%PDF-1.6
%
1 0 obj
<>
endobj
2 0 obj
<>stream
Daffolyn Rachael Fels Elliott, Juliane Perner, Xiaodun Li, Martyn F. Symmons, Brett Verstak, Matthew Eldridge, Lawrence Bower, Maria O’Donovan, Nick J. Gay, the OCCAMS Consortium, Rebecca C. Fitzgerald
Impact of mutations in Toll-like receptor pathway genes on esophageal carcinogenesis
www.plosgenetics.org
www.plosgenetics.org
endstream
endobj
3 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 13 0 R/Annots 14 0 R/Contents 15 0 R/TrimBox[0 0 612 792]>>
endobj
14 0 obj
[16 0 R 17 0 R 18 0 R 19 0 R 20 0 R 21 0 R 22 0 R 23 0 R 24 0 R 25 0 R 26 0 R 27 0 R 28 0 R 29 0 R 30 0 R 31 0 R 32 0 R 33 0 R]
endobj
16 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref001)>>
endobj
17 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref002)>>
endobj
18 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref003)>>
endobj
19 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref004)>>
endobj
20 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref005)>>
endobj
21 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref006)>>
endobj
22 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref006)>>
endobj
23 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref007)>>
endobj
24 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref008)>>
endobj
25 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref009)>>
endobj
26 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref010)>>
endobj
27 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref012)>>
endobj
28 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref013)>>
endobj
29 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref014)>>
endobj
30 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref015)>>
endobj
31 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref016)>>
endobj
32 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref017)>>
endobj
33 0 obj
<>/Border[0 0 0]/A 34 0 R>>
endobj
34 0 obj
<>
endobj
15 0 obj
[35 0 R 36 0 R 37 0 R 38 0 R 39 0 R 40 0 R 41 0 R 42 0 R 43 0 R 44 0 R 45 0 R 46 0 R 47 0 R 48 0 R 49 0 R 50 0 R 51 0 R 52 0 R]
endobj
35 0 obj
<>stream
q
0.955 g
0 w
199.9998 713.9999 m
575.9997 713.9999 l
575.9997 533.0004 l
199.9998 533.0004 l
f*
0.83 0.64 0.02 0 k
415.0488 432.9071 m
419.811 432.9071 l
h
f*
422.022 432.9071 m
426.7843 432.9071 l
h
f*
426.1039 406.9417 m
430.8661 406.9417 l
h
f*
433.1339 406.9417 m
437.8961 406.9417 l
h
f*
474.1795 380.9197 m
478.9417 380.9197 l
h
f*
481.1528 380.9197 m
485.915 380.9197 l
h
f*
529.0016 289.9276 m
533.7638 289.9276 l
h
f*
327.2882 276.9449 m
332.0504 276.9449 l
h
f*
262.3748 237.9402 m
267.137 237.9402 l
h
f*
269.4047 237.9402 m
274.1669 237.9402 l
h
f*
282.5575 224.9008 m
292.0819 224.9008 l
h
f*
297.2409 224.9008 m
306.7654 224.9008 l
h
f*
492.8315 224.9008 m
502.3559 224.9008 l
h
f*
521.4047 172.9134 m
530.9291 172.9134 l
h
f*
519.9874 133.9087 m
529.5118 133.9087 l
h
f*
338.4567 81.9213 m
347.9811 81.9213 l
h
f*
350.2488 81.9213 m
359.7732 81.9213 l
h
f*
0 g
1 j
1 J
10 0 0 10 209.9905 696.9826 cm
BT
/F6 1 Tf
1 TL
-0.014 Tc
0 0 Td
(diversity.)Tj
3.77 0 Td
(Next)Tj
2.1033 0 Td
(generation)Tj
4.4107 0 Td
(sequencing)Tj
4.6148 0 Td
(studies)Tj
2.914 0 Td
(have)Tj
2.0239 0 Td
(shown)Tj
2.7949 0 Td
(that)Tj
1.7405 0 Td
(accumulation)Tj
5.5559 0 Td
(of)Tj
0.9977 0 Td
(somatic)Tj
-30.9257 -1.2982 Td
(mutations)Tj
4.1952 0 Td
(occurs)Tj
2.7723 0 Td
(along)Tj
2.3697 0 Td
(the)Tj
1.44 0 Td
(metaplasiadysplasiacar)Tj
9.8645 0 Td
(cinoma)Tj
3.1578 0 Td
(sequence)Tj
3.7757 0 Td
(in)Tj
1.0205 0 Td
(EAC,)Tj
2.3187 0 Td
(and)Tj
1.7008 0 Td
(it)Tj
0.7653 0 Td
(has)Tj
-33.3805 -1.2983 Td
(been)Tj
2.0862 0 Td
(proposed)Tj
3.8721 0 Td
(that)Tj
1.7348 0 Td
(groups)Tj
2.9084 0 Td
(of)Tj
0.9977 0 Td
(genes)Tj
2.3925 0 Td
(involved)Tj
3.5659 0 Td
(in)Tj
1.0205 0 Td
(similar)Tj
2.914 0 Td
(processes)Tj
3.8778 0 Td
(or)Tj
1.0771 0 Td
(pathways)Tj
3.8551 0 Td
(could)Tj
2.4038 0 Td
(have)Tj
2.0182 0 Td
(a)Tj
-34.7241 -1.3039 Td
(cumulative)Tj
4.541 0 Td
(effect.)Tj
2.5228 0 Td
(The)Tj
1.7518 0 Td
(Toll-like)Tj
3.5263 0 Td
(receptor)Tj
3.4753 0 Td
(\(TLR\))Tj
2.6192 0 Td
(signalling)Tj
3.9684 0 Td
(pathway)Tj
3.5036 0 Td
(is)Tj
0.8278 0 Td
(critical)Tj
2.8686 0 Td
(for)Tj
1.3606 0 Td
(host-)Tj
-30.9654 -1.2983 Td
(microbe)Tj
3.4695 0 Td
(interaction,)Tj
4.7112 0 Td
(and)Tj
1.7008 0 Td
(therefore)Tj
3.7643 0 Td
(mutations)Tj
4.1953 0 Td
(in)Tj
1.0148 0 Td
(these)Tj
2.2053 0 Td
(pathways)Tj
3.8495 0 Td
(could)Tj
2.4037 0 Td
(be)Tj
1.1282 0 Td
(important)Tj
4.1953 0 Td
(in)Tj
1.0148 0 Td
(the)Tj
-33.6527 -1.2982 Td
(pathogenesis)Tj
5.2327 0 Td
(of)Tj
0.9978 0 Td
(EAC.)Tj
2.3244 0 Td
(Here)Tj
2.1656 0 Td
(we)Tj
1.3039 0 Td
(show)Tj
2.2621 0 Td
(that)Tj
1.7404 0 Td
(TLR)Tj
1.9559 0 Td
(pathway)Tj
3.5036 0 Td
(genes)Tj
2.3925 0 Td
(are)Tj
1.4173 0 Td
(recurrently)Tj
4.5694 0 Td
(mutated)Tj
3.4809 0 Td
(in)Tj
-33.3465 -1.3039 Td
(15%)Tj
1.8992 0 Td
(of)Tj
0.9977 0 Td
(EAC)Tj
2.1033 0 Td
(tumours)Tj
3.566 0 Td
(and)Tj
1.7008 0 Td
(other)Tj
2.296 0 Td
(solid)Tj
2.0806 0 Td
