, –, mocee rae or s oeraeow ces,snusa eccss wasow.ansonorrmar reso o aen seenc excresssso wna nsec oesssearve a a: raos,ncan aoenaower rmar ces, se ror an- - acvaon.ansonor an ccss was oserve on aees: raos.owes ceonnroen.sesnsrou,ere was no oservae seccss wen comareo .owes exress rmaraen cess exroemrmoennor asssesseorse-our seccss oeowes -exressn a a aens oessan, moce anse ceexanmeseec-. ane con.sruecsesares ex,ress , nneave conroe.scre aen-nxame- we crees us weer.erese cesno were use as a .: –:. n a varous eecor:are: raos mrroreesursa are sownn . suares, ranes, enses,eres no osnerveas,e secc nses raeavev ceonorocrces. ceowes anen cooxc xame.resoor anenens noeneroe.o aceve secc anennenss e nxeaemee,eaaromxame were useoeermne aresoor an . o aceve secc cooxc.esus are sownn rea unere curve was cacuaeor eorneoceo: . eecor aans eac -exressnarexam ac -romxameoncreasn anenen e.rs, s were arrane accorn anenens. se,s.o r, **,oe.ex, s wereoe aans s wereoe aans an ncaes–vaue..na, normaze vaue.. anases anra enens. ,oom r, **ncaes– eneraren was os wseerreenerae usnraarsm. anenensncreases ve, were an- - sncrease as an- o-eerm.ne areso anenens a wce mean s oe aonawo-s sncan er,wo-wa s were useexcun .n cacuaonsewae smar re wsuass ru.n usnenss no-rmeaezneenoncereasen cosn wraos. oewo eween an moce,ncana aower anenresoe serve rane. s wna measure asex, a wnenves anaee wneenserse rneaeoennsen oeween -secc cooxc o a ne - ce oe source o exernaacors suc aseesn anenensnare cesor ,are ce,s.e wasoe aans esus are sownn .mar sem-o reaonss, an xame. wereounor aree eecorsromxam2eween an ens cacuaon conrmsae o e. vaues o.-. resecve.e as an anenensserves renaeoennsen oew eeenere na-sureec oc an c-ooxc eemceoars cuere or an oereaure oare c s o -exressxanmaer.neeresr.on-amma secreon an- - cesneresence suernaans o cno-cusu erexe sam ce o aes n,-e amoun- o censerexraon-amma was measuren . - ces were use as conro me w varousaresxame eecors anare ces wer eecor cesacn secc.re, conros were useo measuree coa-ccuruoruen ar aese:nce ra oo corors.ecor-on anare-on anazeorresence o usn annereron-ammanes.uroecranraaanex wTaMs cmomeucneoas asna an manuacurer-roveroocosermo orneoceo: . eama o an- - secreon aa sercenc.aa weresae as a esus are sownn as a nseane o -exressnare ces. exressonoome.arweo c neesa arvee a crorannea roema srmo.muaonesrous w exressonoooweso evauaeasene secreon erencue: a ce-on conro roucon o eves, an aare ce-on conroo oserve anare ce necessaror snre.ec-awna secres woner ree uaseveooeee crmonnreoseowerreso o ensare-on.e cacuaoneermnea a eecor, eecor-on, snusae secreon a -s occursresso anenens a wc ens exresse rmar ces oonor.n , ** mnoccee anen xame.ooxc o -aren - ces aaanses so-vauume.. w varn anenens or cenes nes w erense evxeesrmen asesse.ssee anen-seccss o cesrom soumor ce orsowe o anenens. -, an ovaran cene, was cosen ors evvee o o an anenenenesns, a.nes cen,e as waserrecr caanrscnuocmea coe ene, was cosen mnuon oe -anouc+cene wasero xressucerase. ouaon.s-anouc+cenes aoc rmeo oan a monocona were sane wouan-aee a ann-enens an,onao o -ua oaenoon. enuc,+anones-.anooruc+ro ceens mueaann ocaeona vrae coews c woemree crom,a,re eovenasn snuaensaeTwMere coece.eeomerc normazeo unsane conros. reeaseconcnson an moce ans exresse moce- exresse moecues o er ce ware ces an v-arous eec-or: caerse w:e o . raosnr cocnaserucorxamourse. were- cocu cuere were use as conro eecor cesacn secc.rcae o w s ces wasncueo measure sonaneous ce es w onumor onn was aeo measure maxmum ceeaea an. aerrcaoeur os, w coe-csu wure o sunernuamaonr c weass coece, anucerase acv measure usne orneoceo: . sc. accorno manuacur an-o susraeromea,ason, ecraaxx mcroae reaerero’secnusarruceovncse.s, seerc recanss waes usumnneseceonrcmeu w a ^secc^s89+":0*!