621
286316470016778155
Amal79511160234138315452561
Hussain141411160234148298394489627679839
Ibrahim23121116023452168327464612664841
Al321111160234138246
Haddad351611160234148285454623748917
Department7951330014981156232313348384495569643679
of15111330014975112
Physiology16591330014959129188233252327347422503563
College7951474014989164183203277358433
of12651474014975111
Medicine141314740149110184264284353373446521
and19701474014981155236
Health22421474014974148229248285354
Sciences26331474014954123142217290359433478
Dissertation7951787017098132193255344389431524566599689773
Title79519810122426696120184
Identifying1831198401202291156217251271302356376437504
the2363198401203495160
Molecular25501984012092158178243307368388456487
Mechanisms30641984012092157222283351412432471565604
of3695198401206697
Early38201984012053122152172226
Cachexia40731984012082150214276340388408477
Using45771984012066105125186253
Whole48581984012096157222242307
Transcriptome5193198401204373141202241306336356424458523617682
Sequencing18312104012050115183244309370434455516583
in2441210401202082
Muscle25502104012092153192256276341
and29192104012068129198
Fat31452104012048116150
Biopsies3323210401205777143211250270335374
from3724210401203262127221
Cancer39732104012081150211275340370
Patients43712104012059127161181246307341380
Faculty7952256012248114178238262292350
Advisor11732256012274140196220264328360
Prof.1831225901205989154186213
Thomas20722259012043104169263331370
E.2470225901205381
Adrian25792259012074142172192261322
Defense7952411012270134162226286330394
Date12172411012270136166230
1018312414012055111
June19702414012048109170235
201522322414012056111166222
Abstract7952727012274140184214246312376406
Cachexia1831273309665120171220272311327381
causes2234273309669123172203255286
one2542273309669118170
third273427330964392108132187
of294327330966994
cancer–related3059273309668123172223275299339363415431486513565620
deaths3701273309671123178205254285
and4008273309671120174
contributes4205273309668120169196220236291339366418449
to467727330964396
that479527330964392147174
of499127330966994
many5107273309692146195238
others.536727330966996145197221252274
Despite5663273309676128159214230257309
extensive5994273309668107134186235266282326378
research,183128290962476107159213238289338360
themechanisms221328290961968120209261313362416465481512587618
of284628290965277
cancer2937282909652107156207259283
cachexia3235282909651106158207259297313368
are361728290965579130
poorly3762282909654107159183199242
understood.401828290964998152204228259287339391446468
Identification450928290961064116165192208228247299354381397449498
of502128290965378
early5113282909652107131147190
changes5317282909652101155204258310341
in56802829096857
gene5751282909654106155207
expression597228290965290145169221252283299351400
in183129250961665
the191829250963988140
major2092292509675130146199223
cachexia2337292509664119170219271310326380
target273929250964094118172224251
tissues30132925096395586117166218249
will328429250967995111127
improve3433292509628103158182234278330
the378529250964088140
understanding3948292509660109164216240271298353402456472521575
of454529250966590
its46572925096285586
mechanisms.4778292509675127179227282331347378453484506
We5319292509676125
investigated546629250962877121173204231247301356383435490
the597829250963988140
entire6140292509664113140156180232
transcriptome,183130210962751106155186237262278332359412487539561
using24093021096498096145199
next2625302109649101139166
generation2809302109654106155207231285312328381430
sequencing326130210962678133181233282334350399452
(Illumina3736302109625435975123198214263318
HiSeq407130210965571111163217
2500),430630210964489133177207229
to455730210962375
identify465430210961166118167194210235278
altered49503021096547097149173225280
expression524730210965291145170221252283299352400
of566530210965278
genes5760302109654106155207238
in602030210961160
muscle6098302109675123154206222274
and1831311709655103158
fat201131170963488115
from214831170963458110185
cancer2355311709660114163215267291
patients.2668311709663117144160212261288319341
Samples3032311709647102177232248300331
of338531170966086
rectus349331170963283135162211242
abdominis3757311709663117172224300316364380411
muscle4199311709675123154206222274
and4495311709663112166