(tumour)Tj
3.2088 0 Td
(types)Tj
2.2281 0 Td
(exposed)Tj
3.3732 0 Td
(to)Tj
1.0034 0 Td
(microbial)Tj
3.9742 0 Td
(communities,)Tj
-28.4313 -1.2983 Td
(including)Tj
3.9514 0 Td
(uterine)Tj
3.0104 0 Td
(endometrioid)Tj
5.5899 0 Td
(carcinoma)Tj
4.3596 0 Td
(\(59%\),)Tj
2.7723 0 Td
(cutaneous)Tj
4.1839 0 Td
(melanoma)Tj
4.371 0 Td
(\(38%\),)Tj
2.7723 0 Td
(colorectal)Tj
-31.0108 -1.2983 Td
(adenocarcinoma)Tj
6.752 0 Td
(\(27%\),)Tj
2.7723 0 Td
(and)Tj
1.7008 0 Td
(stomach)Tj
3.5206 0 Td
(adenocarcinoma)Tj
6.7521 0 Td
(\(26%\).)Tj
2.7722 0 Td
(TLR)Tj
1.9616 0 Td
(mutant)Tj
3.0841 0 Td
(cases)Tj
2.177 0 Td
(were)Tj
2.0806 0 Td
(asso-)Tj
-33.5733 -1.2982 Td
(ciated)Tj
2.5341 0 Td
(with)Tj
1.9559 0 Td
(more)Tj
2.3017 0 Td
(proximal)Tj
3.7701 0 Td
(tumours)Tj
3.5603 0 Td
(and)Tj
1.7007 0 Td
(metastatic)Tj
4.1783 0 Td
(disease,)Tj
3.1634 0 Td
(indicating)Tj
4.1669 0 Td
(possible)Tj
3.3336 0 Td
(clinical)Tj
2.9933 0 Td
(sig-)Tj
-33.6583 -1.304 Td
(nificance)Tj
3.753 0 Td
(of)Tj
0.9978 0 Td
(these)Tj
2.2053 0 Td
(mutations.)Tj
4.405 0 Td
(A)Tj
0.8958 0 Td
(better)Tj
2.4831 0 Td
(understanding)Tj
5.9357 0 Td
(of)Tj
0.9978 0 Td
(how)Tj
1.9049 0 Td
(altered)Tj
2.88 0 Td
(TLR)Tj
1.9559 0 Td
(signalling)Tj
-28.4143 -1.2982 Td
(contributes)Tj
4.6431 0 Td
(to)Tj
1.0091 0 Td
(the)Tj
1.44 0 Td
(inflammatory)Tj
5.5842 0 Td
(tumour)Tj
3.2145 0 Td
(microenvironment)Tj
7.6591 0 Td
(in)Tj
1.0148 0 Td
(EAC)Tj
2.109 0 Td
(could)Tj
2.4038 0 Td
(help)Tj
1.8935 0 Td
(inform)Tj
2.9593 0 Td
(can-)Tj
-33.9304 -1.2983 Td
(cer)Tj
1.4116 0 Td
(prevention)Tj
4.4787 0 Td
(strategies.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 502.9795 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Introduction)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 485.9716 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Esophageal)Tj
4.7054 0 Td
(adenocarcinoma)Tj
6.8882 0 Td
(\(EAC\))Tj
2.8176 0 Td
(is)Tj
0.8447 0 Td
(increasing)Tj
4.3313 0 Td
(in)Tj
1.0375 0 Td
(incidence)Tj
4.0705 0 Td
(and)Tj
1.7292 0 Td
(has)Tj
1.5477 0 Td
(poor)Tj
2.1203 0 Td
(survival)Tj
3.3335 0 Td
(outcomes.)Tj
-33.4259 -1.2982 Td
(The)Tj
1.7801 0 Td
(main)Tj
2.2904 0 Td
(risk)Tj
1.7178 0 Td
(factor)Tj
2.5398 0 Td
(for)Tj
1.389 0 Td
(EAC)Tj
2.1316 0 Td
(is)Tj
0.8504 0 Td
(Barrett's)Tj
3.5716 0 Td
(esophagus,)Tj
4.5694 0 Td
(a)Tj
0.6577 0 Td
(pre-malignant)Tj
5.9413 0 Td
(glandular)Tj
4.0195 0 Td
(epithelium)Tj
4.5411 0 Td
(that)Tj
-35.9997 -1.2983 Td
(develops)Tj
3.6793 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(setting)Tj
2.88 0 Td
(of)Tj
1.0148 0 Td
(gastro-esophageal)Tj
7.3473 0 Td
(reflux)Tj
2.5455 0 Td
(disease.)Tj
3.2429 0 Td
(Over)Tj
2.211 0 Td
(time)Tj
2.0296 0 Td
(exposure)Tj
3.821 0 Td
(to)Tj
1.0205 0 Td
(refluxed)Tj
3.4979 0 Td
(acid)Tj
-35.7956 -1.2982 Td
(and)Tj
1.7291 0 Td
(bile)Tj
1.6611 0 Td
(in)Tj
1.0374 0 Td
(the)Tj
1.4684 0 Td
(lower)Tj
2.4548 0 Td
(esophagus)Tj
4.3426 0 Td
(leads)Tj
2.211 0 Td
(to)Tj
1.0262 0 Td
(chronic)Tj
3.2881 0 Td
(inflammation,)Tj
5.9244 0 Td
(increased)Tj
4.0025 0 Td
(cell)Tj
1.559 0 Td
(turnover,)Tj
3.9458 0 Td
(pro-)Tj
-34.6504 -1.304 Td
(duction)Tj
3.3165 0 Td
(of)Tj
1.0148 0 Td
(reactive)Tj
3.3165 0 Td
(oxygen)Tj
3.0841 0 Td
(species)Tj
2.999 0 Td
(and)Tj
1.7291 0 Td
(DNA)Tj
2.3754 0 Td
(damage)Tj
3.3279 0 Td
([)Tj
0.83 0.64 0.02 0 k
(1)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(2)Tj
0 g
(].)Tj
2.3017 0 Td
(The)Tj
1.7801 0 Td
(combination)Tj
5.3462 0 Td
(of)Tj
1.0148 0 Td
(exposure)Tj
3.821 0 Td
(to)Tj
-35.4271 -1.2982 Td
(noxious)Tj
3.3958 0 Td
(substances)Tj
4.4561 0 Td
(and)Tj
1.7178 0 Td
(defects)Tj
2.9593 0 Td
(in)Tj
1.0261 0 Td
(DNA)Tj
2.3698 0 Td
(damage)Tj
3.3165 0 Td
(repair)Tj
2.5965 0 Td
(enable)Tj
2.795 0 Td
(cancer)Tj
2.8346 0 Td
(cells)Tj
1.9105 0 Td
(to)Tj
1.0148 0 Td
(accumulate)Tj
4.7735 0 Td
(muta-)Tj
-35.1663 -1.2983 Td
(tions,)Tj
2.4264 0 Td
(evidenced)Tj
4.2406 0 Td
(by)Tj
1.1792 0 Td
(characteristic)Tj
5.5445 0 Td
(mutational)Tj
4.6035 0 Td
(signatures)Tj
4.2746 0 Td
([)Tj
0.83 0.64 0.02 0 k
(3)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(4)Tj
0 g
(].)Tj
-21.0726 -1.3039 Td
(Next)Tj
2.1486 0 Td
(generation)Tj
4.5014 0 Td
(sequencing)Tj
4.7168 0 Td
(studies)Tj
2.9877 0 Td
(have)Tj
2.058 0 Td
(shown)Tj
2.8516 0 Td
(that)Tj
1.7745 0 Td
(accumulation)Tj
5.6806 0 Td
(of)Tj
1.0148 0 Td
(somatic)Tj
3.3278 0 Td
(mutations)Tj
-32.258 -1.2983 Td
(occurs)Tj
2.8346 0 Td
(along)Tj
2.4207 0 Td
(the)Tj
1.4684 0 Td
(metaplasiadysplasiacarcino)Tj
11.8487 0 Td
(ma)Tj
1.474 0 Td
(sequence)Tj
3.8551 0 Td
(in)Tj
1.0375 0 Td
(EAC)Tj
2.1373 0 Td
([)Tj
0.83 0.64 0.02 0 k
(5)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(])Tj
2.075 0 Td
(and)Tj
1.7291 0 Td
(potentially)Tj
-30.8804 -1.2982 Td
(impair)Tj
2.8969 0 Td
(important)Tj
4.2803 0 Td
(cell)Tj
1.5591 0 Td
(functions.)Tj
4.2122 0 Td
(However,)Tj
4.0819 0 Td
(few)Tj
1.6157 0 Td
(genes)Tj
2.4378 0 Td
(are)Tj
1.4513 0 Td
(mutated)Tj
3.549 0 Td
(in)Tj
1.0375 0 Td
(greater)Tj
3.0047 0 Td
(than)Tj
2.0296 0 Td
(10%)Tj
1.9275 0 Td
(of)Tj
1.0148 0 Td
(cases,)Tj
