%PDF-1.6
%
1 0 obj
<>
endobj
2 0 obj
<>stream
Anieta M. Sieuwerts, Willemijne A. M. E. Schrijver, Simone U. Dalm, Vanja de Weerd, Cathy B. Moelans, Natalie ter Hoeve, Paul J. van Diest, John W. M. Martens, Carolien H. M. van Deurzen
Progressive APOBEC3B mRNA expression in distant breast cancer metastases
www.plosone.org
www.plosone.org
endstream
endobj
3 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 16 0 R/Annots 17 0 R/Contents 18 0 R/TrimBox[0 0 612 792]>>
endobj
17 0 obj
[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 34 0 R]
endobj
19 0 obj
<>/Border[0 0 0]/Dest(Lsec005)>>
endobj
20 0 obj
<>/Border[0 0 0]/Dest(Rpone.0171343.ref001)>>
endobj
21 0 obj
<>/Border[0 0 0]/Dest(Rpone.0171343.ref002)>>
endobj
22 0 obj
<>/Border[0 0 0]/Dest(Rpone.0171343.ref003)>>
endobj
23 0 obj
<>/Border[0 0 0]/Dest(Rpone.0171343.ref004)>>
endobj
24 0 obj
<>/Border[0 0 0]/Dest(Rpone.0171343.ref005)>>
endobj
25 0 obj
<>/Border[0 0 0]/Dest(Rpone.0171343.ref005)>>
endobj
26 0 obj
<>/Border[0 0 0]/Dest(Rpone.0171343.ref019)>>
endobj
27 0 obj
<>/Border[0 0 0]/Dest(Rpone.0171343.ref018)>>
endobj
28 0 obj
<>/Border[0 0 0]/Dest(Rpone.0171343.ref020)>>
endobj
29 0 obj
<>/Border[0 0 0]/Dest(Rpone.0171343.ref005)>>
endobj
30 0 obj
<>/Border[0 0 0]/Dest(Rpone.0171343.ref021)>>
endobj
31 0 obj
<>/Border[0 0 0]/Dest(Rpone.0171343.ref022)>>
endobj
32 0 obj
<>/Border[0 0 0]/Dest(Rpone.0171343.ref023)>>
endobj
33 0 obj
<>/Border[0 0 0]/Dest(Rpone.0171343.ref005)>>
endobj
34 0 obj
<>/Border[0 0 0]/Dest(Rpone.0171343.ref024)>>
endobj
18 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]
endobj
35 0 obj
<>stream
q
0.955 g
0 w
199.9998 608.9102 m
575.9997 608.9102 l
575.9997 479.7505 l
199.9998 479.7505 l
f*
0.45 0.36 0.35 0.01 k
575.9997 633.9101 m
199.9998 633.9101 l
199.9998 634.4101 l
575.9997 634.4101 l
f*
0.83 0.64 0.02 0 k
446.0598 419.9244 m
450.822 419.9244 l
h
f*
376.6677 406.9417 m
381.4299 406.9417 l
h
f*
537.5055 367.937 m
542.2677 367.937 l
h
f*
255.8551 341.915 m
260.6173 341.915 l
h
f*
371.1685 237.9402 m
375.874 237.9402 l
h
f*
323.4331 211.9181 m
328.1953 211.9181 l
h
f*
333.3543 211.9181 m
342.8787 211.9181 l
h
f*
278.4189 172.9134 m
287.8866 172.9134 l
h
f*
290.1543 172.9134 m
299.6787 172.9134 l
h
f*
319.0677 146.948 m
323.8299 146.948 l
h
f*
326.0976 146.948 m
335.5654 146.948 l
h
f*
337.8331 146.948 m
347.3575 146.948 l
h
f*
332.2205 120.926 m
341.7449 120.926 l
h
f*
245.3669 94.9039 m
250.1291 94.9039 l
h
f*
252.3402 94.9039 m
261.8646 94.9039 l
h
f*
0 g
1 j