visceral46843117096526899151203227281297
fat500431170963387115
were5149311709666118142194
collected5365311709660112128144196248275327382
at576931170966390
surgery588131170963988112166218242285
from618831170963357109184
patients1831321309655109136152204253280311
exhibiting216132130965291140156210226253269318372
5-10%255232130964471115160222
weight2793321309666118134188237264
loss30793213096136596128
prior32263213096547894147171
to341932130962476
surgery,351832130962876100154206230273295
compared3832321309652105180234289313365419
with427032130966783110159
stable-weight445132130962855110164180232259325377393447496523
patients.4993321309655109137153205253280312334
Also,534632130965975106158181
selected55493213096288096148199227279333
differentially59023213096547095121173197249297324340395411427470
ex-pressed183133090965290117172196247278309361416
genes2269330909664116165217248
were2548330909667119143194
confirmed2765330909661113162182201225302354409
using319633090965990106154208
real-time342633090963486140156183210226301353
RT-PCR.380133090965893119167232280303
In412633090962776
muscle,4234330909675123154206222274296
30455333090965398
genes4673330909663115164216247
showed494233090964190142209261315
highly528033090965874128176192235
significant553833090964056110159175194214265320369396
change5956330909661110165214268320
in629833090962574
expression183134050965290145169221252283299351400
(25225334050963377121
down2399340509655107174223
and2647340509654103158
52827340509647
up:2896340509652106129
P<0.0005304734050965098143165209254298342
-3411340509630
P<0.00001,346334050965099143165210254298342387409
FDR3894340509642101150
0.2).406634050964769114143165
The425434050963785137
25441334050964892
downregulated4530340509655107174222247298352401417471498550605
genes5160340509654106155207238
included542034050961968119135184239291346
75788340509647
involved585734050961968112165181225277332
with621434050966682109158
metabolism1831350109675127154209263316332348379454
(5230735010963175
mitochondrial);240635010967591118170222271323372427451467521537567589
43017350109646
with308635010966783110159
signaling;326735010963248102151205221237286340362
43651350109646
with372035010966783110159
ubiquitination;3902350109649103119174222238266282330385412428480529551
and4477350109654103158
34657350109646
with472635010966783110159
intracellular49073501096176693117172223275291307356372427451
trafficking.538035010962852107132152171223263279328382404
Multiple5807350109674122138165181236252304
genes6134350109654106155207238
involved183135970961665109162178222274329
in218235970961564
glycogen226835970965470112164217270322371
metabolism2661359709675127154209263316332348379454
were3136359709667119143195
downregulat-ed,3352359709655107174223247298352401417471499525577632654
correlating4028359709651104128152204220274301317366420
with447035970966682109158
the465035970962776128
lack480035970961570122162
of498335970965378
glycogen,508335970965369112164216270322371393
muscle5498359709675123154206222274
weakness,5794359709666118173213262314345376398
and6214359709654103158
fatigue;183136930962580107123177225277300
characteristic2152369309652101156180234286313365389405436463479531
of270536930965277
cachexia.2804369309652107158207259298314368390
The321736930963382134
53373369309644
upregulated3439369309649103127179233282298352379431486
genes3947369309654106155207238
include420736930961564116132181235287
24516369309645
involved458336930961564109161177221273328
with493336930966682110158
calcium5113369309652107123174190239314
signaling544936930963147101150204220236285339
and5810369309654103158
25990369309644
with605636930966783110158
cell6236369309652104120136
matrix1831378909675130157181197235
interactions.20883789096126188140164219271298314366415446468
Expres-sion257437890964382136160212243270301317369418
of301037890965278
genes3106378909654106154206237
previously336237890965478130174190243291322338381
thought376537890962372125173227276303
to409037890962376
be4184378909654106
important431237890961288142194219246300349376
in471037890961261
cachexia,4789378909652107158207259298314368390
including520237890961260112128177232248296350
several557437890962779124176200254270
inflammatory5867378909612608099154229304359386438462505
cyto-kines,183138850965295122174201241257306358389411
was2260388509667121152
