Date lg [ .

20\5

3. Enzvme -\inred recegldr,

JFwrc+iov1s Os 04 enzyfiQ/ossocio{ed \^ri{^ encyfirs +ho+ +hty qsri{rtg.
a funmed h7 s\na\e- qoss -trWrsrvrew,lsrune poteMs.

J How lfgmd-roind\nO Outrt(Q +hQ cel\ ond O cS+6\V+iC /enzym€ r"ivrdin3-si{Q, Mstde.

G - p*+",rr-linKe( tpcep{ors (gpCR.s) / Sevn- Tronsrnemtmn?-- Hs\ix Recr?+ors ('7Tt1 receetons) /

Ser?sntine tece?\ors
t \e lorots+ f,uvrnit,1 of ce\\- sur{g\ce rece-ftors. eytmce[utor for+ion

i Eoch iS rnodt. oe gt slne\g po\yfp}\do cha\vr +hcrr

N
{\\wod,r \oocB crd Srrq ocyoss +l^e \ipid b\\o8n

I
5gvtn drI\gs.
'lhe cYtbptosrnic
tor\tons 6+ .rh€ rtcefrbyls W,
i[[3
res6nsi\r\e {rr Jlltlt,ll
Urvrc}inO s{ lhe C: fro+fi,, tnsid€
tl^g Ce\\.

a Umnfu lj,'nd\nC +o +l^is rece,ftoy ru/itt ac*iva\r- +he

G-p^rctn, whlcL AchWt\eS d^ g{q€c+o cra2ym€ +I^at cyloflosrhig ?orrron
6€n{fnf&S O tecond f!/\esjenr€F.

G -p.o€rn coupted
"e"epto"s
a Tnrrr+riC rnotegutor ortr?li0ieYs L*,P,T s\)tunrls, ordl ore liriol-linred -tvrus nr,rvhkule Uov$d)
d blnds .to 7-irq11:,,6n^tyq,\q r€gef,hoys
^
oh {l^e utTtssotiO s\69.
+neeftd^ o(*iw{ibv1 -+ s\,ud^e.r Crp +b GTp + flissocio$on o? o- ltgw p7.
-rG en+arvr is a rnotecuh. svri\ch. when ii UinO" to 6DP, it .rwrkhe.s oe{.\theni{ b\rrds to G'tP
it sy*ches on.

GDP 6rP
oy
Gdl
t GF Gpr GA
G"pI

fLcqtar elkottrs

L6o
 Date t$ . tt . 2OtS

1. c AMP sisnoling

2 . Pnosfr.ottdvl lnosrtol siornlinq

G groleirs ocriYotes {he gAMP p*huroy

sigrsr[ motcDqE,

-r G ?noerns "bv\o[ roy

1!" !i1lt
;rrtEii o€ o,olic-A{trc*e nrooglrcfsote (cAt{?).

r ?ro*rvr k(Yrqre 15 ( PrA) {v€dhf,s rnos+

XgYotti e{Ctc*s o€ CAVI?.

PKA

C{TCEOL
Exe,\fte oJ ctU res(oh*, rcd\ohd b,

cAttP; e{rvrtq\r\rg
*6pi\sfhYihe lints .to alt p-Al.errr3ic
recQftlF At oolivu€r {te 6 poetX.
r- the
r4E (q YtrO+.rn @t\usc .ths
go+lh qcrlu$6 .r\+- et*ccrys
e€&cr6g
\
whigh covrv{Yts &'C? to otu'rc Atr? r
I
o.d inoair0 ?KA +o oc+ive ?KA. I

e AcWo{(s o\\c6$h phos?hoWiore ( broKs I

dovn 3rycorrh *r 11" :,lrl I

'f,rr ft\UrLtg. I

drur$otsl

nrw f"0lolh

t-l :3i ira:

1,6 1
I-\
I

f:. ,

Date lt ' t[ . 2ot6

G gro+ern oc+ivo{es \nosito\ ?hrghdi pi{ sisnotin. gothwory

tD ccebloho\ine r voso0er$nr -$rrurnbin.

Enzvme-\inred S,ur{ucg rec-eptor

+FUnGionS or U €y1e.{{ne i+ i{ recefYB st 5igncr\.
+ A {rsnsnrevnLvOne rec€.,?to. Whe}e +€ bMding 66 oh el*}acettvhn tigo1d coJes ehUrrytoric.

oc$vitv oh t\t ihtracefl\,tur sid\g.

* Exon4rS
- [ecegtqv' dfos\ne KrY\os€ I fhu:f,norvhr&s sgec.r+tc +yvosines 6n O srrvrot\ s4t o€ in+rercrcu{r10^

sigvrq\\n5 ProteVls.
-llvosrvre-ftrOr.e +
- ossocigled receehrs osscciotd wirh iQvqce[vh^ pro{e\ns }hr f.oe {.rrOsi\e
Kinose qc,Hvlty.

- ReceVfurlife ttvosrh€ phorp,nroses .+ rews'f9 Pnmfiole rynfS &fn lVrosine 6+ ryeci&i.,

iut{rusqNk. slCvrOtiyg pro{trns.

-Recr{to. Ssb.\ng/+hyefhne KiY\Or$ + ghurph6fytorqs speci€ic .-9true.l}hrcgnry\a oh Assocra{€d

ln\cnt ,erE neAu\otrurl (\trirvls.

- Rece.ttor gu0nyh/l cyctos +{ts g'odvottozr o{ cGMP rn +he cvtosol.

+ ca{dlvz.e,
- hiStid\ne-Rrv$-O6soo\Otd he*?^""S+ ucwot<t C Z-cotqurevrt siCv\o\iyB ?o{hwcr.v in whieh
in whicla 4re Eihoe (vrosehoryforce ltstlq sh his+iiline,
*g {.1^en ifnn*iltq}q{ tYonl&rs {l*, florfiqp ,o G recond

,t**6glhtth, sioao\$5 floturtrs,

; eVhdoUmC Jromoin qc{s Os O^ en?r/'{\e / ftrtvs o cornftex ur*lr m$+l^QF trbls{h lhnt oqs 09

O^ ena6nt,.

MibOen-aot,wttd Pvotdvr K'tnuseS CI'{APK)

i prtAcivr Kinurts {t^ok 0r€ sfecietc
o*it*-6gidsi serrYtt, +h'sOniW, a.,d {vrosine.
+o
-n thg, rcgu\orig c€t\ {rrnc{ion= i6"tvdi\5 ProtiRrotlovlr &ht er(tcsrio , dicfto&iotton, rni}gsis,
cett r\,fviwlr ond ou0wtDsis.

['4APK -pv\o{h0vyto$0n cuscod0/ Mner "iorntrho 0o{hr,roy

a kfK oc*No*S Gt?-lindins ?roteih RAB.

*ROS is o n^on0m^sAc Gg.t- hihdino ?rvte\n (a. srhmirt oq e*,tmrn)
* \,t*$ oclivof,{, il prno8l 'lt6 Gatiwtt$ oe o ?hos{^owhr{o cssLqdt- i} cart,'es o signu\ $op +t^e
?\cmo to {hc nuc\eus + t1A?K oosc@.

1oz
 Date t$ tl . zotg

t RTK biwds r.rilh {hq Gtp, ilirns.ize, ond *Lcn outoqhos?horytolEs. drnpnee , cow,b\y\B Wil\ q
st*tgcrs SR$2
+ {\osflhot, $mr\or fo {$rvvr q drfYttr
4 qR92 tinds $o &AS +u,teh gei. Cr..o. CtO I Cr zOz)

,HAPKis tut\r{ tq+hoq*rd lve +o \{.e goccrr sls\e.

,I{APK ttca,wg tt^a tr6rfiqlu d,svr.r rL*, G1? o,v{osted {o +t^t tTK, sacou,.\n, nctiw.

JAK - STAT 3ietro\rn$ ?othwoY

5AK

4lcnoun JAKs + IoKsl, Soksllr xor*3, {yK2 O.l*,

6Q cybnlhg sicl^ots.

* Erv+hro?oietih CEpo) is o dlqogyo\ch +hot c-o^hnts RSc A'tdoctwt + erounge 64 JAK-S'IAI siarao\tho f0thuov.
Fir .! :rl ).:i5 iir,i,S

163
Date l$ I ep\6

Sorpnd fY\esghoers
-t irYEr\ r oowPOte\Y\, hlu{cf so\uUe rvrot€cu\€c 0r \6Vr3'

+ Cqrv\erotq divided into 3 gnrrys;

1. Cvctic nuctgsr{idgs CcAttP, cc2$e) + hyilrDohi\ic

L.lnosrtot'i-thosdnore (tt?) oa; dtucvloqcemt COAO) -r hvdoVholaig

3. Cu'+ Ccotcitrvn tuy)r) + hyar.fv'*t"

tnsSttol lrl{r5 -ttrn\osft.*1g C\P

cAmP / cGMP _ _cotcr\nq !on- 3)

Dioc,itot{G}"l 6DAC)

1. Cyc\ic nuc\eotides
0. cvctig At4P -, Hn+L€,ri?.€d {hhNsL [*er*/Vl cve\qse .
ah6rvnon(5, .{.at use cAHP inc\r{€ ihs,h, g[uctr 0h, Ulgtni?,i!5 hOrrnone CLtf).
: Brndinr of *hoJ€ horrysaes oc,srotc G rt*c{vr I which in trrrn gctiro\af 0A{ht,IY\
t.l{ct0't , rcs\$}\n, i\^ .l^e, ni.rg O{ CAtt? wh\C,h hrns 6n *\t- qgloyrl'O\e
raIV6nE i,^ +hO cerr by e.{il.tr/b0\.1^,
- clsovg {Lc $ levth, oc}trihes ih *h€ Cvbsol r ofIn 6in5 pKA - n cAil? .tttand,ert

?{)run kthqDe g\0,r p\os&o"r;\u{e-9 {q6e+ p,Dtefhs.