1 J
11.4998 0 0 11.4998 200.0125 706.3937 cm
BT
/F2 1 Tf
1 TL
-0.0035 Tc
0 0 Td
(Conclusion)Tj
ET
Q
q
1 j
1 J
0 w
9.5 0 0 9.5 200.0125 689.3858 cm
BT
/F6 1 Tf
1 TL
-0.0042 Tc
0 0 Td
(APOBEC3B)Tj
/F0 1 Tf
5.5797 0 Td
(mRNA)Tj
3.145 0 Td
(levels)Tj
2.7391 0 Td
(are)Tj
1.6471 0 Td
(significantly)Tj
5.3172 0 Td
(higher)Tj
2.9599 0 Td
(in)Tj
0.9847 0 Td
(breast)Tj
2.9719 0 Td
(cancer)Tj
3.1867 0 Td
(metastases)Tj
5.2933 0 Td
(as)Tj
1.2652 0 Td
(compared)Tj
-35.0898 -1.474 Td
(to)Tj
1.0443 0 Td
(the)Tj
1.5934 0 Td
(corresponding)Tj
6.4808 0 Td
(ER-positive)Tj
5.2754 0 Td
(primary)Tj
3.515 0 Td
(tumors.)Tj
3.5328 0 Td
(This)Tj
2.0887 0 Td
(suggests)Tj
4.1833 0 Td
(a)Tj
0.7699 0 Td
(potential)Tj
3.9446 0 Td
(role)Tj
1.8619 0 Td
(for)Tj
1.3785 0 Td
(APO-)Tj
-35.6686 -1.468 Td
(BEC3B)Tj
3.4731 0 Td
(in)Tj
0.9847 0 Td
(luminal)Tj
3.3419 0 Td
(breast)Tj
2.9659 0 Td
(cancer)Tj
3.1927 0 Td
(progression,)Tj
5.6573 0 Td
(and)Tj
1.8619 0 Td
(consequen)Tj
4.8398 0 Td
(tly,)Tj
1.486 0 Td
(a)Tj
0.7638 0 Td
(promising)Tj
4.5056 0 Td
(role)Tj
1.8619 0 Td
(for)Tj
1.3726 0 Td
(anti-)Tj
-36.3072 -1.474 Td
(APOBEC3B)Tj
5.5797 0 Td
(therapies)Tj
4.2788 0 Td
(in)Tj
0.9847 0 Td
(advanced)Tj
4.5056 0 Td
(stages)Tj
3.1389 0 Td
(of)Tj
1.0444 0 Td
(this)Tj
1.7604 0 Td
(frequent)Tj
3.8432 0 Td
(form)Tj
2.208 0 Td
(of)Tj
1.0444 0 Td
(breast)Tj
2.9719 0 Td
(cancer.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 209.9905 591.7606 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Highlights)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 209.9905 572.7685 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
()Tj
0.7823 0 Td
(APOBEC3B)Tj
5.0797 0 Td
(is)Tj
0.8447 0 Td
(a)Tj
0.6576 0 Td
(gain-of-function)Tj
6.8371 0 Td
(enzymatic)Tj
4.303 0 Td
(source)Tj
2.8346 0 Td
(of)Tj
1.0148 0 Td
(mutagenesis.)Tj
-22.3538 -1.6043 Td
()Tj
0.7823 0 Td
(Levels)Tj
2.6702 0 Td
(are)Tj
1.4457 0 Td
(higher)Tj
2.8006 0 Td
(in)Tj
1.0375 0 Td
(breast)Tj
2.6135 0 Td
(metastases)Tj
4.4334 0 Td
(as)Tj
1.0148 0 Td
(compared)Tj
4.2462 0 Td
(to)Tj
1.0262 0 Td
(corresponding)Tj
6.0604 0 Td
(primary)Tj
3.4526 0 Td
(tumors.)Tj
-31.5834 -1.5988 Td
()Tj
0.7823 0 Td
(This)Tj
1.9899 0 Td
(implies)Tj
3.1181 0 Td
(a)Tj
0.6576 0 Td
(novel)Tj
2.3981 0 Td
(role)Tj
1.7688 0 Td
(for)Tj
1.3833 0 Td
(APOBEC3B)Tj
5.0797 0 Td
(during)Tj
2.9253 0 Td
(breast)Tj
2.6192 0 Td
(cancer)Tj
2.8403 0 Td
(progression.)Tj
-25.5626 -1.5987 Td
()Tj
0.7823 0 Td
(This)Tj
1.9899 0 Td
(makes)Tj
2.7496 0 Td
(APOBEC3B)Tj
5.0797 0 Td
(a)Tj
0.6519 0 Td