-35.0983 -1.304 Td
(underlining)Tj
4.9605 0 Td
(the)Tj
1.4684 0 Td
(heterogeneous)Tj
6.0264 0 Td
(nature)Tj
2.8233 0 Td
(of)Tj
1.0148 0 Td
(point)Tj
2.3584 0 Td
(mutations)Tj
4.286 0 Td
(and)Tj
1.7291 0 Td
(small)Tj
2.3244 0 Td
(indels)Tj
2.5965 0 Td
(in)Tj
1.0375 0 Td
(this)Tj
1.6724 0 Td
(type)Tj
1.9162 0 Td
(of)Tj
1.0148 0 Td
(can-)Tj
-35.2287 -1.2982 Td
(cer.)Tj
1.661 0 Td
(As)Tj
1.2643 0 Td
(a)Tj
0.6576 0 Td
(result)Tj
2.4491 0 Td
(it)Tj
0.7824 0 Td
(is)Tj
0.8504 0 Td
(difficult)Tj
3.3505 0 Td
(to)Tj
1.0261 0 Td
(pinpoint)Tj
3.6907 0 Td
(the)Tj
1.4684 0 Td
(genes)Tj
2.4434 0 Td
(that)Tj
1.7802 0 Td
(are)Tj
1.4456 0 Td
(relevant)Tj
3.4243 0 Td
(to)Tj
1.0204 0 Td
(tumorigenesis)Tj
5.862 0 Td
(using)Tj
2.3925 0 Td
(tra-)Tj
-35.5689 -1.2983 Td
(ditional)Tj
3.3165 0 Td
(approaches)Tj
4.7338 0 Td
(based)Tj
2.4718 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.474 0 Td
(frequency)Tj
4.1839 0 Td
(of)Tj
1.0148 0 Td
(mutations)Tj
4.2803 0 Td
(in)Tj
1.0374 0 Td
(a)Tj
0.6577 0 Td
(single)Tj
2.5285 0 Td
(gene.)Tj
2.3074 0 Td
(It)Tj
0.856 0 Td
(has)Tj
1.5421 0 Td
(been)Tj
2.1259 0 Td
(proposed)Tj
-33.8057 -1.2982 Td
(that)Tj
1.7744 0 Td
(groups)Tj
2.9707 0 Td
(of)Tj
1.0148 0 Td
(genes)Tj
2.4435 0 Td
(involved)Tj
3.651 0 Td
(in)Tj
1.0318 0 Td
(similar)Tj
2.9877 0 Td
(processes)Tj
3.9684 0 Td
(or)Tj
1.0999 0 Td
(pathways)Tj
3.9288 0 Td
(could)Tj
2.4548 0 Td
(have)Tj
2.0579 0 Td
(a)Tj
0.6576 0 Td
(cumulative)Tj
4.6375 0 Td
(effect.)Tj
-34.6788 -1.304 Td
(An)Tj
1.4513 0 Td
(example)Tj
3.5489 0 Td
(is)Tj
0.8504 0 Td
(the)Tj
1.4684 0 Td
(SWI/SNF)Tj
4.0705 0 Td
(nucleosome)Tj
5.0059 0 Td
(remodeling)Tj
4.8189 0 Td
(complex)Tj
3.6227 0 Td
(\(ARID1A,)Tj
4.3313 0 Td
(SMARCA4)Tj
4.7168 0 Td
(and)Tj
-33.8851 -1.2982 Td
(ARID2\),)Tj
3.6396 0 Td
(for)Tj
1.389 0 Td
(which)Tj
2.6475 0 Td
(gene)Tj
2.0806 0 Td
(members)Tj
3.9458 0 Td
(are)Tj
1.4514 0 Td
(mutated)Tj
3.5489 0 Td
(collectively)Tj
4.6318 0 Td
(in)Tj
1.0375 0 Td
(20%)Tj
1.9275 0 Td
(of)Tj
1.0148 0 Td
(EAC)Tj
2.1373 0 Td
(tumors)Tj
3.1068 0 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(].)Tj
1.5987 0 Td
(Compu-)Tj
-34.1572 -1.2983 Td
(tational)Tj
3.2541 0 Td
(tools)Tj
2.1373 0 Td
(such)Tj
2.058 0 Td
(as)Tj
1.0147 0 Td
(PathScan)Tj
3.9232 0 Td
([)Tj
0.83 0.64 0.02 0 k
(7)Tj
0 g
(])Tj
1.3776 0 Td
(have)Tj
2.0579 0 Td
(been)Tj
2.1203 0 Td
(developed)Tj
4.2747 0 Td
(to)Tj
1.0261 0 Td
(identify)Tj
3.2938 0 Td
(cellular)Tj
3.1351 0 Td
(pathways)Tj
3.9345 0 Td
(that)Tj
1.7801 0 Td
(are)Tj
-35.3874 -1.3039 Td
(targeted)Tj
3.4582 0 Td
(by)Tj
1.1849 0 Td
(somatic)Tj
3.3278 0 Td
(mutations)Tj
4.286 0 Td
(above)Tj
2.5455 0 Td
(the)Tj
1.4683 0 Td
(background)Tj
5.0286 0 Td
(mutation)Tj
3.9175 0 Td
(rate.)Tj
-24.0206 -1.2983 Td
(Epidemiologic)Tj
6.0321 0 Td
(evidence)Tj
3.7076 0 Td
(has)Tj
1.5478 0 Td
(linked)Tj
2.7269 0 Td
(the)Tj
1.4683 0 Td
(rising)Tj
2.5001 0 Td
(incidence)Tj
4.0762 0 Td
(of)Tj
1.0148 0 Td
(EAC)Tj
2.1373 0 Td
(with)Tj
1.9956 0 Td
(the)Tj
1.4684 0 Td
(eradication)Tj
4.7224 0 Td
(of)Tj
/F11 1 Tf
1.0148 0 Td
[()31()15()12()]TJ
-35.6085 -1.2982 Td
[()7()13()4( )6()-4(\n)11()2()]TJ
3.4412 0 Td
[()12(\r)3()4()11()-9()]TJ
/F6 1 Tf
2.4548 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(9)Tj
0 g
(],)Tj
2.3017 0 Td
(and)Tj
1.7348 0 Td
(studies)Tj
2.982 0 Td
(have)Tj
2.0636 0 Td
(suggested)Tj
4.0705 0 Td
(that)Tj
1.7802 0 Td
(the)Tj
1.4683 0 Td
(esophageal)Tj
4.5581 0 Td
(microbiota)Tj
4.6261 0 Td
(are)Tj
1.4457 0 Td
(altered)Tj
2.948 0 Td
(in)Tj
-35.875 -1.304 Td
(Barrett's)Tj
3.5716 0 Td
(esophagus)Tj
4.3426 0 Td
([)Tj
0.83 0.64 0.02 0 k
(10)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(12)Tj
0 g
(])Tj
3.3222 0 Td
(and)Tj
1.7291 0 Td
(EAC)Tj
2.1373 0 Td
(with)Tj
1.9956 0 Td
(decreased)Tj
4.1386 0 Td
(microbial)Tj
4.0592 0 Td
(diversity)Tj
3.6453 0 Td
([)Tj
0.83 0.64 0.02 0 k
(13)Tj
0 g
(].)Tj
2.0806 0 Td
(The)Tj
1.7802 0 Td
(Toll-like)Tj
-32.8023 -1.2982 Td
(receptor)Tj
3.5546 0 Td
(\(TLR\))Tj
2.6702 0 Td
(signaling)Tj
3.8211 0 Td
(pathway)Tj
3.5716 0 Td
(is)Tj
0.8504 0 Td
(a)Tj
0.652 0 Td
(key)Tj
1.593 0 Td
(component)Tj
4.8132 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(innate)Tj
2.7383 0 Td
(immune)Tj
3.6283 0 Td
(system)Tj
2.9367 0 Td
(and)Tj
1.7291 0 Td
(one)Tj
-35.0473 -1.2983 Td
(of)Tj
1.0147 0 Td
(the)Tj
1.4684 0 Td
(main)Tj
2.2904 0 Td
(ways)Tj
2.1543 0 Td
(in)Tj
1.0318 0 Td
(which)Tj
2.6532 0 Td
(tumor)Tj
2.7439 0 Td
(cells)Tj
1.9219 0 Td
(interact)Tj
3.2825 0 Td
(with)Tj
1.9956 0 Td
(the)Tj
1.474 0 Td
(microbiota.)Tj
4.8472 0 Td
(TLRs)Tj
2.3471 0 Td
(are)Tj
1.4513 0 Td
(pattern)Tj
3.1124 0 Td
(recogni-)Tj
-33.7887 -1.3039 Td
(tion)Tj
1.8425 0 Td
(receptors)Tj
3.9117 0 Td
(that)Tj
1.7802 0 Td
(bind)Tj
2.0693 0 Td
(unique)Tj
3.0217 0 Td
(molecular)Tj
4.2179 0 Td
(components)Tj
5.176 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(microbiota)Tj
4.6261 0 Td
(and)Tj
1.7291 0 Td
(generate)Tj
3.6057 0 Td
(a)Tj
0.6576 0 Td
(pro-)Tj
-35.121 -1.2983 Td
(inflammatory)Tj
5.7089 0 Td
(innate)Tj
2.7382 0 Td
(immune)Tj
3.6284 0 Td
(reaction)Tj
3.4922 0 Td