- Turnitl6 on .the 1eu g61t+qr!., &n Sone +rwcrtvltM.
tt c*lt? induci\\e terre ax(€ssion:
. qc+iYoltoh o+ ?kA
a cREg
fios&orvtqriotn
a gygsssl0h of cl,tr? - indrrs\€ geneg

I6+
 \laJ.

Date tS 20r5

- Rebutqlio'l .* PKA
I \nOc,lrvg {rrm of PKA connstu of L v=.grrb1ry 5lbuvr*J m( 2
CPlqtVlte un\ds.

r $inilrq of & +f'€.

cAM? s\io\rni\s 'rtrd\we"r .the dtssoctqtl6[^ of ,{'€
Co{alyttc 5,1LrniU [rm fcoAatora1 sG$vt*t; thc ocA"\e {onm of t fA. is u}evr
^l^e
l|p aafsk+tc sudyits oe re\qftd{ {,!w\ +\"e rearh'ury srtuvr}ts. TV€ caral-rtt(, w\it
t\en ,oes +o $e. huc\eos.

b. cVctlc Gt'tP -f Nn$csiz"ed ${{n GV\P un'y\e suqhv\vt tvclose.

I ,ew?s Or O lecond ,tg$cnt0r o€:
- qtriq\ rs,Irrutstig foo$dg CAN?)
- trihric oriile CNo)
- rerfo^.B oF f\9 ftdS fo tl^f, rQf^hq o€ *lrp 1ichl.

€ sovns e[€tc}J o+ CGHp dre ,r,.Bdtu,tA .ttu,uusL ?YA , o C Qtt? de?.{nd<ht t(vote.

2 . InoSitot *ripVoseho.\q, (t?r) qrd dlqcvlgtycen l (DA O)

1. \c- lilonA n6n- gevqlentty bihds *o +I-t-

Rst&!{* ucl{.{utio
rtfr{\r CGtcf<) , * qe{Naros i+.

2-. Ge. ac+yatd nece(*6i\^ l"ltlds 6l+v, {he

G grg+ern Co*4oc)*{r 'lo t\e c(-J\)tr'lvri{ ), 44n4
e*c.l^o^9c d.€ GOp to 619 occ-ufs. '\he cL

SrLunil di-$octc(\cr {loy,^}he P O"d' f, svbuvril.

a. lhe- d. svbvn\t bind,s ptlh on qv\alvhe

Cghosq\"otr16g C) r &c.r.rrcr\s +he e11zyrv\e . OLe

iJ ut€4 )6 Airtrl ivr +IL
I
Ac$vlftun o.{ Co}t C3\\ '0.€.fhbY0^g).
ghos€no\fid,r

ehorngb in rh€ tt.

etrdo(crmtc'rltcrJuYn ActiVoted PLC tJ{et ev\erty{o Ureqr 4Le bohd
be{rcen .ttg Leod onq +ur\ 0u(l o{ +he
enarhe I fr}oryLbri$d

nomd ?hos*q+idyt inosi+e1 r[, rr bipy6l?hote

Tt'-,k* CPIPz) - the PLC love6B 1"sx6g te+utt€h 4hg

oxv6en @ fhusghgrus 'rn ?{P1 +o rt(oro\e
+ht, tqi\ ond .tt.e kqd. the resU\s qre

DftG 0^d PtP 3

(.secondoy hesreh6eg.

5. t?g rettosed &otnthe cert nntmtron€, di+.Ssts inl-o +\.e cybsol ona bivr6s ao .the Cqrt chgnlet,
Casinb-t\g g\6nret .to o?en; CqLt is ne\tctnil rnio {no c,j{66o[ (i"u* +hc PR).
6. TLt re\s06ed Cqtt tinds wrrh Fnrern Kinoe C (?KC). P<c birsg y{i.th DAg , eeerlorin5 1;" pKC
'useS .to
N\nich is thosghovrp\u\e Qvo€\n.
tet
j\lo

Darc t$ \t L015

1 . hhen {he ?yo{ervl b\nd6 w\th PKC; ?KC tol49 tte eu**!o* .tnm ftIP r ?hosdnrvlultovr occu{s
40 th grote\Yl/s stde o\qr0.

8 Re\eusrd Co"t bivrts tD co\tvroduttn fcs.\ciuu mod$o\ed lrotorn), 6hich colsts 0 co{{ot^tm\ion0\
ohonOe lo occrrrn .t0 ph,{.I{-l , Seve.q,\ cg\lu\qr r€f$$es ong flt{rtcsil: fnd'nonl, o'fo(}05i$,
^Ie
iw\Y\,\!\e feseor\rg/ rns\abo\Bm.

3 Cq\crurn lons (Co"*)

a \. Q/bcess ir inteoruted wi{b \Px ond DA8.
-r 1he nise o€ Cuzt con .rnigSef : 1. ttuscfe con+roc*ion
2 . ExoCv+osis (e.g. re\€gsg o{ hreurc{tunsrnit{tr5 q\ -ilg s}rn6ps{)
3 . A.,tixo*\vr of J cer\s ond B cetts.
4. heo'erris
S. A rorietY of btoohern\cA\ cho,n.ie.s fhtdto+€d by PKC.

?hosehorvto\ion Cqscode

o
gronin (inose tl
Propin- OH + ATP Pro{eift-O-P-O- + ADP
t
o-

Pi H,.O

€l\ony cq?dmts qye regubtcd bV covn\qt ot+od"$0^ent o+ fh6cf\6+e (in et{rr. tihKqte ) b +he

sidq-choin's hy$,oxVl Ooue o+ o go^+rcukr orvirr6 gci& rerioUe (Sen, Tht or Tye)
LU o gnleivr fivrre tYS^se\^{ +hg prwr\0\ qhosghq\L Ot AIP to a
hyd.vUxyt grau? or,r o grofe\h.

Lo A gnl$h (h(Fficoe, co.\otyaes refts.tu\ 9.F -t\e ?i by hydmHsir.

( A reloy nlotecvtg oetivgtgs pr,\,p\h Kihqse 1.

1. Aeive ?ryern r\nore 1. konser-r o ghocrhqlc Sorn A1p 1, o^ [noc{\ve rhot(cu\t o t ?ntetn
ktvrsse 2, thu5 qc+i\qt\ho this \econd y-$Sse.
j. Active. j,o{er\^ Kinose 2 +l.wr co{OtyzpS {^e fher$u\\0\b[^ ond octNot\0vr o.€ lrstih Piv|ost 3.
4. FivrotlV r octivt' p,g{e,n Finqyo 3 evror'Ohonlloltl a go€tn 'fl.at brixrs abouf *Lg Ce,rt's cesf Ovr.f(
+o rht, sisnq\.

5.Enzymes gqttoil Wb\.tih thorflno,toses C?P) cotetvzes .tl^e run^$ru\ oe 'the lhosthqtt-
$rouos &om rlg,
Pb€rhsr r$qK\n6 {ho{h lhqchw md orfoi\ot\t fon fur$g Feusg.

164
 Date tt \1 .lOtE

{hm6orltut\on Cqscode Stegs

qctivq{d relst
fndecutg

?hos?horvtoton cosodle

t
APP

J
lr0--'
DVsfunetion of
Cet\ siqno\\nq \n d'\seqsg
rt the reseonse h q \\.Ier cBU to /etinSlr:tY=..
-g-t$cqgon
Ge liver ce[ restonfu +o 0\ucqron/e$nephnin0 {rnoruc\ o G gne\n-coud0d. reqc+ton CGPC-R), ond

sA$,lP. ltre ?KA rhos*rovyblccl ochro{c1

$q(orvtase K\v\ose," whicrn t" ** s\yeren
"i*t
thoseVroqttsg 1'r,rtrich roreuk dowt g\y1,qrs/l ivrto glucose), hd rv,oeltwcs ot{cs"Qn stnthute.

* Endgcnne {isste in {he ?O0Cfeoi +rn odd\{ton +b eroc\.ihs/ocivrm c€tts, +hs pohcreas contqihs
evrdocring +\ssog g$m,'stin6 of rrhe istet 91 Lorjohqs, the iskt covt\orvrs sertrql dteererr +nes o€ cc\b,
eorl,,. of which excr,e{aS 0. sGc*ic gstYttp+lde hsr.tones.