not2431388509649101128
significantly25813885096284497146162182201253308356383399442
different.30423885096557196121173197249298325347
FBXO32,340738850963985134203247292314
which3739388509667116132183232
encodes3990388509652100152205259311342
atrogin-1,435138850965482106158212228276303347369
upregulated4739388509648103127179233281297352379431486
in524738850961261
an5326388509655104
in545238850961261
vitro55313885096456188112164
cachexia5713388509652107158207259298314368
model,6100388509675127182234250272
was1831398109666121152
actually2004398109655107134182237253269312
downregulated.2337398109655107174223247298352401417471499551605628
No2986398109659111
transcripts311939810962650105154185237261277331358390
for353139810962476100
the365339810962675127
dermicidin3801398109655107131208224276292347363412
gene,4234398109654106155207229
which4484398109666115131183232
codes4737398109651104159211242
for500139810962476100
proteolysis-inducing512239810965579131158210263279322353369400426442491546594646662711765
factor,590939810962479130158210234248
were6178398109666118142194
detected.1831407709655107134186238265317372394
Expression224740770965795150174226257288304356405
of267440770966692
myostatin2802407709675118170201228283310326375
and3199407709669117172
its33934077096305789
receptor350440770963889141193248275327351
(ACTR2B)3878407709643102167201250294340370
were4270407709680132156208
significantly450040770964561115164180199219271325374401417460
decreased,4982407709669121173197249303334386441463
possibly5467407709669121153184200254270313
reflecting580240770963890109129181233260276324378
end6202407709666115170
organ183141730965276130185234
adaptation2087417309662117171226253308335351403452
to256141730963587
tumor267041730963584159211235
produced292741730966286138193242294346400
myostatin.3357417309675118170201229283310326375397
In377641730962675
visceral38734173096526899151203227281297
fat,419241730963388115137
expression435141730966098153177228259290306359408
of478141730966085
64888417309652
genes4962417309661113162214245
were5237417309666118142194
downregulated5453417309662115181230254306360408424479506558613
and6088417309662111166
10627641730965296
upregulated1831426909649103127179233281297352379431486
with233842690966682109158
high251642690964965119168
statistical270642690962957111138154185212228280335351
signifi-cance30794269096294599148164184203230281336385437489
(P<0.001-0.0002).359042690962875123168190234279323349394416460505549593623645
Several425742690963890135187211265281
of455942690965278
these465942690962574126157209
encode4888426909652101153205260312
metabolic5221426909675127154209263315331347399
enzymes.5641426909652101135177253305336358
Of601942690967095
genes6134426909654106155207238
in183143650961665
fat191843650963589116
previously205643650966488140184200253302333349391
impli-cated2470436509625100155171187213265320347399454
with295543650966783110159
cachexia,3136436509661116167216268307323377399
such355843650964089140189
as376943650966495
hormone3887436509658110134212264313365
sensitive427443650964092141172188215231276328
lipase46244365096254196150181233
and4880436509664113167
adipose5070436509664118134189241272324
tissue54174365096365283114163215
triglyceride56544365096376177131147189241293317333388440
lipase,61164365096264296151182234256
were1831446109666118143194
un-changed.2047446109652101128179228283332385437492514
In258444610962170
contrast,2679446109652104153180204259290317339
leptin304044610961971126153169218
was3283446109667121152
significantly345744610963551105153169189208260315363391407449
downregulated3932446109655107174222246298352401417471498550605
and4562446109655104159
the474344610963079131
zinc-α-2-glycoprotein489644610963753102154180240267311338392408450502555609633685712764780829
(lipid57474461096334965120136190
mobi-lizing5963446109675127182198224240256290306355409
factor)183145570962580132159211235265
was2125455709667121152
significantly229945570963955109158174193213264319368395411454
upregulated2775455709656110135186240289305359386438493
as329045570966293
expected.340645570965997152204256283335390412
These384045570964190142173225
studies408745570963966115169185237268
explain437845570965997152168223239287
some468845570963890165217
documented4928455709662114166215290342390418470524