(through)Tj
3.4469 0 Td
(nuclear)Tj
3.1918 0 Td
(factor)Tj
2.5399 0 Td
(kappa)Tj
2.6191 0 Td
(B)Tj
0.7994 0 Td
(\(NF-)Tj
/F12 1 Tf
()Tj
/F6 1 Tf
(B\))Tj
3.634 0 Td
([)Tj
0.83 0.64 0.02 0 k
(14)Tj
0 g
(].)Tj
2.0806 0 Td
(TLR)Tj
1.9899 0 Td
(sig-)Tj
-35.8693 -1.2982 Td
(naling)Tj
2.7269 0 Td
(exerts)Tj
2.5625 0 Td
(an)Tj
1.2018 0 Td
(effect)Tj
2.3698 0 Td
(on)Tj
1.2756 0 Td
(epithelial)Tj
3.8664 0 Td
(cell)Tj
1.5591 0 Td
(function)Tj
3.6283 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(gastrointestinal)Tj
6.3496 0 Td
(tract,)Tj
2.2733 0 Td
(including)Tj
4.0422 0 Td
(stimu-)Tj
-34.3613 -1.2983 Td
(lating)Tj
2.4774 0 Td
(repair)Tj
2.6079 0 Td
(of)Tj
1.0148 0 Td
(damaged)Tj
3.8494 0 Td
(enterocytes)Tj
4.7508 0 Td
(\(lipopolysaccharide)Tj
7.8009 0 Td
(\),)Tj
0.7824 0 Td
(enhancing)Tj
4.405 0 Td
(cell)Tj
1.559 0 Td
(proliferation,)Tj
5.4935 0 Td
(and)Tj
-34.7411 -1.3039 Td
(triggering)Tj
4.1612 0 Td
(secretion)Tj
3.8437 0 Td
(of)Tj
1.0148 0 Td
(antimicrobial)Tj
5.6126 0 Td
(peptides)Tj
3.5546 0 Td
(\(lipopolysaccharide)Tj
8.0163 0 Td
(and)Tj
1.7292 0 Td
(flagellin\))Tj
3.7247 0 Td
([)Tj
0.83 0.64 0.02 0 k
(15)Tj
0 g
(].)Tj
2.0749 0 Td
(Along-)Tj
-33.732 -1.2983 Td
(side)Tj
1.7971 0 Td
(TLRs,)Tj
2.5795 0 Td
(inflammasomes)Tj
6.548 0 Td
(also)Tj
1.7688 0 Td
(contribute)Tj
4.3937 0 Td
(to)Tj
1.0205 0 Td
(inflammation)Tj
5.6976 0 Td
(through)Tj
3.4469 0 Td
(recognition)Tj
4.8472 0 Td
(of)Tj
1.0148 0 Td
(pathogen-)Tj
-33.1141 -1.2982 Td
(associated)Tj
4.2576 0 Td
(molecular)Tj
4.2179 0 Td
(patterns.)Tj
3.6963 0 Td
(NLRP6)Tj
3.1521 0 Td
(is)Tj
0.8448 0 Td
(a)Tj
0.6576 0 Td
(member)Tj
3.583 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(NOD-like)Tj
4.2236 0 Td
(receptor)Tj
3.5546 0 Td
(family)Tj
2.7326 0 Td
(that)Tj
1.7802 0 Td
(plays)Tj
-35.1834 -1.304 Td
(a)Tj
0.6519 0 Td
(role)Tj
1.7688 0 Td
(in)Tj
1.0375 0 Td
(regulating)Tj
4.2633 0 Td
(inflammation)Tj
5.6976 0 Td
(and)Tj
1.7348 0 Td
(epithelial)Tj
3.8664 0 Td
(cell)Tj
1.5647 0 Td
(repair)Tj
2.6022 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(intestine)Tj
3.6567 0 Td
(and)Tj
1.7291 0 Td
(has)Tj
1.542 0 Td
(been)Tj
2.1203 0 Td
(impli-)Tj
-34.7411 -1.2982 Td
(cated)Tj
2.3243 0 Td
(in)Tj
1.0375 0 Td
(colorectal)Tj
4.0989 0 Td
(carcinogenesis)Tj
6.0434 0 Td
([)Tj
0.83 0.64 0.02 0 k
(16)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(17)Tj
0 g
(].)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 133.6819 23.6976 re
W* n
q
133.6252 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 322.4692 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Impac)Tj
2.6787 0 Td
(t)Tj
0.4961 0 Td
(of)Tj
1.0417 0 Td
(mutations)Tj
4.4859 0 Td
(in)Tj
0.9779 0 Td
(TLR)Tj
2.0835 0 Td
(pathway)Tj
3.8835 0 Td
(genes)Tj
2.8914 0 Td
(on)Tj
1.311 0 Td
(esophageal)Tj
5.2938 0 Td
(carcinoge)Tj
4.252 0 Td
(nesis)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
95.5276 34.9228 m
251.8299 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(Genetics)Tj
4.1102 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4749 0 Td
(https://)Tj
2.9551 0 Td
(doi.org/10.13)Tj
5.7331 0 Td
(71/journal.p)Tj
5.1237 0 Td
(gen.100)Tj
3.5433 0 Td
(6808)Tj
0 g
3.1819 0 Td
(May)Tj
2.0835 0 Td
(22,)Tj
1.5874 0 Td
(2017)Tj
33.4916 0 Td
(2)Tj
0.7654 0 Td
(/)Tj
0.496 0 Td
(21)Tj
/F9 1 Tf
-0.025 Tc
-66.402 84.0904 Td
(\(NIHR\),)Tj
3.0756 0 Td
(a)Tj
0.6449 0 Td
(Programm)Tj
4.011 0 Td
(e)Tj
0.6449 0 Td
(Grant)Tj
2.2677 0 Td
(to)Tj
0.9426 0 Td
(RCF)Tj
1.7574 0 Td
(from)Tj
2.0127 0 Td
(the)Tj
-15.3568 -1.3748 Td
(Medical)Tj
3.0968 0 Td
(Research)Tj
3.6993 0 Td
(Council)Tj
2.9693 0 Td
(\(RG72746)Tj
3.848 0 Td
(\),)Tj
0.7512 0 Td
(a)Tj
0.6449 0 Td
(NIHR)Tj
-15.0095 -1.3749 Td
(Professors)Tj
4.0252 0 Td
(hip)Tj
1.3606 0 Td
(to)Tj
0.9496 0 Td
(RCF)Tj
1.7575 0 Td
(\(RG67258)Tj
3.8481 0 Td
(\),)Tj
0.7512 0 Td
(and)Tj
1.5874 0 Td
(a)Tj
0.6449 0 Td
(United)Tj
-14.9245 -1.3748 Td
(European)Tj
3.7346 0 Td
(Gastroentero)Tj
4.819 0 Td
(logy)Tj
1.7858 0 Td
(prize)Tj
1.9701 0 Td
(to)Tj
0.9496 0 Td
(DRFE.)Tj
2.5158 0 Td
(The)Tj
-15.7749 -1.3748 Td
(funders)Tj
3.0472 0 Td
(had)Tj
1.5874 0 Td
(no)Tj
1.1693 0 Td
(role)Tj
1.6087 0 Td
(in)Tj
0.8929 0 Td
(study)Tj
2.2607 0 Td
(design,)Tj
2.8984 0 Td
(data)Tj
1.793 0 Td
(collection)Tj
-15.2576 -1.3748 Td
(and)Tj
1.5874 0 Td
(analysis,)Tj
3.4087 0 Td
(decision)Tj
3.2953 0 Td
(to)Tj
0.9496 0 Td
(publish,)Tj
3.1464 0 Td
(or)Tj
0.9993 0 Td
(preparation)Tj
4.4362 0 Td
(of)Tj
-17.8229 -1.3748 Td
(the)Tj
1.3677 0 Td
(manuscript.)Tj
/F8 1 Tf
-1.3677 -2.126 Td
(Competing)Tj
4.3795 0 Td
(interests)Tj
3.3307 0 Td
(:)Tj
/F9 1 Tf
0.4819 0 Td
(The)Tj
1.5875 0 Td
(authors)Tj
3.0401 0 Td
(have)Tj
1.963 0 Td
(declared)Tj
-14.7827 -1.3748 Td
(that)Tj
1.6228 0 Td
(no)Tj
1.1693 0 Td
(competing)Tj
4.1599 0 Td
(interests)Tj
ET
endstream
endobj
36 0 obj
<>stream
endstream
endobj
37 0 obj
<>stream
endstream
endobj
38 0 obj
<>stream
endstream
endobj
39 0 obj
<>stream
endstream
endobj
40 0 obj
<>stream
endstream
endobj
41 0 obj
<>stream
endstream
endobj
42 0 obj
<>stream
endstream
endobj
43 0 obj
<>stream