{*n - groogov\ P a.U* ir\sutin 5 o,, -r somoos+s+in

I -,,r.-.ll'4, lr ,'J:ih laAF 1 ll,l/\ ; li iLr L,.l ':1!

167
l'l c,

Datc 10 t\ 20r5

* Rqu\o$on of gehe e'/Pre})lon bv insu\ir\

1. lnsu\ivt r€ce0hfs bin& insutin ond unilergoeS 0$tDfut?hory\ott0fl orrr i'ls coYLoxYl -lerr\i\o\
4yrosine residves.
t. \nsuhn necefbts f\osgVorvntss IRS-1 sn i{s {yrosife rqgld{e.s. (tRS = inqtivr recefhr s,rb*vu\t)
3. SH2- downin oS Grroa binds +o @Tvr o{ tR5t. ges \6in0s *o Grb2, +}€n +o Rus,
Crusrng GD? re\eose o^d G1P l,\nd\n, 'lD RqS.
4. Aei'Iokd tqs brnils ond gc+\o€s fcF€-1.
5. R$-f ?hosehontlOtts tlEK on 2 ser\hg r€Eroues, 6c+'ryo$rg i+. l'1EK fhosftro\tolt,s DRK
oh o *hwonihe, ond q .tgrosing nesiilv(/ 0eriyc*\ng )+.
6 f,RK mgv€s \nb +he n\cteug ond p\osphorv\utcS ntc\€o^ rrronscni?lioh foanrs srrch o9
E\k 1r octivotrvlg +hsm.
-7.
?hord^orVtaed Etf l Jo\ns sRF lb sl\rnUlnF t\e +ru^schsf+ion of u sQ,\ of O.cnes

needcd $* crr\ dtusion.

Ac,tiYo$o\n oe g\lcooen syvythus€ by iNu\in

1. lgs-t, {he insultvr Fece$Dr oc-tivo{ss Pl"lf b"l tindinS '+o ils st12
?hosphorytotod bv
do$orn. ?1-ar cov\rrfls ?t?, -+6 ?t?a.
2. PKS borrO +o flPc is ?hcsphonrhlea by ?DK L. t$s qc,h{oh.q , PKb thosfl,oryuws GsK6
on o s€r.\he residve r insct\U$nb i+.

3. GSK 3 , lylqc,n\rqled by phosghoyto+ion , canrn$ coh\tac+ Sbtcoleh Svhtlot CGS) tb i{s

iYtqr,trve ,sf* hf phorpln6rryBllon , -ro it rsYna\v\s oo,livg.

4. Syn*herts 6q g\Uco6e$ .[,ow, gtvcce iS occt\rro+ed.

5. ?Kb 6lriw6*" nn6Vgrrnenr of GLUTII {h$^ ih1qrnq\ rhefy.btr,g vr,sic\ts, lnct"cqslylg +\e
ullore oF olucose.

lnsu\in-dependent diote$ netHus (Tvpe 1 DM)

4 the cu^9th[q\ dtJthrc+16\^ o+ a\t- $-certs ut +he pqueas:
YolyvniU (osvotiC Jiurgss dVe & erthce\turo^ hyQero\yc.eyvliq o^d glucosur.io)

Polydigsiq (seor fhrnt due 40 +te tos of sqrt ord ,role")

- Loss o'Q wtlbht dve tb exrtyrcet\ulo^ {tu\d. wNrW CECV) Aegle+i6n ond
.tht tvcqrdovvr O{

lissrre xhres ( i.e. {"e cq&oLo\\c e.fec+ of \rn:u\ih d<Cicirqgy) vith r*pid v,ns\l1g.

- Dioter\c Kttoocrtosis Co{JeS by incxosng hept\c Kei$o"esis.

Non insulri[t^de(endenf dtqte\t-s rre\\hs ( Tvrc 2 Dn)
a $-cet\ dtEc.Ls incr,rd\n, oevretc d(&cts , ntxttr\hl rh oLnorhnQl ivsO\nn qvoillclion'
) lorgtt Le.tl dcQs\ s inctud\vr9 rece9tsr {o\\ure.

. -)roc\o\rJ inUUde obesi\, the tucp o( e{tvgi5s, sod tleqhslcY,

168
 ill
Daro 20 . ll 2et5

* Tqrqst Le\\ mottu,nst'br8 'rv\ Dyl (tv?e 2 )

+ \nsu\\n {oc0ffiq de{ecrs rndud€.: tRs'l arDva\n : P\3K oc*\\Aq
: t(S - 1 +tvosine pvosphsry\o\\on I GtUItt mRNA ond grtrcrvr

* \nheni+d dtru.dgr. rt\o{eil {o D}'1

t'\u{a+ions ft.\oled fo \nsrr\\vr reteore 0^d tiorVn{hes'rs"

i t\ulo+ion o€ S-c,etts hc.rtoK\nose lV ( l\ucorrnu*)r \^,hie\ il€\ecls e.xltrho\ Q\rrcasg + ftdvces
'iq5{\ih ret€flre.

4 \\u\ot\nS \vr \e Kir" 6.a K" chOnvret/ ASCCts su\VhonV\uv-ee r€ccpW7 whbln c.ornstr\\or{. a\e
A1?-r.nsi+ive K* (KA1P) ehonn€\s -+ redvces 'rhg oUrsH oA A1? +u d€po\u^i?U +\e nevnLr.the
srrQqicie.vr+tv {o +t'tofiv. $s re\eqse o€ 1n5v\ih, $$+q\ig\^s in ABgCB h6/e ue€.h idtv.l\Qiet nn n 66y
c05es os ntAh$\(|\ dioLprcs.

j !\U\o,ttong O{ +\e tttrscnt{t\on locttr ht?o+ocv+e nvcl|eo.. {scror 4 * CHttF 4 a.) ; r"edvciyU t\e,
S{nt\,esis ot \hjo\in.

ilt\o{ro^s relqpd 1o -l[e Oc]iov\ o€ insurin :

f \e o+ 5yc\tkqt h{s4e b\y65rrh fne,rqto\(snn is re}vqd ht o nonreWg fh\,,\O\t6h ih

\rrs\in Ontlot
+t^e tot GA? cq\ed Tbclq4
-' fttve,s .tf.*- -tr"wvtocnlim ot 6tU14 {o .the ftcsn'u rnr.yrntro^t De

sKegls\ $^wclg , co,rs\vrb ihru\rh r€sulo @.

* Cl- ohqv\ne\S
+Chtotihg (e cr ln$or sei6h iyl cetls,. [+ reeu\ults rnevnwnne po€ntio\ ond Cer\ \tD\\,t/h{ regu\o\ion.
) lyps of chtor\de c.hqnhsl ?ro\e\hs:
- Co2+ stnsifive Cf chonnds CCLCAs) 4 smy c€\b eyQrrss CLCA9 +[ot rerUcnd O on ihcveq,r1,
tr )vttrqce\\utu. Cu-+ tY qoliYo\in, q C\- cvrr€nt {16d+ is e\+ht-r ivrwrd /orr+t-o{ , de{end\no oy,t

4l"e Cf egvi[b"Wtn ?o\eo\io[.

- Cotion - c.h\OridQ cotrmrgorltrs
- cuc chtoddg ch$vre\s o,'.a .+ronspor.ter5
- CVs+iC FiLrosis lrunrrvevnbrong Condvtlonre tqrngbr -> O\l"Us{S, int-*ina1 -tvoc.tS, O,rd dvc*.r ih qg
QOnCeng r Sr"/€ot 0\0rds r ord ,nor Ae&leru ohq^ne\
I vhich corndvc,ts on\svrs (Ct- o"d RCO a- ) t\ot
coh.thit)r+g to +lrg osrno.tic, oyodient Orodien+ &r. *he grot\t\ ttOU Ot b,ro+ts - ABC {6rug6r+r.
- GABA recef{brs
- GNc\re re€?tbrs Cg\y Rs)

x Dt{<rts in +\,e 'iorr chouheU cnd -+ru sfonltrs co^ ue a coJJt sQ ivrhcritt{ drreases.
L? tnu${ow ih tle CfT( qeye Corff,,! CYst\g {iLYOsr s i reru\\ih5 \n lvng c.Wutst{fi O d inRc4tonS.

L6q
i\C

Daie 20 It ')s15

j Csstiq TrbYbsrs CcF) is 0A a)tDjoYl/o\ necestiy€ ,ehetic disondcer due +o h$ro+lDn in d1€ Cf-1R
genQ, euhich rgo\l\u{es C\- lbnrfont into +he -Il''e
cel\s. OevP €6rn CF T( is on 114\ '2-

Or3*ns afiscM
by cyttic fib3rsis

F*ncraas:
bleeked
tla;.leses:r{: dilcls
lntsstlr:*s:
ccnn$t !ull}'
ab**:b *strents
Reproduciire
orgtns:
{.'?}gre sr!$ le+:a!c}
r*mplr*a*o*s

* Lun5 \neclion .$rom *he oLsence oe {he Cf 'r?. ?o+e\n

a &Sft&if.{T
a a
Vl ?-: rao o ao :ot a Ft0$sd
(
o rO ::?
J S
g-
E o
0a F lny{ll qq Pq+\norevfC
o yl
z t
\) boctcri0 (b\D{i\lu)

['tz0

surt<ndd
boc{cr{e
hvdmled mucoos
\o1cr
x How the chtoride chunnel worKs
) cAt\P s+\hu\otes 9KA .tb odd thorfigAe grou?s 1u 't!'g C\. rrgU\uto! dtrtuin.
"1'ts'f\ntl's
) ATt g,x6, 1" +te Cr- chunntl, frO iS hvdrrtvz*d .to ADP + f i. \is cqrres the shoge oi
CFTA- {o oh0^0r / o{{r\\ho +he Ct- chqnhct.