evi-dence5475455709659103119146201253301353405
in590245570962472
cachexia5997455709659113165214266304320375
pathogenesis,1831465309655109136185238291343392444475491522544
highlight239846530965773127176192208262310338
ambiguous2758465309663138193209263311364412443
data3224465309663118145200
from344646530963458110185
animal3653465309664112128203258274
models,3958465309675128182234250281304
and4284465309663112167
reveal447346530963385129181236252
unexpected4747465309657106158196251303355382434489
changes5258465309660109164213267319350
in563046530962573
gene5726465309662114163215
expression596346530966199154178230261292308360409
that183147490962776131158
underlie2011474909657105160212236252268320
the235347490963684136
pathophysiology2511474909663118145194246301349392423439492508560614657
of319047490966086
the329847490963584136
cachectic3456474909660114166215267319346362414
state389247490963966121148200
in411447490962473
cancer.4209474909660114163215267291307
These453847490964291143174226
results478647490963384115164180207238
bring504647490966387103152206
reliable,527447490963284100116170225241293315
representable,561147490963284139163214245297346373428482498550573
and6206474909662111166
consistent1831484509652104153184200231258310359386
data2242484509655110137192
from245648450962852104179
the265748450963079131
clinic28134845096526884133149201
and3039484509655104158
back3223484509654109161201
to344648450963083
the355148450963079131
bench3707484509654106155207256
with398848450966783110158
more4172484509675127151203
focused439748450962881132181212264319
insights47384845096196899115169218245276
to503648450963083
be5144484509654106
investigated527348450961967112164195222238292346374426480
and5779484509654103158
verified.595948450964799124140159179231285307
Research7515016017081171232322414459549633
Relevance14235016017081171204294372465549638728
and21905016017093177269
Potential24985016017079168210300384426459552585
Impact31235016017039170263355445487
Most751521309674126157184
patients957521309660115142158210259286317
with130252130966682109158
cancer1482521309657112161213265289
exhibit179352130965796144160215231258
marked2079521309675129153194246300
wasting2407521309666121152179195244298
of272752130965883
skeletal283252130963777129145197224279295
muscle3154521309675124155207223275
and3451521309660109164
anorexia3637521309660109161185237275291346
which4010521309667116132183232
is426452130962253
known433952130964694147213262
as462352130966091
the473752130963281133
cancer4892521309657112161213265289
cachexia5203521309657112163212264303319373
syndrome.559852130963780128183207259335387409
Cachexia6034521309665120172220272311327382
is75153090961647
a823530909655
major903530909675130146199223
cause1151530909652107155186238
of141553090965277
cancer1517530909652107156207259284
death1826530909655107161188237
and2089530909654103158
it226953090961946
affects234153090965479105157209236267
the263053090963079131
quality2786530909655103158174190217260
of307253090965277
life,31715309096193561113135
the332853090963079131
response348153090962779110165217266297349
to385253090963083
therapy,395753090963079131155210264307329
the430853090963180132
ability4465530909655109125141157184227
to471453090963183
withstand482253090966783110159190217272320375
the521953090963179131
rigors53735309096274397149173204
of560353090965277
therapy570253090963179131155210265308
and6035530909654103158
even621853090965297149198
the75154050962776128
psychological90154050966495138190239291307360413429481536552
wellbeing1485540509666118134150205257273321375
of188254050966288
the199254050963685137
patients2151540509664119146162214263290321
and2494540509665113168
their268454050963786138154178
families.288454050963589165181197213265296318
The322454050964492144
mechanisms3400540509675127179228282331347378453484
of390654050966388
cancer4016540509661116165216268292
cachexia4331540509661116167216268307323377
are473054050966589140
not4893540509658110137
well5062540509667119135151
understood.5235540509658107162214238269296348401456478
We5744540509677125
hypothesized5892540509658101155208235284336367383417469524
that75155010962776131158
changes931550109657105160209263315346
in129955010962170
gene1391550109659111160212
expression162555010965795150174226257288304356405
in205255010962170
early2144550109657112136152195