endstream
endobj
44 0 obj
<>stream
endstream
endobj
45 0 obj
<>stream
endstream
endobj
46 0 obj
<>stream
endstream
endobj
47 0 obj
<>stream
endstream
endobj
48 0 obj
<>stream
endstream
endobj
49 0 obj
<>stream
endstream
endobj
50 0 obj
<>stream
endstream
endobj
51 0 obj
<>stream
endstream
endobj
52 0 obj
<>stream
BT
10.3394 72.3407 Td
(exist.)Tj
ET
Q
endstream
endobj
53 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 13 0 R/Annots 54 0 R/Contents 55 0 R/TrimBox[0 0 612 792]>>
endobj
54 0 obj
[56 0 R 57 0 R 58 0 R 59 0 R 60 0 R 61 0 R 62 0 R 63 0 R 64 0 R 65 0 R 66 0 R 67 0 R 68 0 R 69 0 R 70 0 R 71 0 R]
endobj
56 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref018)>>
endobj
57 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref019)>>
endobj
58 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref005)>>
endobj
59 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref006)>>
endobj
60 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.g001)>>
endobj
61 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.s001)>>
endobj
62 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.g001)>>
endobj
63 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.s011)>>
endobj
64 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.s011)>>
endobj
65 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.s011)>>
endobj
66 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.s011)>>
endobj
67 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref020)>>
endobj
68 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.s012)>>
endobj
69 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.s002)>>
endobj
70 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006808.ref006)>>
endobj
71 0 obj
<>/Border[0 0 0]/A 72 0 R>>
endobj
72 0 obj
<>
endobj
55 0 obj
[73 0 R 74 0 R 75 0 R 76 0 R 77 0 R 78 0 R 79 0 R 80 0 R 81 0 R 82 0 R 83 0 R 84 0 R 85 0 R 86 0 R]
endobj
73 0 obj
<>stream
q
0.83 0.64 0.02 0 k
350.6457 706.337 m
360.1701 706.337 l
h
f*
362.4378 706.337 m
371.9055 706.337 l
h
f*
541.1906 706.337 m
545.9528 706.337 l
h
f*
548.2205 706.337 m
552.926 706.337 l
h
f*
405.4677 470.0976 m
430.8094 470.0976 l
h
f*
435.0614 470.0976 m
467.5465 470.0976 l
h
f*
256.0252 444.1323 m
281.5937 444.1323 l
h
f*
360.6803 418.1102 m
383.811 418.1102 l
h
f*
562.4504 392.1449 m
571.8047 392.1449 l
h
f*
200.0126 379.1055 m
211.9748 379.1055 l
h
f*
502.1858 340.1008 m
525.4299 340.1008 l
h
f*
534.0472 340.1008 m
543.1181 340.1008 l
h
f*
310.5638 275.1307 m
334.3748 275.1307 l
h
f*
330.9165 197.1213 m
364.1386 197.1213 l
h
f*
322.8661 81.9213 m
327.6283 81.9213 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 211.9748 707.4141 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Genome-wide)Tj
5.913 0 Td
(association)Tj
4.6261 0 Td
(studies)Tj
2.9877 0 Td
([)Tj
0.83 0.64 0.02 0 k
(18)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(19)Tj
0 g
(])Tj
3.0274 0 Td
(and)Tj
1.7291 0 Td
(next-generation)Tj
6.5933 0 Td
(sequencing)Tj
4.7169 0 Td
(studies)Tj
2.9877 0 Td
([)Tj
0.83 0.64 0.02 0 k
(5)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(])Tj
-33.7774 -1.3039 Td
(have)Tj
2.0579 0 Td
(identified)Tj
/F11 1 Tf
4.0592 0 Td
[()]TJ
/F6 1 Tf
2.3924 0 Td
(gene)Tj
2.0806 0 Td
(mutations)Tj
4.2803 0 Td
(in)Tj
1.0375 0 Td
(solid)Tj
2.1316 0 Td
(tumors)Tj
3.1011 0 Td
(including)Tj
4.0422 0 Td
(EAC.)Tj
2.3641 0 Td
(We)Tj
1.61 0 Td
(hypothesized)Tj
5.4652 0 Td
(that)Tj
-34.6221 -1.2982 Td
(somatic)Tj
3.3278 0 Td
(mutations)Tj
4.2803 0 Td
(may)Tj
1.9332 0 Td
(collectively)Tj
4.6318 0 Td
(target)Tj
2.5115 0 Td
(the)Tj
1.4683 0 Td
(TLR)Tj
1.9899 0 Td
(signaling)Tj
3.8267 0 Td
(pathway)Tj
3.566 0 Td
(in)Tj
1.0375 0 Td
(EAC)Tj
2.1373 0 Td
(and)Tj
1.7291 0 Td
(alter)Tj
1.9956 0 Td
(inflam-)Tj
-34.435 -1.2983 Td
(matory)Tj
3.101 0 Td
(signaling.)Tj
4.0535 0 Td
(We)Tj
1.6044 0 Td
(aimed)Tj
2.6929 0 Td
(to)Tj
1.0262 0 Td
(interrogate)Tj
4.6261 0 Td
(TLR)Tj
1.9956 0 Td
(pathway)Tj
3.5659 0 Td
(mutations)Tj
4.286 0 Td
(and)Tj
1.7291 0 Td
(expression)Tj
4.4617 0 Td
(in)Tj
1.0375 0 Td
(a)Tj
0.6519 0 Td
(cohort)Tj
-34.8318 -1.2983 Td
(of)Tj
1.0148 0 Td
(EAC)Tj
2.1372 0 Td
(and)Tj
1.7292 0 Td
(Barrett's)Tj
3.5716 0 Td
(esophagus)Tj
4.3426 0 Td
(patients)Tj
3.3676 0 Td
(with)Tj
2.0012 0 Td
(clinical)Tj
3.0728 0 Td
(outcome)Tj
3.7303 0 Td
(data.)Tj
2.1373 0 Td
(We)Tj
1.6101 0 Td
(then)Tj
2.0183 0 Td
(investigated)Tj
-30.733 -1.3039 Td
(whether)Tj
/F11 1 Tf
3.4752 0 Td
[()]TJ
/F6 1 Tf
2.3924 0 Td
(mutations)Tj
4.2803 0 Td
(in)Tj
1.0375 0 Td
(EAC)Tj
2.1373 0 Td
(affect)Tj
2.3754 0 Td
(downstream)Tj
5.193 0 Td
(inflammatory)Tj
5.709 0 Td
(signaling)Tj
3.8267 0 Td
(using)Tj
2.3868 0 Td
(an)Tj
/F11 1 Tf
1.2019 0 Td
[()12()]TJ
1.0148 0 Td
[()-13()14(\n)7()20()]TJ
/F6 1 Tf
-35.0303 -1.2982 Td
(model)Tj
2.7439 0 Td
(system.)Tj
3.1634 0 Td
(Finally,)Tj
3.1691 0 Td
(we)Tj
1.3266 0 Td
(aimed)Tj
2.6929 0 Td
(to)Tj
1.0262 0 Td
(determine)Tj
4.3199 0 Td
(the)Tj
1.474 0 Td
(broader)Tj
3.3619 0 Td
(relevance)Tj
3.9685 0 Td
(of)Tj
1.0148 0 Td
(TLR)Tj
1.9899 0 Td
(pathway)Tj
3.5716 0 Td