1,lc
 Date LO ll . LO|S

\_ * CFTR dowroinS

TttDC+tonsrye{nLru\e dom\n) -t towvrs '$,e o\onre\?ore o\lovin6 cl' {Ir^r?d't.

NgD CnuUeorrde t\r0rn9 dorrro\n) 4 binds AlP
\- Regututgry dO.mOih CB.)-) regrilotes +he oho$€,lr ufo*lhtriteqtn-slctottsi *b qsriva{B.t}€, c;ronnst.

* Mony gF rYlutot\o$s oct,vr.ih NSD1" i lnc\uding d{€rion FsoB, white {eu4r occur^i1 NgD2.

\- *' \mplicotlovb ovr *Le s$eot glonil

\_ A CI.[R Ylu+ortoh Ce{s$c, Sibtsts) rc"sullE ih o d1s.(anc,ho$01 *ut1 oLsorftion / ft.$r$\h0 ih
h*lprttoni,C Sufeg+.

\- * CFTR in norfhol ?o creq5

+ gF1( ls locotd on r\g oqtco\ rrwtn\ront of 'purrtqnL drorr cct\9, ord ?lcr{s o lcty r6tg. iyt HCOg-
Secrotionl it"ele\ thqihto\urnD {c q({ro0r\ole vo\lhe ud qtt of t0 .aolrc se*e.{ton9.
\- tNotrvtul e*ocr\hg fig
?o^sYtqr d\tc{S Ur+o^?pd lnto ctus8ns -tLo+ t4 rsrpv1'ird€ fr* poducing
\_ cn2r{$,\ts h diq6tt trsliryrs ond Up\ds ih 4q" 6\,Oflen$yq.
e oFTR seclttr.s ct' od Hc,og- inlu *L€,. \5vn€n e.€ ?moraltc duc+6 , tvrorru6lniyrl .41ng esrr€c*

Olko[ih9 ?H lensun'1og \nt Sto5nq6h iS tevtntizga q Qcncneg*Ic \*CxrbonoA4.

qctil Ond +l,gr] 6vl

\- O?+irhot envlbNrent ig CKo+td &r .$g Or*ivtty Df, ?o}\cl{€t$C Eyte{vhqs.

* lmsic0hons o[ CF on +V\e qorloros

+ nqsuus in ef ochine gon(Jdctic i\s0.tctcteht, md cu^re?v€n$ut molru^ri{ion.
\-- -: CF[Q. d.{S$rrrgttOy. imtolrs lstgr g,t- O^d $CO3' J€cy&tro{t pfe .lh€ l\r{h€h. b,lo*tr socyclrt6vr ir
OISO i{h?o'{reo AVe. .b *hP lqoe At 6 -sr€Qidevrt ojvY\or'r0 AraNerr+ ro dr\ve {he $q{er into
+\^o duc+.

€ This reN\\s ih +\a o* ducts by \rrscruj -e€c)€Aa +aql- plevt,h*s ?o^creo,Uo enarrhgs
obs+rucliorn
\_- firrvn reochlvrC *hg Oul O\il {vrgtUnrvtg of ff, OfrWS\ pH.
t QVtr +vnt, i* con car$, a{te\gsir 0^d 'rn{tuhrnq*ieh oP a\g exoq,rihe fo1gFeo,S tt te,et
lllrto'led; tsodth, +o jq"tlqlaotrr _Iq\ry {o {hn\Ye. &r a cu^rt?veh(e, mmY

ss€Qrerr of CF tt re,\tmt on tn2"rs€ ,L*na?y.

l( Dro5nosiS ot Cf
, S\rcft *es+ ( s+lvnu\ot5 s\^,ec{ e$Auttt0h wi+h gi\oerrrr(ing).
\-- -) c€Tq firuto{o\^ ovru\ysis.

f.1 ru eC .i 35 linea

L1L
I-
I

Date 20 . lt ' 2Ol5

l{ vos+'reniu Grovis
* A drsorger Of reuvDmrlsc'.rton Jvnc\td/t .

-) Avr outois^{vr,hg drsorder - Ue Qod\eJA{ hqs o^+il.odi9s u5oitor ,r}tciF

own qce+ilcholih, r€c.?br.
-) Svm?tovvu iho\Uilg: fY\use\g \reoKneE ( q'ro*\Yhat livh\o , e*waocubf , y\gqg nr\usc\g)

: {iredness
: dit*tcully in liQling tl,'ei\n l,r^od ) 1 fid swattowtng.
rho!*\co+toh

+ [V A rtdvced nurn!€r o{
Resutlcd oc&+yloholi}€. I"tcey{ovc in {hC- fnoftt'e.nd flo{s.
r Anticholineshrrst con tg rrstd {O P}b\ong aegvlcl4oti\e e.eec+ \h *he syna(2j€, +.vnVovanily.
-) Av*itodias Oro\vl'.+ Uc€tytsho\the r€c€V+$rs L\octs +!€, rec€f+!tu @\d decyeases $S ouqil0bi\ry
Ot {vee. vtlefbfsJ inhiloiffnl svnofllc *rrrrrrni$iolr q^d tghce fhuse\e eon+'rUe+ton.

llu\fipre scteros\g
J qn iht-t0fnmctDv\, diseag ln whic-h a1^g {or}Y ry\ye\ih sheo+hs orilvra +\€ axohs oF {he
tuAtna {D o^q scrfrina os we\ qs a
AY ry =4,*L:! lg dCIl,yrored , deYv\Yatmo+tcr
b,aod s$e*rth^ of st0hs Ond sywvfioWrs.
: $tS o+&.c,tr -lhe dti\E o{ hrr,vlr^.s in +Le 6yuiYr ord slirta\ coyd rO con^h^uyricog.€ willa e-acl.,

o*ten e+{€c4ivly.
+ {to bOdy,s o6rn lnrrnurtt. SVser"' o+{ac&S A^d dqfiot7€s .{he rnyetih. \r{heh myglill is [Oe[r 4ht axons
co^ ng tovra<r <,.e€eo$vetY csqlvo/. gt5vrots.

+ lf iS ns* e Senedihry Aic{trp,. Hor.rer(r", o n^flnL-qn o+

f]t*,c ]gllqtto.'at !1a{e @qn dnorn
b inc.|ca;c .t^c- risK o{ dloretDflvt, +\'e disesB.
+ Svnr,(tumS iheju{C &*Dua, corni+ivs in^f0iyyhet/*, dt1rcss64, dysor.+hriq, dysfhAOta h^ant(Y\€ s I r

sfqe.Yrs, P01Y1/ droffhe/csnJ$po+iorl r 6d irrclvrd.\h9vlce.,

-e 1horht +o tc itrdvced bY 'tt.e go^ern\ior,r os TH-t +{fe mye\n-reqcrive Le,tls {hyh Fxcuffo,*
ce\lS ClHQ)r \^i"tch O"o f"rsuvntA +o be 4r.i9.z+CJ by coss.eqs+...e mlrqevE svch qS yinuseS,

LlL
 Date aZ . lt .LOt5

Dt^. lrfet Suriorrusq\S

i fndl'iB{Imt nto?h'Sm ss o{ d(s€qs€s ivr whtc,h q obw Ot cer\s dis?q ureontm\ed

-+ o ol,s

rtorrq\ ti{hits) tnrction Civl+1siuh q^d 4sslvvetlorin of odpcent ii${es)r

IglL(aiutstora b1Vonil I
rmd TounetrwreS 1.l.1e3'3il!:9,€4ilt1 to othen tocotrornr irn 't\^e bo{y via tv,/hth / b\ooil)
limor cneottqs"')'
lllHlrr :f
t 'fi
,. #r*li; J;,:,-*, T'X;J#Rrutv'r
oq ee*s

Necrtosio + M.w orow\h. 4 6 _g1gutt dilovq€)" chgraolenizrd uy 3ene}\[ otterordons {l^a+ t€oils 'to
[OSs Ot -tl1e nonmOl CanAO\ r\ec,*,.Lrrs1vrs th4t r€Su\O]€

md di&'an'lirUiovt.