(promising)Tj
4.3483 0 Td
(target)Tj
2.5115 0 Td
(for)Tj
1.3833 0 Td
(anti-APOBEC3B)Tj
6.9789 0 Td
(therapies.)Tj
-26.4754 -1.5987 Td
()Tj
0.7823 0 Td
(Especially)Tj
4.1612 0 Td
(in)Tj
1.0375 0 Td
(advanced)Tj
3.9912 0 Td
(stages)Tj
2.5681 0 Td
(of)Tj
1.0148 0 Td
(breast)Tj
2.6136 0 Td
(cancer.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 438.0094 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 421.0015 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Breast)Tj
2.6872 0 Td
(cancer)Tj
2.8459 0 Td
(is)Tj
0.8448 0 Td
(the)Tj
1.4683 0 Td
(fifth)Tj
1.8935 0 Td
(cause)Tj
2.3868 0 Td
(of)Tj
1.0148 0 Td
(overall)Tj
2.9026 0 Td
(cancer)Tj
2.846 0 Td
(related)Tj
2.9424 0 Td
(death)Tj
2.4321 0 Td
([)Tj
0.83 0.64 0.02 0 k
(1)Tj
0 g
(])Tj
1.3776 0 Td
(and)Tj
1.7291 0 Td
(this)Tj
1.6724 0 Td
(mortality)Tj
3.9175 0 Td
(is)Tj
0.8504 0 Td
(largely)Tj
-33.8114 -1.2982 Td
(caused)Tj
2.9139 0 Td
(by)Tj
1.1849 0 Td
(progression)Tj
4.9209 0 Td
(of)Tj
1.0148 0 Td
(metastatic)Tj
4.2747 0 Td
(disease)Tj
3.016 0 Td
([)Tj
0.83 0.64 0.02 0 k
(2)Tj
0 g
(].)Tj
1.6044 0 Td
(Therefore,)Tj
4.3937 0 Td
(one)Tj
1.6951 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(most)Tj
2.2053 0 Td
(important)Tj
4.2803 0 Td
(chal-)Tj
-33.9928 -1.3039 Td
(lenges)Tj
2.6872 0 Td
(in)Tj
1.0375 0 Td
(breast)Tj
2.6135 0 Td
(cancer)Tj
2.8459 0 Td
(research)Tj
3.5547 0 Td
(includes)Tj
3.5433 0 Td
(the)Tj
1.4683 0 Td
(genetic)Tj
3.0727 0 Td
(changes)Tj
3.4016 0 Td
(and)Tj
1.7291 0 Td
(molecular)Tj
4.2236 0 Td
(mechanisms)Tj
5.2044 0 Td
(by)Tj
-35.3818 -1.2983 Td
(which)Tj
2.6475 0 Td
(cancer)Tj
2.846 0 Td
(cells)Tj
1.9218 0 Td
(acquire)Tj
3.1748 0 Td
(their)Tj
2.1033 0 Td
(metastatic)Tj
4.2803 0 Td
(ability.)Tj
2.9197 0 Td
(The)Tj
1.7801 0 Td
(generally)Tj
3.8381 0 Td
(accepted)Tj
3.6907 0 Td
(hypothesis)Tj
4.4617 0 Td
(is)Tj
0.8504 0 Td
(that)Tj
-34.5144 -1.2983 Td
(metastases)Tj
4.4333 0 Td
(are)Tj
1.4457 0 Td
(caused)Tj
2.9196 0 Td
(by)Tj
1.1792 0 Td
(multiple)Tj
3.5717 0 Td
(intricate)Tj
3.5489 0 Td
(steps)Tj
2.1827 0 Td
(that)Tj
1.7745 0 Td
(arise)Tj
2.0806 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.474 0 Td
(primary)Tj
3.4526 0 Td
(tumor)Tj
2.7439 0 Td
(site)Tj
1.5704 0 Td
([)Tj
0.83 0.64 0.02 0 k
(3)Tj
0 g
(].)Tj
1.6044 0 Td
(Nev-)Tj
-35.0133 -1.3039 Td
(ertheless,)Tj
3.8777 0 Td
(discordances)Tj
5.3972 0 Td
(between)Tj
3.5319 0 Td
(primary)Tj
3.4526 0 Td
(tumors)Tj
3.1067 0 Td
(and)Tj
1.7292 0 Td
(corresponding)Tj
6.0604 0 Td
(metastases)Tj
4.4333 0 Td
(are)Tj
1.4457 0 Td