(muta-)Tj
-33.8227 -1.2983 Td
(tions)Tj
2.1996 0 Td
(in)Tj
1.0375 0 Td
(other)Tj
2.3471 0 Td
(cancers)Tj
3.2031 0 Td
(using)Tj
2.3924 0 Td
(TCGA)Tj
2.8913 0 Td
(data)Tj
1.9162 0 Td
(and)Tj
1.7292 0 Td
(the)Tj
1.4683 0 Td
(COSMIC)Tj
4.0025 0 Td
(database.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 584.2204 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Results)Tj
/F0 1 Tf
0 -1.5023 Td
(The)Tj
1.9275 0 Td
(TLR)Tj
2.093 0 Td
(pathway)Tj
3.9023 0 Td
(is)Tj
0.9308 0 Td
(significantly)Tj
5.3197 0 Td
(mutated)Tj
3.7937 0 Td
(in)Tj
0.9874 0 Td
(EAC)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 549.1842 cm
BT
/F6 1 Tf
1 TL
-0.025 Tc
0 0 Td
(To)Tj
1.2925 0 Td
(determine)Tj
4.1386 0 Td
(whether)Tj
3.3278 0 Td
(the)Tj
1.406 0 Td
(TLR)Tj
1.9276 0 Td
(signaling)Tj
3.634 0 Td
(pathway)Tj
3.4242 0 Td
(is)Tj
0.805 0 Td
(dysregulated)Tj
5.0287 0 Td
(through)Tj
3.2995 0 Td
(somatic)Tj
3.1861 0 Td
(mutations)Tj
4.0932 0 Td
(in)Tj
-35.5632 -1.2982 Td
(EAC,)Tj
2.279 0 Td
(we)Tj
1.2812 0 Td
(interrogated)Tj
4.9039 0 Td
(the)Tj
1.4117 0 Td
(mutational)Tj
4.388 0 Td
(profiles)Tj
3.033 0 Td
(of)Tj
0.9752 0 Td
(171)Tj
1.5817 0 Td
(EAC)Tj
2.0749 0 Td
(tumors)Tj
2.9821 0 Td
(and)Tj
1.6667 0 Td
(matched)Tj
3.5263 0 Td
(germline)Tj
3.617 0 Td
(controls)Tj
-33.7207 -1.2983 Td
(that)Tj
1.6951 0 Td
(were)Tj
2.0352 0 Td
(sequenced)Tj
4.2009 0 Td
(as)Tj
0.9695 0 Td
(part)Tj
1.7575 0 Td
(of)Tj
0.9751 0 Td
(the)Tj
1.4059 0 Td
(International)Tj
5.2101 0 Td
(Cancer)Tj
2.9593 0 Td
(Genome)Tj
3.532 0 Td
(Consortium)Tj
4.8812 0 Td
(\(ICGC\))Tj
3.1578 0 Td
(esophageal)Tj
-32.7796 -1.3039 Td
(study.)Tj
2.4888 0 Td
(Non-synonymous)Tj
7.1602 0 Td
(somatic)Tj
3.1805 0 Td
(mutations)Tj
4.0932 0 Td
(affected)Tj
3.1578 0 Td
(the)Tj
1.4059 0 Td
(Toll-like)Tj
3.4243 0 Td
(receptor)Tj
3.3902 0 Td
(signaling)Tj
3.634 0 Td
(pathway)Tj
3.4242 0 Td
(in)Tj
-35.3591 -1.2983 Td
(25/171)Tj
2.8006 0 Td
(\(14.6%\))Tj
3.1634 0 Td
(of)Tj
0.9694 0 Td
(EAC)Tj
2.075 0 Td
(samples.)Tj
3.4412 0 Td
(Missense)Tj
3.6907 0 Td
(mutations)Tj
4.0932 0 Td
(\(and)Tj
1.9843 0 Td
(two)Tj
1.6497 0 Td
(splice)Tj
2.3301 0 Td
(variants\))Tj
3.5433 0 Td
(were)Tj
2.0352 0 Td
(identified)Tj
3.8495 0 Td
(in)Tj
/F11 1 Tf
-35.6256 -1.2982 Td
[()]TJ
/F6 1 Tf
2.3073 0 Td
(\(5.8%\),)Tj
/F11 1 Tf
2.914 0 Td
[()-16()]TJ
/F6 1 Tf
2.931 0 Td
(\(1.8%\),)Tj
/F11 1 Tf
2.914 0 Td
[()]TJ
/F6 1 Tf
2.3074 0 Td
(\(1.8%\),)Tj
/F11 1 Tf
2.914 0 Td
[()]TJ
/F6 1 Tf
2.3074 0 Td
(\(1.2%\),)Tj
/F11 1 Tf
2.914 0 Td
[()]TJ
/F6 1 Tf
3.2145 0 Td
(\(1.2%\),)Tj
/F11 1 Tf
2.9083 0 Td
[()-16()]TJ
/F6 1 Tf
2.7949 0 Td
(\(1.2%\),)Tj
/F11 1 Tf
2.914 0 Td
[( )]TJ
/F6 1 Tf
-33.3408 -1.3039 Td
(\(0.6%\),)Tj
/F11 1 Tf
2.9139 0 Td
[()-16(!)]TJ
/F6 1 Tf
2.9311 0 Td
(\(0.6%\),)Tj
/F11 1 Tf
2.9083 0 Td
[(")]TJ
/F6 1 Tf
2.313 0 Td
(\(0.6%\),)Tj
2.9084 0 Td
(and)Tj
/F11 1 Tf
1.6667 0 Td
[(#)]TJ
/F6 1 Tf
2.3131 0 Td
(\(0.6%,)Tj
0.83 0.64 0.02 0 k
2.5908 0 Td
(Fig)Tj
1.4173 0 Td
(1A)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.5421 0 Td
(S1)Tj
1.1338 0 Td
(Table)Tj
0 g
(\).)Tj
2.8573 0 Td
(Applying)Tj
3.7531 0 Td
(the)Tj
1.406 0 Td
(PathScan)Tj
-32.6549 -1.2983 Td
(tool)Tj
1.6951 0 Td
(showed)Tj
3.1237 0 Td
(that)Tj
1.6951 0 Td
(genes)Tj
2.3358 0 Td
(in)Tj
0.9921 0 Td
(the)Tj
1.406 0 Td
(TLR)Tj
1.9275 0 Td
(signaling)Tj
3.634 0 Td
(pathway)Tj
3.4242 0 Td
(were)Tj
2.041 0 Td
(significantly)Tj
4.8188 0 Td
(enriched)Tj
3.5603 0 Td
(for)Tj
1.3266 0 Td
(mutations)Tj
-31.9802 -1.2983 Td
(\(p)Tj
1.0318 0 Td
(=)Tj
0.7823 0 Td
(8.7x10)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 242.8157 449.6314 cm
BT
/F6 1 Tf
1 TL
-0.0333 Tc
0 0 Td
(-5)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 248.5984 445.2094 cm
BT
/F6 1 Tf
1 TL
-0.025 Tc
0 0 Td
(\).)Tj
0.83 0.64 0.02 0 k
0.7426 0 Td
(Fig)Tj
1.4173 0 Td
(1A)Tj
0 g
1.338 0 Td
(presents)Tj
3.3562 0 Td
(the)Tj
1.406 0 Td
(mutation)Tj
3.753 0 Td
(and)Tj
1.6668 0 Td
(copy)Tj
2.0352 0 Td
(number)Tj
3.2939 0 Td
(status)Tj
2.3754 0 Td
(for)Tj
1.3209 0 Td
(known)Tj
2.9027 0 Td
(recurrent)Tj
3.787 0 Td
(alter-)Tj
-34.2535 -1.2982 Td
(ations)Tj
2.5115 0 Td
(in)Tj
0.9921 0 Td
(EAC)Tj
2.0748 0 Td
(in)Tj
0.9922 0 Td
(the)Tj
1.4059 0 Td
(context)Tj
3.0388 0 Td
(of)Tj
0.9694 0 Td
(TLR)Tj
1.9332 0 Td
(pathway)Tj
3.4186 0 Td
(mutated)Tj
3.4072 0 Td
(samples,)Tj
3.4356 0 Td
(and)Tj
1.6667 0 Td
(these)Tj
2.1544 0 Td
(events)Tj
2.6021 0 Td
(are)Tj
1.3833 0 Td
(compared)Tj
-31.9858 -1.3039 Td
(with)Tj
1.8992 0 Td
(the)Tj
1.3946 0 Td
(remainder)Tj
4.2065 0 Td
(of)Tj
0.9638 0 Td
(the)Tj
1.3946 0 Td
(ICGC)Tj
2.5058 0 Td
(cohort)Tj
2.7213 0 Td
(in)Tj
0.83 0.64 0.02 0 k
0.9808 0 Td
(S1)Tj
1.1168 0 Td
(Fig)Tj
0 g
(.)Tj
1.6101 0 Td
(As)Tj
1.2132 0 Td
(expected)Tj
3.5433 0 Td
(in)Tj
0.9808 0 Td
(EAC,)Tj
2.2677 0 Td
(most)Tj
2.1089 0 Td
(samples)Tj
3.2258 0 Td
(showed)Tj
3.1125 0 Td
(muta-)Tj
-35.2457 -1.2983 Td
(tions)Tj
2.0976 0 Td
(in)Tj
/F11 1 Tf
0.9921 0 Td
[( "!)]TJ
/F6 1 Tf
(,)Tj
2.4094 0 Td
(independent)Tj
5.0456 0 Td
(of)Tj
0.9695 0 Td
(whether)Tj
3.3335 0 Td
(or)Tj
1.0545 0 Td
(not)Tj
1.508 0 Td