* ?huses oQ neoptos\0

h,"lqsiW
Neoflqs{q
:?e invfis'r€
-- : c&1g€l^
lreu,rsors frecorcef,
= fttwB\tirno^f, = llrottg^snt

oloeftvu C€oqr dvsttstt\C

-Fotiuafr6l
thr?ert\osiq l.4iurin^lqsioY)

3q
a
?2.
a

\ ,/ ' c]onot exftnsion

"r*,n
nebfi{hotio!.r . l0 -30 veors
/ \
*' Neoflusrrr (Tumor)
+ oLnglrnql fxoss gq i fhe onourrl,. St uhtct" exceedlqr& iq rrvlgoosdinnptr yri+h *ho+ o{ hoy"olat
{issug

lissv€,s, oni jersu+s irn +he sofig exce$'rve wwv\yreh g-P{r l}e casrGtion oe j"e S{w\llti which
evoksd {ne chonge.
i Eenign fumor -t sr*-t\hlre0, doer no{ iwode 0^d rrrdo$osize. * is mitil ord hoh-tygrvesivg? mo.ty
krtnils of \oehiBh &fnoss ate l^unwr [e,ss t0 hest+h.

irlt r!1. /l I :tr tl|,:ll

113
No.

Date L\ Ir aotS

J hre-motiOvront tuwrof t Pre-cd c€rous/ carcinotn& tn situ CC\S)

4 edrtY {6rwr o€ cov(lnoYhq ds$lyeil la.1 {'v'e ohreh€ 6f, invggiqh .a
g,v"qunOlng +issv€s. $,e h<oftsshc selts ?ntlRru& in {r
a'{6q
\rI\0,\ noon*a
+ H6Jy ,fonvnr Ot ccfic{.r OrtO\n6{es dvOu,r q C\s ttsioh.
+ NO\isnont {UmOr + cr^CP\l^t rresdqsn 4hot infoilqs onil *t_*rols +he Surrsuv\ilinb +issvt,s, yns/

ftrn 6g.tgsdtrses, eveoluu\\y fitk +Le hos+.

^d
Heouhy Dysgtosiu/ C\5

Beniqn {umOt^ lvlolr,gnont tumgr ( con cer)

* AvroflusiQ J loss of dfttrrtl1\+\o$dn of cr.tts md oc -t\ti'^ or\sntu{\ah +0 ohg unot\tn cnd tu +\t\r
o(cU .[rorv,ewor( 0rd t"lcod vesre\s.

Benign vs Moligvrorr turner5

* Benign + UI{olly csueiY\td ,lo q S?€cr€io Oreq.
-) c-QI\S simitr ln S*ru*urg {o etls Fwnl V,,l,,ich l\ey origrhote.
J kerr - dtaneil borders
r Sl,ovr qroyltn q^d tiu"tdtd b h ureq

) ?ossr\ qmwlrh disfrscer,.<vrt Ciut not invqsiovr) lo aOiqcsnt tlssre.

u+
 Darc L5 ll . 'l-olE

* l'lo\igngnt t hgil ahc0?51rts+til/ cohesivg , ond 0,. irreSutqr pg+{rftt oS 0r6^,th.

+ ho rgtan l"\mue b +hf Cet\ o€ cri6th.
i ho r,&r\-deei\€d b$de$
3 grwrd iv.to o4lqc{y* CA[s ru$fr {fun disptqcine on pujhihg rher"., 614q.
j na$d 6$o,+h rrtr6gh qq11 dlvisidn 0^t multtfttotion
\_

-t\e, most c-ou\^rY!u\^ tv{s of co^ser/ arites €vom t|-g cetrs {vqt c,oven e{tehnqt and

iwbmo\ bodY sur4n6,gs (e.g.hrn s, tf,e$s{7 [ivtr^, goton;

_ 0.tftots inttfl\Dt 6r,0ng
\_
W Sorcsmqs
LP Qnrnama

- co {r&fs or(sin3 Sovn CgrlS &urr& 'n +hg s\,f'P0r*Vl, \ts$res oP +he body Ce.O. bot\e, s0!sti\oa(,
fute, csrn*',e$i$C ti6s\r9' oi,\iil i,ruscre). Ce.o. So$, \a6ner, rtrrrcttr)
try Lrwhornqs

- C-0'\CrrS 4ttrrt gsrs€ .Fnrn +[re, tgnnql^ noOes

Otd +i$uer o€ {fr€, louty(s ivnvrruM Sys{ofll .
L? Leurg6qqg
- COACerS 6* .t\g iyrvhoh,yQ laood Cet\s +ho+ g'a,u, ih 4t.g td^g mh$m\, fr^d +€$dE +o
Oeo.umutO{+ in tm2e 6urnlera in fLe 669d..1+rrtm.

Norr,ing cq,^cers
Pre$rx
:f€ryiing
odeno - stmd

chondro- coEt\otC

erylhvo- 0O Uto66 qptl

hunor6lg- btooO WrsUs

he?oto - tiven

tigo - {or
lyrnth - tVryit'mXtP

rnst0^o' F$IuO^I Cg\

ft\ye\o - lagYlg fho$row

rnYo - musc\e

Os+es- bone

6 Hot\nnorks o€ Conscr
* Seq - $Jt$icXehq, (h qrovt[ s(ino\s x ihrevBi+\vih, to o*i-6yourh si6na\S
tr etmdin$ ufof'te5{5 rF +(ssve iY\.rstioh o^d mehf+osig
*' sus+CIne{ onaiq6er'osiS x ltrnires s re(\iqq11vg ?c,\eneiul

nnr rule(,'xl5 li[e s

17s
f1
Date 23 ' l\ 2.o\E

Ernerainb hot\murKSr 'tF deregdohn5 Ce\lu\qr enrero<'+igs

t o.ro\din5 \wnrvg gsrrucrig6

LnobtinS ohutoc\crts+ics * 1enor\e ;vrstoti\ifi Od mufq+iofl

* Turrror -prooding ihfto11\mo+ion

The Cetl cvc\e (30-6o n"er,i+;

c*U erDl^,lh cQoer-mi661s;
Qt
GO
Re6,$io{-ron prnt
crtgubtrl b.1 Snowl\ {oc,totl

G1 chec.rjoiffi {ar donoaeA Ptrg

Rb q/d. pSj h6\ts lht cgc\€

l-'l
Nucttur q^d
a.1u1n" dtvisibh

Horneos+usi5
G2 c}exfO\t 6r darturol-
DNA re+ticO+isvr tvrcmr{\€te
GZ [.'f;il ffi ca"e-r''{osk)
tlncontrot\eil qfow.th
* Ce( Proti&v,otton a cett Oeo+h /o&p+osiS

Cre0ulotl$0 of 4t"e Ccowttol Ot A?o?rgsis) I+ *,rnno,r forr,no{ovr cg^q3-r

1
cclt cvcte)

Loss oe nofinul Srow+h confiol

Nofivtet cs\utun
divistoh

co$(Pn ceu
divistorrr
untottt'tt16
oYu/tt^

176 td Lt&/toltr
nr,rtotlov\ f$,lsHgl
 Dare LL lt . 2016

deod ce\ts sheC

o ao 6
Covrc4.f Cet\S ord
{Yu^rfor*d bY +h4
cJYcUtdtDy Iyr{Awl
{o disto^.r s!{cs

FI tt\
J
c.O^13v\ Ce\S
Ejidewri5 invode*raaotnc eo,rc€,F C€\19
+tlsvg O^d lfood nst$ndt€ ord Orcur
diviilrng crls ih V?ststs sl rcl/ toc*tor5.
bossl lqsr urda\int
{is+e

|,1 e+qsaoris

tn+Y0vqss+iov1

frtwrOry +uvY\or
lvrp5te4

h
/ne{o.stosts
'\-z Cston(zo.hbYl
,hicrbfhr4oslosiS

a 11',e rvrovgmeql/sgreodtnS of cg'cer geuf .Fi,'yh me vrA o.€ d\c Lody/6v9q7 +iswe +o s^or[eh
-) UNottV ryeods fhhvoh rhr
btood+reowr/ [yqgh ryfl&m.
t A fu*o" {orv\ed tv cslE *ho+ hos sjveod it cotted
fl':

u fhejrosro{c +$ynors, coh{oihi,h6 cetts +h* tre lik€

trnose in {te ortciv,gl C19irng\r) t\Nv\Sl
* \r*r0vosotion
- l$rqsiol1 of ccncsr Cf\ts th\Nrh -tte Lqss\ rwtun\mre iydo o Lhod/ [vntl.,o"\ic wsse\. tt is orte eanty s.ttg M
{h€ rhet(rj}otb cnsco$e, ond re{cqs * ,r\t o^\ry 0+ u aJ(0f\n9 {ulhs\r c€rls ih,io {he
wscultr-turg.