cachexia2361550109657111163212264302318373
would2761550109667119168184238
shed302255010963685137191
light32355501096223891140167
on3424550109658107
pathways3558550109654109136185252306349380
involved396055010962170114167183227279334
which4321550109667116132183232
would4580550109667119168184239
then484155010963281133182
pave5050550109654109153205
the527755010963381133
way5438550109666121164
for562455010963082107
a5758550109654
more5840550109675127151203
targeted606555010963287111165217244296351
approach751559709655109164188240295346395
to116855970962375
therapeutic126555970962372124148202257309358385401453
intervention.17405597096116087139163207259308335351404453475
The223755970962978130
entire2385559709652101128144168219
transcriptome262755970962246101150181232257273327354407482534
of317855970965378
skeletal327855970962667119135187214268284
muscle3580559709675124155206222274
and3872559709655104158
visceral40485597096446091143195219274290
adipose4355559709655110126180233264316
tissue46935597096233970101149201
was4912559709667121152
investigated508655970961261105157188215231285340367419474
using55775597096498096145198
next-generation5793559709649101139166193247299348400424478505521574623
sequencing75156930963183138186238287339355404457
and1231569309661110165
the141856930963483135
major1582569309675129145198222
changes1826569309659107162211265317348
confirmed2196569309659111160179199223300352407
by2625569309661104
fast275156930963287118145
real-time291856930963183138154180207223298350
RT-PCR.329056930965690117164229278300
These364156930964190142173225
studies388856930963865114168184236267
indicate417856930962271126142194248276328
the452856930963483135
involvement468556930962271116168184228280355407456483
of519056930966085
several529756930963890134186210265281
metabolic5607569309675127154209263316332348399
pathways6029569309661116143191258313355387
that75157890962776131158
explain93157890965694149165220236284
much1242578909675123175224
of148857890965782
the159257890963180132
clinical17465789096567288137153204259275
observations2043578909657111142194218263317345361413462493
in255857890962069
cancer2649578909656111159211263287
cachexia.2958578909656111163211263302318372395
The337557890963887139
data3540578909655109137191
confirms3753578909656109157177196221298329
some410457890963587163215
of434157890965681
the444457890963281133
documented4603578909655107159207282334383410462517
evidence5142578909656101117171223272324376
in554057890962069
the563157890963280132
pathogenesis5790578909654109136185237291343392444475491522
of633457890965682
cachexia,751588509652106158207259297313368390
highlights116358850964965119168184200253302329360
ambiguous1545588509655130184200254303355404435
data2002588509655109137191
from221558850962549101176
animal2413588509655104120195249265
models,2700588509675128183235251282304
and3026588509654103158
reveals320658850962476120172227243274
unexpected350258850964897149188242294346373425480
changes4004588509651100155204257309341
in436758850961564
gene4453588509654106155207
expression468258850965290145169220251282298351400
that510458850962776130157
underlie528358850964998152204229245261313
the561858850962775127
pathophysiology5767588509655109137185238292341384415431483499552606649
of75159810965278
the85159810962775127
cachectic1000598109652107159207259311338354406
state142859810963158113140192
in164259810961665
cancer.1729598109652106155207259283299
Once2050598109670119170222
confirmed2294598109652105153173192216294346400
in271759810961564
other280359810965380129181205
groups303059810965478130178233264
of331659810965277
patients3415598109655110137153205254281312
with374959810966682109158
cachexia3929598109652107158207259298314368
these431959810962776128159211
findings45525981096203988143159208261293
are486759810965478130
likely50195981096163272124140183
to522459810962780
lead532659810961668122177
to552559810962780
improvements562759810961691145169221266318393445494521552
in620159810961665
the628859810962776128
prevention75160770965579130175227275303319371420
and1197607709654103158
treatment137760770963155107161189264316364392
of179460770965378
cachexia1894607709656110162211263301317372
in228860770962069
patients2383607709654109136152204253280311
with272060770966783110158
cancer.2901607709655110159210262286303