(they)Tj
1.8425 0 Td
(contain)Tj
3.1011 0 Td
(TLR)Tj
1.9275 0 Td
(pathway)Tj
3.4243 0 Td
(mutations.)Tj
4.2972 0 Td
(There)Tj
2.4718 0 Td
(was)Tj
1.6385 0 Td
(no)Tj
-36.1131 -1.2983 Td
(significant)Tj
4.1556 0 Td
(enrichment)Tj
4.66 0 Td
(of)Tj
0.9751 0 Td
(other)Tj
2.245 0 Td
(known)Tj
2.897 0 Td
(driver)Tj
2.5115 0 Td
(mutations)Tj
4.0932 0 Td
(in)Tj
0.9921 0 Td
(the)Tj
1.406 0 Td
(TLR)Tj
1.9275 0 Td
(pathway)Tj
3.4243 0 Td
(mutated)Tj
3.4015 0 Td
(samples)Tj
3.2372 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S1)Tj
-35.926 -1.3039 Td
(Fig)Tj
0 g
(\).)Tj
1.9389 0 Td
(TLR)Tj
1.9275 0 Td
(pathway)Tj
3.4242 0 Td
(mutated)Tj
3.4015 0 Td
(tumors)Tj
2.982 0 Td
(did)Tj
1.4797 0 Td
(not)Tj
1.508 0 Td
(show)Tj
2.2167 0 Td
(significant)Tj
4.1556 0 Td
(differences)Tj
4.337 0 Td
(in)Tj
0.9921 0 Td
(the)Tj
1.406 0 Td
(numbers)Tj
3.634 0 Td
(of)Tj
0.9751 0 Td
(total)Tj
-34.3783 -1.2982 Td
(SNVs)Tj
2.4038 0 Td
(\(Welch's)Tj
3.5545 0 Td
(t-test,)Tj
2.3244 0 Td
(p)Tj
0.72 0 Td
(=)Tj
0.7767 0 Td
(0.134\))Tj
2.5625 0 Td
(or)Tj
1.0544 0 Td
(non-synonymous)Tj
6.9732 0 Td
(SNVs)Tj
2.4038 0 Td
(\(p)Tj
1.0375 0 Td
(=)Tj
0.7767 0 Td
(0.147\))Tj
2.5625 0 Td
(compared)Tj
4.0762 0 Td
(to)Tj
0.9807 0 Td
(wild-type)Tj
-32.2069 -1.2983 Td
(tumors)Tj
2.9764 0 Td
(and)Tj
1.6667 0 Td
(did)Tj
1.4796 0 Td
(not)Tj
1.5137 0 Td
(show)Tj
2.2167 0 Td
(significant)Tj
4.1555 0 Td
(enrichment)Tj
4.6602 0 Td
(of)Tj
0.9751 0 Td
(any)Tj
1.593 0 Td
(of)Tj
0.9751 0 Td
(the)Tj
1.406 0 Td
(molecular)Tj
4.0309 0 Td
(subtypes)Tj
3.5036 0 Td
(recently)Tj
3.2428 0 Td
(defined)Tj
-34.3953 -1.3039 Td
(on)Tj
1.2302 0 Td
(the)Tj
1.406 0 Td
(basis)Tj
2.0466 0 Td
(of)Tj
0.975 0 Td
(their)Tj
2.0013 0 Td
(dominant)Tj
4.0025 0 Td
(molecular)Tj
4.0308 0 Td
(signature)Tj
3.7304 0 Td
(\(Fisher's)Tj
3.4242 0 Td
(exact)Tj
2.16 0 Td
(test,)Tj
1.7234 0 Td
(p)Tj
0.7144 0 Td
(=)Tj
0.7767 0 Td
(0.57,)Tj
0.83 0.64 0.02 0 k
1.9955 0 Td
(S1)Tj
1.1282 0 Td
(Fig)Tj
0 g
(\))Tj
1.7348 0 Td
([)Tj
0.83 0.64 0.02 0 k
(20)Tj
0 g
(].)Tj
-0.014 Tc
-31.8838 -1.2983 Td
(To)Tj
1.3209 0 Td
(investigate)Tj
4.3539 0 Td
(other)Tj
2.2961 0 Td
(potential)Tj
3.668 0 Td
(sources)Tj
3.1294 0 Td
(of)Tj
0.9921 0 Td
(altered)Tj
2.8744 0 Td
(function)Tj
3.5489 0 Td
(of)Tj
0.9978 0 Td
(the)Tj
1.44 0 Td
(TLR)Tj
1.9559 0 Td
(pathway)Tj
3.5036 0 Td
(genes,)Tj
2.6078 0 Td
(we)Tj
1.304 0 Td
(inves-)Tj
-35.189 -1.2983 Td
(tigated)Tj
2.863 0 Td
(copy)Tj
2.0805 0 Td
(number)Tj
3.3619 0 Td
(and)Tj
1.7007 0 Td
(structural)Tj
3.9799 0 Td
(variants)Tj
3.3051 0 Td
(potentially)Tj
4.354 0 Td
(affecting)Tj
3.566 0 Td
(the)Tj
1.44 0 Td
(TLR)Tj
1.9615 0 Td
(pathway)Tj
3.498 0 Td
(in)Tj
1.0148 0 Td
(the)Tj
1.4399 0 Td
(ICGC)Tj
-34.5653 -1.3039 Td
(cohort.)Tj
3.0104 0 Td
(Analysis)Tj
3.4978 0 Td
(of)Tj
0.9921 0 Td
(the)Tj
1.44 0 Td
(copy)Tj
2.0806 0 Td
(number)Tj
3.3619 0 Td
(profiles)Tj
3.1181 0 Td
(of)Tj
0.9978 0 Td
(the)Tj
1.44 0 Td
(TLR)Tj
1.9615 0 Td
(pathway)Tj
3.498 0 Td
(genes)Tj
2.3924 0 Td
(indicated)Tj
3.8494 0 Td
(copy)Tj
2.0806 0 Td
(number)Tj
-33.7206 -1.2982 Td
(gains)Tj
2.245 0 Td
(for)Tj
/F11 1 Tf
1.355 0 Td
[( )]TJ
/F6 1 Tf
1.8367 0 Td
(and)Tj
/F11 1 Tf
1.7008 0 Td
[($)-16(%)8()]TJ
/F6 1 Tf
(,)Tj
2.7042 0 Td
(while)Tj
/F11 1 Tf
2.3188 0 Td
[(!)]TJ
/F6 1 Tf
(,)Tj
/F11 1 Tf
2.5681 0 Td
[( )14(&)]TJ
/F6 1 Tf
2.7496 0 Td
(and)Tj
/F11 1 Tf
1.6951 0 Td
[($&)]TJ
/F6 1 Tf
2.4321 0 Td
(frequently)Tj
4.2066 0 Td
(showed)Tj
3.1918 0 Td
(fewer)Tj
2.3584 0 Td
(copies)Tj
2.6589 0 Td
(com-)Tj
-34.0211 -1.2983 Td
(pared)Tj
2.4434 0 Td
(to)Tj
1.0035 0 Td
(the)Tj
1.4399 0 Td
(average)Tj
3.1578 0 Td
(ploidy)Tj
2.6815 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S2)Tj
1.4797 0 Td
(Fig)Tj
0 g
(\).)Tj
1.9956 0 Td
(Three)Tj
2.5285 0 Td
(samples)Tj
3.3108 0 Td
(showed)Tj
3.1918 0 Td
(homozygous)Tj
5.2101 0 Td
(deletions)Tj
3.7303 0 Td
(in)Tj
1.0205 0 Td
(TLR)Tj
1.9559 0 Td
(path-)Tj
-35.1493 -1.2983 Td
(way)Tj
1.7631 0 Td
(genes:)Tj
/F11 1 Tf
2.6079 0 Td
[()]TJ
/F6 1 Tf
3.2654 0 Td
(in)Tj
1.0148 0 Td
(ICGC-30,)Tj
/F11 1 Tf
4.0478 0 Td
[()-16(&)]TJ
/F6 1 Tf
2.8517 0 Td
(in)Tj
1.0148 0 Td
(ICGC-24,)Tj
4.0535 0 Td
(and)Tj
/F11 1 Tf
1.7008 0 Td
[()]TJ
/F6 1 Tf
(,)Tj
/F11 1 Tf
2.5681 0 Td
[()]TJ
/F6 1 Tf
2.3528 0 Td
(and)Tj
/F11 1 Tf
1.7007 0 Td
[()-16(&)]TJ
/F6 1 Tf
2.8517 0 Td
(in)Tj
1.0148 0 Td
(ICGC-10.)Tj
-32.8079 -1.3039 Td
(Interestingly,)Tj
5.3517 0 Td
(several)Tj
2.8629 0 Td
(TLR)Tj
1.9616 0 Td
(pathway)Tj
3.4979 0 Td
(genes)Tj
2.3925 0 Td
(were)Tj
2.0863 0 Td
(affected)Tj
3.2428 0 Td
(by)Tj
1.1622 0 Td
(loss)Tj
1.6554 0 Td
(of)Tj
0.9978 0 Td
(heterozygosity.)Tj
6.0661 0 Td
(Loss)Tj
1.9445 0 Td
(of)Tj
0.9978 0 Td
(hetero-)Tj
-34.2195 -1.2982 Td
(zygosity)Tj
3.3619 0 Td
(events)Tj
2.6701 0 Td
(overlapped)Tj
4.5411 0 Td
(with)Tj
1.9559 0 Td
(SNVs)Tj
2.4491 0 Td
(in)Tj
/F11 1 Tf
1.0148 0 Td
[()]TJ
/F6 1 Tf
2.3527 0 Td
(in)Tj
1.0148 0 Td
(four)Tj
1.8765 0 Td
(samples)Tj
3.3109 0 Td
(\(ICGC-24,)Tj
4.3823 0 Td
(ICGC-156,)Tj
4.5127 0 Td
(ICGC-18)Tj
-33.4428 -1.2983 Td
(and)Tj
1.7008 0 Td
(ICGC-141\))Tj
4.626 0 Td
(and)Tj
1.7008 0 Td
(in)Tj