111
Date Ll, . tt 1rt5

* E*lvuvq$$on
- fvtOvcrnent of ce\E ao+ot ( btood ws€t lhto *is$/e dvrie iw\qvhvno*i$ / ,rrg+qsrosis (tht
su."G "+ "*.e">

Couses of cmcer

Stees oe Corcinugenssis
11.. lniliqtion , hrJt slcp of corgr dovcto0oncr^t lni[tototS cerg rvr$ots8 tn DNA . L. eS0ects 6v6
inre\reBibte i ovr(e O pgflicuto^ Cet\ hns L€,th 0gRcjed t"{ A^ ini+io,tol", it is S\rjcef+tqg
4a gomolttrn unt\l itt ileo{h. @.0. chr0$^q60$1rl hed6d6e, h1ft Oild$cr {6rrv'+rtn)

2. Pyf,tl , one€ lh:}\skd by q^ 'thrliolsyl rr {o {Lg e+Qects of ?ro{hotsrs . these

src.stHLt€
]s
cov{a)nilS ?}omsg. t\e gotilero&n of th€ grlt, $(rE Fist- +o o lmae huxber c[
dop\dtr ce[r covr*ornino *hQ nnrrlor$n creo{ed by r\t ini{iqtOr,

3, PaOrgStion t "frons.tsr{horish 0€ o tq,riovr tt)Ynor into o h€og\oswt, ond to mu$rv\o^(y.

ProotesiSh
o G:F-f,"::
envwred, ce[ ::::?
'l#lr ottsr"* ,Jerrg
e{rtrev\e\lc
diyisio!^,
exfle$bn,
ldtQtcllrt olns
chrcrnotruot otr.ortot*t*'
gfpesr-ton aF ov'rco?gl\eg
hswhot
ceii-
n

f{e-m0$Ds+ic
-4>
\@

cr.ll hYicj.ty

CrYt/o*g th€dnmsfyls

excreliil) )N6 qddrrfi5. 6lh{hosrrur

obY\or.n^oti{leS

eidtloo$ e*?esute

rqrftve ^
sGde3
rtcap\n o,crNofKrn Corcer
efiod^thE Sittv\siht
 *--.-
Duro zj l\ zots

Chs$ico\ Curunoq<-n9
l{> AfSeniC,COilrr.iUm, NCf{C,tCrnelo\S)+ SKih, lunr/ liwr' gvos}otr€, KidY\O{Sr hOsO\ CwitY

LP ftthtoxtn-Sl .) liven

Lc, Astoes+os + tungs

L? Atr+Oling oors$ts , ttvKe$tq

Xt A{t$orin - BL
+ Nu{trroN occuh\v$ [\c!+ox\nSCq +oxio seccmdory nttokttte protvced, hl

{vtt5i, cotrwlon\y Krrotrh qg mdrds), -tOffC chevrr,tq,l prodvcfS pro0-rrcPd b,, tx,6i
tq+ tc{rr\ csh^i.ze croPr.

+ firbd$l(Pd bY rne"y slecr'es 6t Asl1.t i(t-us Co t'i^A,rs) / tht $r\os+ hcktb\e

on(s beih5 ls1enittvs llavrrs md lsfCrlitlvs panstltcvs .

|4erhonism of Gr{gtoyic Corcinogen9

1. Cor",nqqn oeli\ot\oh 2. DtlA binilntl 4. Gene mur,o*ion

]F t'
t*!4> * r+,
rr-Iritr'{Y
t"
rq6Hvtrtt4'l
I
I
t
" ihhclNq'tdt'
*""rroosn

CYP&5os
coairyr,en 1____/
ffffile ffi,*
fOUtCrS Ot{egli^or Concgl" &rrvrOtrOn + tobocco rlse CcioOn$t&r 0^d lung concer)
t rqdiotim C*hry radr\$m o d Le\,Eeynio)
CUV rq6ir*.. ond sl.ita concer)
Le C\erngtyt (zgU Rt6) , o si?niQic$t crmoLrnt o(
A?l^i\
fodiouotile tvrqter,iq\ \ros re\,AEA (a 7f mole_ rho^ Fuf.ushiwro).
Theno vrtts no Con*IO\ On
foot dirtl.ilrurf o.r Ord ivrl,o\€ ; *.f O
l^esb\t, thr.le rrrqs a dyqs+\c ih(recse o^ +h/yb\& cgas€r
. ltrg 1nq.c0,se in Jdld corr.err 64 benigvr
Sn^Shtlk c.h\dr,en

diJes.er fuR, not beeyr sc(Qh+ilicott.1 d$norns-\rqp[,

€ YirUstS ( Odqguiros, ppiloWtvinfs r re*y9y1yyg65/ hr)^?eJviyqg
Lr tls{rrn- B6e yruus t.l osroclO{rd \nrh $wKrI.\ tWnfhomO
onil nusoghqnyqreol canqlneMA-

ttq
naLe at tt . 1s\c)

* Eps{trn -Sow, Virus 0\d Concer

t?qern.Bo.t \\ws \n[ec,tisn

{
Lottnt tQ&-stiorn of B tVn^*hrattet lhtec{tsr' o'q ?h0ryn0g0\ e?{tLetiuvr

{ \ t
I
\rnrnrne Chbn\o \lnlfiD\{n Loh^t in€ccttsn9
3t?gres>ion ,tnslohi0 a"-S"alat: in rrug

csntlhued qn$a
I
cj.rtt",osovuot suldsl Guetic
I kdis?ositi0h

-T--
'lvo,rltuoltoo I
in ol.sencg oe 9e[elk die*unr Crrirooeng,
C-rnyc Oc+i\at{on chonftS
innrv'trhs kr\tlo\

I
PoE,t-lvonsplot
I
Burritt
t
RoilgrinrE
Cgtlu{r Oaetic.

t
cho^oeS

lywrrhma tYeng\drng lvrnrlomu Nuso*or1n1tg\ concq^

*$ndBci0 ud goynOoh csrcer t W.abrc*r

Nlori.
to StsrnocJn ulcers i oastric ocid ond H.Qv\ori
- s+ohnoch utLer re ihebrqilted o/rd darnone* reqr \v\ -$g s*oyvroch \^o\.
- s.tnn3 qcwc.lotts\ h,o{rnpp.n tt.Oft0fi "rheed{r Ovd stomocf^ U\egrs.

l9 F{. gyrsni is q laocio,iv\n -thot Co,r suwiW: *l,re crc\ltc c{r d-\+iu s O& atr€ t1ovh'ch. l+ feCvetCs
\reF, rnfidr]r hedr6tiLcf tl,t2 ocjd , g\ounvr$ tor {rrn$S/ cdoni"o+i0y1.
tv tt SUo ltrretQ"s h\)s\n0re to de?rqds 'tlre livrinl 9f 'the s{DYvroc}a \^,at\/ atto\nw9 it to bnrrow
into +h€ \in\nr.
- D<gmfofron oe {h€ ?DtectMe \inlna ldY H. jvlgn olbs Srn dunnoge +o tl"e srrtvnnch umtl by
aclds LcwnnC ulcers).

- Pro\onfld lvcftryt, o€ sb^nod4 Utc-ers $c^, ttqd lo ,{"e 6rUo{tO,n o€ S"l6vvrst,h c.OncsrS.

* f(tfedily cq^ Ottes+ mmy +y?es O€ c.oncen ( tnhedltd c$^di+io^s)

- tt€reil*oY", reAhobtqhn/S 4 9erhhsUt0slorh0
- ${vt$e.fvrrn ?iolv€$oE\rfh J sK\h concsn
- $lilrns' drhon + tzldht^l eo/Kf,,s
- Li-fruur'.en, slndrornQ j sqrcouuq6/ loroin , byeq*/ lrutsqfhiq
. [n6i\\o\ qAthoyoqrn\,S fotg?osiS -r gplou, reg0\ ccr^Ce.
- tor{.t'S diS"qe 69 4p bone J bU.'e co^csr
- tOncmi 5 opt$Jtlc ohe$^\u. -) [quKeh^iQ, tlYtln, srih car,Cet

18o
 Dare Li tt . 24tq

Chotqo+eris{igs o€ Cry\ceto05, Cettg

+ Lsqo nrmLer ot dtvtillrrt e.tts

rkr}tr W Wd nm-e]_

I
!

{lqfiutlOyr in clpJl Srz€, 0^d sl,q?e

r Loss otr vnrmUl sFrtotiad eett {uvtf*ion

+ dhourfortzed owurarhRht of carfs

+ fo6{y de[iy€d .tumon bouhdory

inr'r eJ)i35rire3

181
No.

Daie ')-5 il . 2016

+ [ $lsiotqiat flocgss th\olvin, {he rye,*}h 69 ntr.r blood r€.$els $ow1 flvc-esErirD v?xq5.
J A normol 0l\d Vi+s\ ?Q@sE in oYohltt" Oril ttwlopvfent r oS vet\ qr ih wunil t\eo\\ng.
, A tvrilOr,,.'tyrrqr s+ef in {\P ltuNilto^ o{ *umrr [nyn O dorvnUnt s*qt& 1r o r$dtigYro.yr ohe.