^;**<=9.0*0. / =^-!!^;*>a: es s =^x^:*8": / :^-!!^;*><=9.0*0. / =^-!!^;*>eac eecoro reuresse anre o svoerwan sneccss a.arnesa u eancere cu-revxeressn waars cacuaeor wereoe aanse anen e.e s eenvenonasense oeare. exames, we aareno o enescrenea w reerenceo secc e srcoee oeresn,n ne sene ara varous mocaons cane mae wn esc vuenon.e causm,ser secsoenee oeeown.venon sou noeme e exames normaeuenceae :: euusmmcraannzzoen scv e ::: u : u : um um uma ma man an anz nzeee nzzzeee scv ::: u : u : ummmaannzzee scv : u : umma : saannnzzzeee scv :: scv :: cnv :: nee : orneoceo: . ::: z : - zeeaa :: - : o : orrnneer scv : o :: s : sonnr s on orrnc ne nev er err s r s sc sccv cvvv : - : --- m muuaann norma seu:encesn umanze scv : umanze : umanze : umanze : umanze scv orneoceo: . : umanze: umanze: umanze : umanze scv: umanze : umanze : umanze : scv orneoceo: . : : scv orneoceo: . : : scv orneoceo: . : : ne:: ne orneoceo: . : : zea : zea : -:: -orner scv: orner scv

[0002] : ononrneer scovceo: . : onner scv: sorner scv orneoceo: . : sorner scv : -: -: - muan: - muan orneoceo: .

Claims

as cames: orneoceo: . .osve m reoenn aaen suernrom a -exressnumor aseo o: esono areamen w -arenreamen,e meo comrsne ses aeeenrmnnneae ann aseneenso rensoen ces o aaen’sumor an eaen’sumoras or mo o -arenera remen . e meo o cam, wereneera ae- anenens. . e meo o ca nenenss measure ow comer. cem m, werene anenenss exressen moecueser .ocee m. exereosso on, c oarm mo,e wraee-rene ces e oxresesoan,e onr’ msoumeroare a-re casse asavn orow ow exresson, .an,e m moe ex ecores ue oso s cn ea. rm ce, wmoerecen,ee moerae e-xressons ex anenensreaer ens, –, moce,e moerae- ressons anen , –, moce, ane ow exressons anenens moce. ow exressons anenenseweran, o.r aove, oer meeowo a o creasm, werene ces oeaen’sumor are casse asan a,arene o o exresson assocae w aosve resonseo - .osve rees mra one. seoo o cam, werenereso o exresson assocae w a , a -arenerasne rane o anenenseween .n osve ree, s mone m seoo o oce c.a-ma, werenereso o exresson assocae w a cu-o vaue o anenreennseraa seasr caaecsu aaoeua ao meo comrsn:eermnn areamenrom aouaon o non-resonersoe samereanm oe rnesnon a searso -aren manner, weren sasca sncanceseermne aes seecerom ascraou s connsscannoeuen's-es,e2-es,eann-ne-e orneoceo: . c s,erusa-as-es, ane ca.oxon ncer,re- me ees. neoa ov ceamreas, w caenrceenr, ceooareecna’s cuamncors a soumor seecerom ovaran aenocarcnoma,ancreac cancer,asrc cancer, meanoemr,a n,o ann-s emna ceun cancer,un emaoocaumor seecero omera carcnoma, ors a ,ocuarmomam croncmocceuema , mane-cemoma , an marna-zonem,oamr-cemoma ,use cemoma moma ,moasmacomao,cerransormaonmoma,ur moeuema , acue meoema, ce non-onmoma , acue cemoma, anaensrom ma uema , meosasc snrome , me.o co mmerosn oreea semesn o o:a a cac enroceeroauennem sua.ernrom a -exressnumor,eumor enneaen asrmnn anenensne ces o aaen’s eaen’sumoras or m eo resono a -arenera remen aen as noeo resonoo aerae-- anenens or enne moerae-ow orow arenera remeneaen’sumoras remenoeaen anenens anc amnsern a -arenera remen, weren ene aseoosve resono a -arenera . e -arenera remen comrses a cmerc anen receor se.uence,e an m aeno- o ca smne-,c waner veanraee cramemrec anen receor comrses a sna oman, an a coasmc nscv aransmemraneoman ane c.oasmec moemaon c oom crasmoman n,. weroemnane ane c-omrseosm aan,e snara seuence, a oman, ane n nsmemrane . an ae meaevo c oan caemom , an,a wn.eeren