/F11 1 Tf
1.0148 0 Td
[()]TJ
/F6 1 Tf
3.2711 0 Td
(in)Tj
1.0148 0 Td
(one)Tj
1.6668 0 Td
(sample)Tj
2.965 0 Td
(\(ICGC-78\).)Tj
4.7112 0 Td
(Eleven)Tj
2.8232 0 Td
(out)Tj
1.5251 0 Td
(of)Tj
0.9921 0 Td
(171)Tj
1.6157 0 Td
(samples)Tj
3.3165 0 Td
(showed)Tj
-32.9439 -1.3039 Td
(structural)Tj
3.9798 0 Td
(variants)Tj
3.3051 0 Td
(whose)Tj
2.6759 0 Td
(breakpoints)Tj
4.8415 0 Td
(overlap)Tj
3.1068 0 Td
(with)Tj
1.9559 0 Td
(TLR)Tj
1.9615 0 Td
(pathway)Tj
3.498 0 Td
(genes)Tj
2.3924 0 Td
(or)Tj
1.0771 0 Td
(lead)Tj
1.8142 0 Td
(to)Tj
1.0035 0 Td
(a)Tj
0.6463 0 Td
(potential)Tj
-32.258 -1.2983 Td
(fusion)Tj
2.6589 0 Td
(with)Tj
1.9559 0 Td
(a)Tj
0.6462 0 Td
(TLR)Tj
1.9615 0 Td
(pathway)Tj
3.498 0 Td
(gene)Tj
2.0409 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S2)Tj
1.4797 0 Td
(Table)Tj
0 g
(\).)Tj
2.9366 0 Td
(The)Tj
1.7575 0 Td
(following)Tj
3.8891 0 Td
(genes)Tj
2.3924 0 Td
(were)Tj
2.0807 0 Td
(affected:)Tj
/F11 1 Tf
3.4639 0 Td
[(&)]TJ
/F6 1 Tf
(,)Tj
/F11 1 Tf
2.5682 0 Td
[(!)]TJ
/F6 1 Tf
(,)Tj
/F11 1 Tf
-33.3295 -1.2983 Td
[()]TJ
/F6 1 Tf
(,)Tj
/F11 1 Tf
2.5682 0 Td
[(&')]TJ
/F6 1 Tf
(,)Tj
/F11 1 Tf
3.0216 0 Td
[( )14(&)]TJ
/F6 1 Tf
(,)Tj
/F11 1 Tf
2.965 0 Td
[()-5(\()13( )]TJ
/F6 1 Tf
(,)Tj
/F11 1 Tf
3.5943 0 Td
[()-16(!)]TJ
/F6 1 Tf
(,)Tj
/F11 1 Tf
3.1975 0 Td
[()-16()]TJ
/F6 1 Tf
(,)Tj
/F11 1 Tf
3.2031 0 Td
[()-16(&)]TJ
/F6 1 Tf
3.3392 0 Td
(and)Tj
/F11 1 Tf
1.7008 0 Td
[( )]TJ
/F6 1 Tf
(.)Tj
2.0522 0 Td
(Most)Tj
2.2394 0 Td
(structural)Tj
3.9798 0 Td
(variants)Tj
3.3109 0 Td
(were)Tj
-35.172 -1.3039 Td
(classified)Tj
3.719 0 Td
(as)Tj
0.9921 0 Td
(duplications)Tj
5.0286 0 Td
(or)Tj
1.0771 0 Td
(deletions)Tj
3.7304 0 Td
(and)Tj
1.7008 0 Td
(there)Tj
2.2167 0 Td
(were)Tj
2.0806 0 Td
(three)Tj
2.2167 0 Td
(translocation)Tj
5.3347 0 Td
(and)Tj
1.7008 0 Td
(two)Tj
1.6781 0 Td
(inversion)Tj
-31.4756 -1.2982 Td
(events.)Tj
2.8856 0 Td
(No)Tj
1.44 0 Td
(recurrent)Tj
3.889 0 Td
(events)Tj
2.6703 0 Td
(were)Tj
2.0863 0 Td
(detected.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 126.9921 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Validation)Tj
4.5449 0 Td
(of)Tj
1.0488 0 Td
(TLR)Tj
2.0929 0 Td
(pathway)Tj
3.9024 0 Td
(mutations)Tj
4.5071 0 Td
(in)Tj
0.9827 0 Td
(a)Tj
0.7701 0 Td
(second)Tj
3.4063 0 Td
(EAC)Tj
2.2583 0 Td
(cohort)Tj
2.9717 0 Td
(and)Tj
1.8614 0 Td
(other)Tj
-28.3466 -1.1669 Td
(cancers)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 95.9811 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(To)Tj
1.3379 0 Td
(ensure)Tj
2.8743 0 Td
(that)Tj
1.7802 0 Td
(the)Tj
1.4683 0 Td
(findings)Tj
3.4923 0 Td
(were)Tj
2.1259 0 Td
(generalizable)Tj
5.4198 0 Td
(we)Tj
1.3266 0 Td
(interrogated)Tj
5.1591 0 Td
(exome)Tj
2.8573 0 Td
(sequencing)Tj
4.7168 0 Td
(data)Tj
1.9105 0 Td
(from)Tj
-34.469 -1.2982 Td
(the)Tj
1.4683 0 Td
(Dulak)Tj
2.6589 0 Td
(et)Tj
0.9411 0 Td
(al.)Tj
1.1281 0 Td
(TCGA)Tj
2.8914 0 Td
(cohort)Tj
2.8573 0 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(])Tj
1.3776 0 Td
(using)Tj
2.3868 0 Td
(our)Tj
1.627 0 Td
(computational)Tj
6.0491 0 Td
(pipeline,)Tj
3.6567 0 Td
(and)Tj
1.7291 0 Td
(found)Tj
2.6192 0 Td
(a)Tj
0.652 0 Td
(similar)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 133.6819 23.6976 re
W* n
q
133.6252 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 322.4692 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Impac)Tj
2.6787 0 Td
(t)Tj
0.4961 0 Td
(of)Tj
1.0417 0 Td
(mutations)Tj
4.4859 0 Td
(in)Tj
0.9779 0 Td
(TLR)Tj
2.0835 0 Td
(pathway)Tj
3.8835 0 Td
(genes)Tj
2.8914 0 Td
(on)Tj
1.311 0 Td
(esophageal)Tj
5.2938 0 Td
(carcinoge)Tj
4.252 0 Td
(nesis)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
95.5276 34.9228 m
251.8299 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(Genetics)Tj
4.1102 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4749 0 Td
(https://)Tj
2.9551 0 Td
(doi.org/10.13)Tj
5.7331 0 Td
(71/journal.p)Tj
5.1237 0 Td
(gen.100)Tj
3.5433 0 Td
(6808)Tj
0 g
3.1819 0 Td
(May)Tj
2.0835 0 Td
(22,)Tj
1.5874 0 Td
(2017)Tj
33.4916 0 Td
(3)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
74 0 obj
<>stream
endstream
endobj
75 0 obj
<>stream
endstream
endobj
76 0 obj
<>stream
endstream
endobj
77 0 obj
<>stream
endstream
endobj
78 0 obj
<>stream
endstream
endobj
79 0 obj
<>stream
endstream
endobj
80 0 obj
<>stream
endstream
endobj
81 0 obj
<>stream
endstream
endobj
82 0 obj
<>stream
endstream
endobj
83 0 obj
<>stream
endstream
endobj
84 0 obj
<>stream
endstream
endobj
85 0 obj
<>stream
endstream
endobj
86 0 obj
<>stream
BT
66.402 0 Td
(21)Tj
ET
Q
endstream
endobj
87 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 13 0 R/Annots 89 0 R/Contents 90 0 R/TrimBox[0 0 612 792]>>
endobj
88 0 obj
<>stream
xwfWU>~ABTH @*"`B:(=RC #@P}~.-e}?f=gʳ@A @A @A @A @A oa<A`-R?O9Zr'mA ~.1fX8[@A 0'o|W/O}SnfF"}x#?Ǟp fN @A lw?!9ǘawqЇݪz@A ]=q\g8
s\5G}O~rjpppìZ
A ! *WnYiO{ڃ:u{ݏ~kej
A FO}{3qy{'=I'tF+kF3/u+}e%CA 6[qkLU|mf6-e @A |#p*Z9f5!җtvY@y_r8 @?y[fMU/n~A)? @|_>'Yr\ԥ.v=O?IpQG.+"}"d՟wӝV,$ɂ@A 5ҹ%wwk]jW?#Wխigj A D^h%.?ݑYBpo٦|cӜ4>3KZ?nYdA}}+^ӟZL @A l:Wznu#<