* lurnor moiooerrssis

€ -Tumots
coA o\so s+i0{r\St0 fte".1"y nof.iltO\ ce\\g 4p
tad{re on5iogr,WsiS Si5vg\irb m6tQcu\ts.
a \e r\s\r\+\Yb hew b\ood Yssse\s "Qr'C" Orbwnb ,hvlnorr w\{h oxyowt ond nt\rtents, otlgr^tv16,
thc co^qef ce\\s +o intoAe \QafW .\iss{€ , 112 nnys th}o$Ohcxlr +ht_ to{V ond .funn^
r
hew colOnleS Ot cOrcrf 6p\\Sr C-a\ea\ t\e$roseg.
Lp nowno\ OngtOgonosiS occufg in {oeri(en'lrlonic de'{t\o?fi{l\t), qdttts
Lutrhih& \iniVrg dve +o
?vbtekrtvrA , 'rn .f\ssue dunnD vrouhd hrslhg).

a Nhen flg covlcthtYB{\h SQ 6^Olo?entsit iv.\nrbttile 0A !rio\,r, 6c+\lo*ocs gre lgw. Vghtvr
inhrfibrg 6ng \onr, oclivurt".r dre- hibh.
+ NvrgtoOoneris iS 0 r\Cw a,.to\ . Ge Otdg.. 6\6,6\e\e Ve.yrion i9 VesJt\ *irrfffOn.
J wi+\^ou\ 0^0\o9e\tcis. ,tWvron 0ro,^Ah s*Dfs.
) \Ari+h o^r\oaeneriq, .fuvnor oytwrh groceeis.

* Anqioqeniq bo\once or s\,,i{ch

VEGF, bFGt , lGF-p

inlt4t\ns, 1'114[ , lL8,
h.t(o*iq ,NO/ gtc.
L-

Aqiogtot n . eJdo.*Gr\h,
iNeytrgns, Ttfr\P, erc.

* Activotors o{ qnqiofnesiS o
b ?rrpins t> Smo\\ m6tecu\eS
- aqiogpnifl - cdcrnosna
-Losiq \i"ror{qs+ Ursr.nh {qc\rc (Lf SF) - Vtlc,U\ivrUmide
- eqiJ.ttrTu\ Ero$\ {q*or -to*ub\o'^dins E1 ond. EZ.
- \vrhr\etkrvr t
^ g\Ugrn+ot gto*$\ Sustor
- tutns. hrcvrs S -sgtor ov\q

182
 Date Lg . ll . 2ol5

*' Voscotor enil0thstto[ gr0N$^ toobr

+ ulro Ksouh qs vqsc\rlor teflhtoLiliV &r$or
t flqr q mqlsr rote i0 qngiogenesis,
, L\hds ond acjatob +yrusine riru* rece?lors.
a A mo)or^ ?tqrer ivl cet\ qctirhttonr ?e\iQtrutt00, s^t 6i9tt*i0Y\.

* Arg\sorene$s sigvu\\ng coscodQ

VecaF I uFGf
G{rt*,l' odivuil ---:
in crrt n!19!9

'"Jt'
cmceh cetl
rece?tr^

oN{St'etlsl
cel\ srr[qg
# Erso*uettol ce\\ octitloti$

L. grre*tOn 0t ogirgevric fUc,mrs. 4 Auhdd^ w\tr\y fumorJ goduc0 actoeeniC

{no\ecrr\es srrch os .fCat o^A ,tqi
, +on g,cren.e iS
3. E-tdotheli0\ c€\\ trc\iterott$^ cfd ry\ioto+iovr ho# enOdn .lO t eOirn btoOrl {g$e\ 6rowrh.
/t. *$oronre 0t hew fuwor vqscuhtDrg € ton m6i6e.tBis io l"eg\n, .rhtte ag$,0otSr m6tecrr\B
6. ln$o{osohm. fnuF o.ftrrorr€ 6 sbie+y of o^6iorehq$S inhLitoDs
'tUOt nonw\Orty rqAys\\\s' t4ooJ .IrISe\ orowl{1,

L83
)l"
Date L5 ll 2015

* lnhiL,ilors o{ o\qiogex\esis

l+ ?rop\ns
- OnOiostqliY) -?tDtq\et €oc+or 4

- ehilos+o+in - *hvtfrnl"OstOnilin
- inRrR-vorr - TtVtf C+issvg ivthn",U,^ ce merorgehte\y\c^5g ) 1 tL, b

)F Angiogenqis sg,roulin9 (bcess

* VEG f t5 regubtd by Hvfoxia ivtduc\Llg &Uo. 1-d.(tllF -7d-)

ex?ression
+ ttigh 0t \e.re\S ca0ter tow tevqs 0f H\F.
'i Low tew\s 66 02 co,Its +1^g i-isg o{ hi$h lorels of H\F, cosivro tissrtg cetts t6
secre+e
VEGF , lngrnnl o^0iqs\tsir.

* torg* o&s€s .thst +ri$olers angrogtrne sis in .fr.rmor sgus inc.ludq v96F, GLUT-I, ?A1'1.
lPlR,

x hiorhtrq Hy?o'thesis

'i Corrc(r cet\S d{&r

{vrw, noflrgl h+ntt\ ger.\s in hOw {ht1 Cghyey+
lurt Ci.c. g\r$e) {o energy.
i Itos{ norrnol cel\s ur,tizes **rra rcrp\rohon 1o grolurc encr}/ (66 A-rp/
nrolecule o.t glrrcose).
, c€\\ wt|$qs errorSy +ht$r;\ o"na*u,a ns?iro+\ov\ (lrrp /ry\o\eeu\Q. s{ g\qhss), wi{h
tr\ost concer

\ao\tc qcid, us q LVgoduCt. l;";t e(icieh\ rho^ ocv6"ic resqitot$^)

Lp AccOurr\s
hY {\t qciiliC Ce[qlo. gnnrgft{.nr .O** +o c6^cg$us .{issrtg.
.) Cmc+r cr.t\a Vro& ts **,*g *on 5\ucosg *o querufg eoouoh en{rb\ ,to \lrrvt.
^O^
18+
 No

pate L5 ll ' tOt5

Molecu\or Bosis o{ Cqncer

Hgilollt ro,,tofriqng in:

slggq LgFv_cJ f\!qf

fQgu\ols o{o?{ogis

A?o?tosi
t
Ctonol e

Additt$[qt 4hu*oAio*
ltqryn{'y tvosi

+@
Tumor ?mqre\i$n

* Cquscs o{ mutq{ions ry!'$ql qd rqq*orq

Ltr S9o61Uneous mrtlutions
- so,rsed by DttA FtYrnevOe ey$org dunn5 rldias+tovr

L+ tndued mu{o+ions

- co)sed bv et'rvnicq\ cc.r. hyil$nl0an(\Q, {A{^uiuvh 5v,grni6g,o.ftobx\nrete.), rsdiorsn, $y}l

iveeglions 1HrV, Hg! ).

{c llutolron od Cqncsr cte0olcg of dorrua€il,

durio4t -1".s$n* ot mthAlq_ cj^e.&Srnt

siyroltirg ?oth\lo.l eoth\,o{S
\-

185
\nheni\ed StrdrumCS wi{b D€t€c\s
'\n DNA Regorr

- l"lsHl ,\,6, t'1LHt, 9nnS[ + cobn c,Acer c.nrsvru+ch fcgtirt)

- Yefoiler$Q g\Otnentoxum C*P) q$$(J A-q 4 Sr\n co^ee,r r ge\lu\or Url s+nSirivi{y , 0euYoh&it0\ oroy$riMr0\iHe,
CnUc\gC,\iSe excrs\6rn ce(o\r)

- A\oxiu {e\evr0'iec+qsh CA1) -l tgure,\^q,lvwVluyna/ 0e$oh^€ ivreutitity cdouble sho^d bre6Ks)

-BRCA-2 + breo$ o^d s\oriu^ co csr, ( 0Sg tre@is 6y hovho\oo6)s recovdaih6li6h)

-\t\rerner \nilYlrre + 5eeml co^ce'$s, 0rtbhryt o0\n0 r $ehofi€ \ngto6ri\ (occessory Qyo\r\n Sr e{ofluc\eqfi,

or'd hettcose)

- S\oun sYY\dbrng + sbrem\ concgts , qenotg instoUti\ Coccessory U.tA horros€ {or reltics\igt1

C( Siodrg$icq\ F,\h\r,tslS o.t n.rmOt ond Cg\car cerr5

f 'lhe rcsev@ o€ Sourt!, doc;lrr C\Of +) con c.slE o csu {o gnRr t\e t3\\ qde ohd tt.ndgrgo
mi\osis. \hqt lGf 1 ottog\tg +o o ce\\ rnew,irone l^eLee\,r, i+ q$Vulqs
S Oo\ecu\Sr c-ho\n teoe^run.
+ NortvStly r SfowtL {q.c\or iS reyt\re.d +o sA([r+ lhe ?lt F\huse ?o*hwO1.
H0ulgf I 0 m!,\0lion in
PIt k\ntrss , }'AB q^dlorr Ak't Kinoe Con res\r\+ \n sesyr|gne{us 0c}r\S\\on.

* DNA refiirr o,t oene rnu,totions in brgst concBr

+ Nonnqly, {hq tRCAt gene rs(o\$E a h6r€vr ?IEN gcvle by "sornivd'rt buur {oget\er. }rlhen
6ReA 1 is mrrrored, i+ S;rtts ce.(oiring ,tht PT€N q&ne , Corr*ttrbuhs tO cq^Wr
"\^tt!,
{s'rnovs o,rt rhefog{qsig.
+ N0 neQc(r o{ ?TEr.l oene by BtCA 1 gs,^g res0qs in ce\\ qrNth, ce\\ deorh inhiLiliOn, Cel\
r\^i0m+iu^, vrew lolood v6se\S sg,rorr,\ , o il n^etosros\g.