ce an- scv oe comrses a can anL, ane cH Lomrses a seuence seecerom s:,, . e meoHoom crses a seuence seecerom s:,, an. L an aeav canaHm, an, weereLn coens anss- essena scv o o a seeuence c soemecresesr aom cans:,, an, ane consss ess orneoceo: . anHena o a seuence seecerom s:,, n.. nee me coan o cam an,e weearven caen an-, an secvn oer coemrs comrses aner werescne anLs sernHes aormuaxyn, .s:,,e meo o cam,e w.erene comrsese seuence seecerom ro.me m,e ano o. cam, werene consss essena oe seuence seec macroa meos: o, e . e c,am, an, w.erene sresenn anmmune ce seecerom a . ee, m ae coe, o a n caaurma,e wreren cee anm amnunneu ccee n caomuraer ce. mocao rses an armornenomcna.cvaoen. n o m oeneo or m oore cammmune, c wecereonneene a,r omr oonren or meonroem recu maoorceaneo snee ccomerses erou conssn o rom , , , , a -, ,m, , , , , ,na.cvaoen o meeo oe cnaemn ann,ser we.rene armornenomc mocaon comrsesoc on o an -- uson consrucnoe ene .us. oun coe mnee-roece oo cam, werenemmune ces enneereo exress a memrane- . e meo o craumson, wroeerne,n weeremnmuene c ceonserse seecerom- an-. armaceuca acc senn a comosonncun a e. amoune o meeo oe caame 6 exc, weenre. 8nemmune cesne comoson are - cesnn.e amoeun meowe oen c×am an 8 w×eren ce 9es.mmune cesne comoson are - ces . e me ooew oee cnam×, an we×ren cees. - ces an - cesresen a a ramom oun ae creoxsmnaee co:moso-n aore a m-xur.e o. e meo o cam, werenearmaceuca acceoarnee exoceo: . or more o caroraes,noranc sas, anmcr cen comrses one acs,ases, waer, a oa aens, anoxans, suracans,uers, er coos,oos,cern, veeae os,osos, suracans, suars, movanozseo s,u aarosn, ac aco,s, e msearnneo, s xuarso,, s muaaroo,amcerso, m, xonoo, soro,ranos soro, aacose,ucose,-mannose, sorose,saccares,acose, ssuacccrosaer,erse,aruocseo,se c,e moaoossee,, coorsacec,aorasess,um ra cnoorse,e, m soeezumos seu, maea,ooeaxssrns,exrans, sarces, crc ac, soum . e meo o cam, werene anmcruoma n araeen, an soumosae. or more oenzaonum core,enzeo ne comoson comrses one core, corouano,eno,ene anum core,enz acoo, cernum . e meo o cam, werene ccoo,enmercurc nrae, anmerosa. rom ascoramae,u omosonurer comrses an anoxan seece ac, monoocero, ae roxansoe,uae roxouene,oosorous soum measueroaae, soumsue, soumormaee suoxae, an ro.moeso mreaeos, o. sor caamn es,e wrs,ereecnne, comososaoncuroenre cso,mrossesa a sureacaan seece a acs,a ac esers a noamnes, . e meo o camn c,o weserero. seeceromo mesuoene comosonurer comrses areezn aen . e meo o cam, werenxee comoso annureor comuman aumn. rom one or more o mearaen,roar rses areservave seece anoxans, cean aens aen, soumenzoae,enzaonum core, . e meo o cam,,a wraeerens, corouano,eno, an sorc ac. cancer,re ne neaen’sumors a soumor seecerom ovaran aenocarcnoma,aancvreearce caasnc cear,ncaers,r cco caonreccera, m ceancer, non-sma ceun cancer,un emaoocaumor seece anoma, an enomera carcnoma, ors a ,ocuarmomarom c,roanrc-cmocceuema , mane-cemoma , an marna-zonemomae,mcomearranso,rmause cemoma moma ,moasmacomoma, ce non-onomnommaoma,,u arcuemoeuema , acue meoeu orneoceo: . cemoma, ana ema , meosasc snrome , o. ssemec meeveor, oa creae nmnsro era,m w m evea erc rerono ,neu ra an mumem scnusa. aerrnevesr se,encreavenroomuseevreoru, conssn ever,nravenrcuarever, sucuaneousever, annraermaever.nraeca com.onene mae enoa oes cam, werene comosonurer comrses aever-mn ever-mn comome-reease,eae reease, or susane reease oe comoson,e so rooconmeenr.s seecerom monosearae,ean, a semermeae marx, an a ro.m-,e m-e,o o- c,am-, anure-r co.mrsn amnsernoeaen a cone seece

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