* DNA re?cirr is
not o\No{s bene€iuu\
i in lormOl cetB, DNA reQorr. iS b0neQ\ciot.
a in corrcen co\, Dt'tA re?glr hus q rreotN0 e(€ecAi becors i+ gr6rnots co\c.er ge.[ grow+l,,
ond Pr6[brg1hn.
+ ?Atet (qo\yCAD9; r\bo* gotynergJe) ergrcssi.yl 6x6 oct\!\.ty O€ si5n\€igo^tlY Uprtgu\okd in
m$Y eonc€,rS, jm?tyihb 0A ltrpn*ont rO\e &c +triS ehrv(ne in S\nr\\o\ md gtori&r6+\ovr o{
c-o^ceF Ct\\s.
(t) ttr DNA ne{dF ?o*hus{s csrrdnus ?AR?) ono ugre0ub*d to
in lurn$ co\s- rnoy hos resis+o^ce
cL) tn\ibit'\hg ?AR? rns{ Qo{er*\o\e c\eyh$urno(y / $srd os rons{^rm?y in condi}iong with flve-exisring
DNA ft(oir 6.9.1s ( such qs g?_cA rcso{.{e)
, ?AtP1 in\ir[rlorS rnc\ude 129 - !-ZBt C A*rq TBneo) , Aq6l*6qq C?fir2g), lN0-100r (lrrspy-)1
0^( SSI-tot (Btpor sc\t\ts).

1-86
 1-1 ' rr.2-ol5

OnCogene rrnslon\ frrm ot ?rs\o-onc$De$e3

+ A gene, #nevr nnrrto{eilkxqrescdc{ hilh torets r con 4ufn q rr6tmo\ ct$ to q, {$rrror gQ$;
a A 1wb-oncoOene is q nowno\ cyen0 tho+ COn 0n ovrcoo0n0 dug to fnuto$ovrs/ ihtwosgd extyesslqv\.

-l (t6fisncoqenes cof,Q tor q6*\r6 thot hC\q reg!\$g ce$-grow+h or,d di&renfb$on.

Duq\ nuhre o€ oncqs^€s tt1$fqr,t16, cgrg\\sryty\9, vi${ES,

irrudiutio^, $ewe)iq ft$tsnslfbn

norno\ t:--Pm{o-onogene-l Ce\Ulqt oneAqehg

CgrDto-oncogers)

-lyee.tov*iq\
- gg\utr trrns*\on5
ne.o?\osm

;ohcoqehgs indud0 genss.thG+ Codg {or: -grevrlh foorors - si$o0\ {fwlsilllceB - W\-eYelg eu,iQsr*xrAg

- fegg?t'Ofs -\rqwriptlsn f,ocbrs

+e*on1ks iwlude ggg'Llnerr r c-my0, L-ynr1g , otl , od Srg.

\_- Tumor Sup?ressor gene

tA qet\0 i[ol ?y\Aegrs q co$ lom bew*nt q cfictr. i nsfry\o\l\ inh\b\\s cs\\ ?yoliRrs$sn.
tU hqs 0 dotrr{m\n5f refiese{g c[.Cect on {ht reQunh'on oe the Lr[1 c{o\el gr1n\stcs o(o$rsis ,i 66
Somt&$hes tgrs bofrh.

i ti\ttho{isng ln q .tt0!0r Sqressor qene co^ ca)se 0 toss / red$ot\Sn ,n i{! ejlq 34 q\
!1rg4!x.
Cm ?foore$ 4O Cmcen
r'[utrror 3\r?0resr$r gpr\es t\heA$l\ tiKt 0 huK fdo\, bv in\rbrhnq !!.r{ft, $UnU\\no ?'ott'{t!, on(_ {Yo^Jcn($o^
[qohrs rej€onS\lg {Or c+.rt 6pti$tOtiOn.
ot\€ltg Crecessive rb$lql.o$s) is of
+l\rltuh,tins ih Loth naces,r0rt fur -the inductlon co^ceh.

* Knqdson's 2-hit 5',*6*5"*19 for luMouri$en$is inYo\\'\$b a +0m0r s$Wrgsstr gene LTBG)
-tsg mut$tisn q to
Cq) in nury^u\ et\, teodinO
cet\ sentqic corcer

kogl-e-.ssjs! +o
*UrvUUr {OrrnO$On -
EirS hii ( o irlto$Orr Secmd hit ( 0 ds\qign
ds\qion tn
tn one co?y s&El90:hg o+hsr +4+r o++h* Tsq)
-t,
\- $) 1sG tY$tqlsn i\ q cet\ _u!&0 0effY'!\LorLto{qL lesd! i lo &Sj\N lqcen
-- -

Firs+ hi+ ( rh€ secsnd hit C o

! - o0nm\rr€ rnu\ofrdl) de\ollsn irr rht othetn c6tY

187
L1 tt 2o\5

Mrr\o{ion 6g {hQ ?53 Tuvnor S{?flessor Gene

* rrcmno\ 953 inil\lces ot{rosis 0.d inhibi{s 1trg gg$ cje\t,.
+0 mr$o{ed gsl csnnot rqes, nail\no to u6co\r[s cet!
?stiftn11otq

\qqpui. sYotegies
r F\uvo$nilo\ is q CDK .irah\trtsn dyuo +hol swtyesJcs CgKs Crexonsrb\e tor+\.t regu\o$svr ot
tte cel\ eycE).
Itr ln[i\i{5 {g cel c{de, tcvq\S,nO concth ce\\ fnti&vUtrOn.

i lnhiUi{s CDK 1 , L, t+
. 6

r 1[re ?ntrre s\s(e^s ave nuro,\ions ln - steo0€nes

t tuYtor svyfrt,sr Oenes
= DNA rejoV genes

t : cellulr dit[ven\iOtitvr Deneg

other !e\l\ d€g\ oates
Flowevgr, mu+o{rons con also 9!9uf i!.
: Cer\ sionotiyb eenes : lhclollOsis/ irws$0n mneS
: ce\\ cyctg cher.rfoq oengs I corpivrsagXr ooli$lrrO
I
: c€tlu\o. seheEcgrl€ Oehes dtocl,\YB\tq trhgs

EpigenelicB
., h'en*oL\e chorqe ,n pot{erns of by m€rhonismg o4h€F +h0^
oeng ex?rcssioy\ f^edb{ed
ukh\s i! 19 giqqry nuileor\d,o sE4ence.
+ csfiYnov4 mecl^q^iswls yvrov includg: DNA r*thyl6ttgyl
: His{one fYto{i{icorl0n/ his+ohg .rmim+S

* DNA t'te,lhVtOt\On
4 A -tYpe oe DNA modrt\cuttgn 1go1 cer be in\^€Iilrd qnd srtrgjven,tly rervrovgd wit\N! chonoing
'lht, onig\rrn\ DNA seguence.
+ (h this fvtes, methyl it qttodne$ to the cybsine o+ o C-& poiring.
-r }DNA rnttnv\{runr&mss ( D|^NT!, ousT3A r DMN"| 1S) ore fartonNa\t {or rhg Focpss.
t netlnvls\tU " tr$ns oep r, &y\es.
V-

n rl '2a15

* DNA qe\tNlqlion urd Conqgr5

J \n notmut cet\sr mos& qt rhe cQ honds _g! gllq lto{h$St rt.sisns_ gry. v.nq$hyE44*$S4!E
in crxrcgr gcts rleV ore fnenu\ly rn€,thytqfgt.
) lrmscn$\onu\ si\tnc\nb st qcnes tho+ ngrynut\y eossester m'ri\mor oc+\{itv \roOs to .the

otvror$q\ ce\!\tf everts urt6io\. sov.\firiloutus -lo tlvnor lvogness\on.

4 t\q ECe \ cmgr,tS sroh og co\ov\ r brgusl, l!hb, \ru,noch, tvef , K\dh\ c6^cgfs/

\tr"$otHus ond laugqYn\as.

negulq\iofl

DNA rne,t\to\ion

Cel\ Dit{tren{orron
ApgtosiS

t Histone Modi$rcqtion
+ O co{u\tnt 1os+--trOnr\str\sno\ fnooigicori0n +o hittqne FoteinS whiCh hdrliles fie$,Vlqgoy\ glro:{grylotiovt,
oc3tylq1i6e, utigui{grotiov1, onil stm6y61i66.
+ Tl'e PlP\: rnoil€ +o hisbnes co., ivnfacA
cehe eypressio\^ by orleninq chrovrrol\r,r
slfirc,lure orr yggyui.\ing hrslong 56sSitierS.

t\is+one t6ofli$icgri6hs aet in diverse bio\otic0\ tbcecses sr.ph 0s troag6flbnOt oc{Vol.\ on / ivtoctivo\bn
chnvn0sonie
?qcKsgi!,r6 , o^d lNA dU*oapl rego\r.

Kor(u\,.r LDisE-rE^. , ,rl^B iu ecr x36 iines

Er