(often)Tj
-33.0347 -1.2982 Td
(encountered)Tj
5.244 0 Td
([)Tj
0.83 0.64 0.02 0 k
(4)Tj
0 g
(].)Tj
1.5987 0 Td
(However,)Tj
4.0762 0 Td
(therapies)Tj
3.8438 0 Td
(applied)Tj
3.1521 0 Td
(for)Tj
1.389 0 Td
(disseminated)Tj
5.4765 0 Td
(disease)Tj
3.0217 0 Td
(are)Tj
1.4456 0 Td
(mainly)Tj
2.9934 0 Td
(based)Tj
2.4718 0 Td
(on)Tj
1.2756 0 Td
(pri-)Tj
-35.9884 -1.2983 Td
(mary)Tj
2.296 0 Td
(tumor)Tj
2.7439 0 Td
(characteristics)Tj
5.9074 0 Td
(only.)Tj
2.1997 0 Td
(The)Tj
1.7858 0 Td
(study)Tj
2.3867 0 Td
(of)Tj
1.0148 0 Td
(molecular)Tj
4.2236 0 Td
(differences)Tj
4.5638 0 Td
(between)Tj
3.5262 0 Td
(matched)Tj
3.6737 0 Td
(primary)Tj
-34.3216 -1.2983 Td
(tumors)Tj
3.101 0 Td
(and)Tj
1.7348 0 Td
(metastatic)Tj
4.2746 0 Td
(lesions)Tj
2.9367 0 Td
(may)Tj
1.9276 0 Td
(improve)Tj
3.5773 0 Td
(our)Tj
1.627 0 Td
(understanding)Tj
6.0718 0 Td
(of)Tj
1.0148 0 Td
(disease)Tj
3.0161 0 Td
(progression)Tj
4.9209 0 Td
(and)Tj
1.7291 0 Td
(has)Tj
-35.9317 -1.3039 Td
(the)Tj
1.4683 0 Td
(potential)Tj
3.7587 0 Td
(to)Tj
1.0261 0 Td
(reveal)Tj
2.5739 0 Td
(novel,)Tj
2.6248 0 Td
(potentially)Tj
4.4618 0 Td
(targetable)Tj
4.1215 0 Td
(drivers)Tj
2.999 0 Td
(of)Tj
1.0148 0 Td
(metastatic)Tj
4.2747 0 Td
(progression.)Tj
-27.1274 -1.2983 Td
(Apolipoprotein)Tj
6.4006 0 Td
(B)Tj
0.7993 0 Td
(mRNA)Tj
3.0841 0 Td
(Editing)Tj
3.1634 0 Td
(Enzyme,)Tj
3.6737 0 Td
(Catalytic)Tj
3.7417 0 Td
(Polypeptide-Like)Tj
7.0356 0 Td
(3B)Tj
1.2756 0 Td
(\(APOBEC3B\))Tj
5.7599 0 Td
(is)Tj
0.8447 0 Td
(a)Tj
-36.9748 -1.2982 Td
(member)Tj
3.5829 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(AID/APOBEC)Tj
6.1114 0 Td
(family)Tj
2.7326 0 Td
(of)Tj
1.0148 0 Td
(deaminases,)Tj
5.0456 0 Td
(which)Tj
2.6476 0 Td
(is)Tj
0.8504 0 Td
(recognized)Tj
4.5921 0 Td
(for)Tj
1.3833 0 Td
(its)Tj
1.1451 0 Td
(ability)Tj
2.6986 0 Td
(to)Tj
-34.2876 -1.3039 Td
(deaminate)Tj
4.3936 0 Td
(genomic)Tj
3.6737 0 Td
(DNA)Tj
2.3811 0 Td
(cytosines.)Tj
4.0875 0 Td
(APOBEC)Tj
4.0252 0 Td
(enzymes)Tj
3.6623 0 Td
(normally)Tj
3.8495 0 Td
(function)Tj
3.6283 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.474 0 Td
(innate)Tj
-32.207 -1.2983 Td
(immune)Tj
3.6226 0 Td
(system)Tj
2.9423 0 Td
(and)Tj
1.7292 0 Td
(in)Tj
1.0374 0 Td
(the)Tj
1.4684 0 Td
(protection)Tj
4.3823 0 Td
(against)Tj
3.0274 0 Td
(viral)Tj
1.9899 0 Td
(pathogens,)Tj
4.5297 0 Td
(but)Tj
1.5534 0 Td
(these)Tj
2.2564 0 Td
(enzymes)Tj
3.6623 0 Td
(can)Tj
1.6271 0 Td
(also)Tj
1.7688 0 Td
(gen-)Tj
-35.5972 -1.2983 Td
(erate)Tj
2.1713 0 Td
(C)Tj
/F12 1 Tf
0 Tc
(!)Tj
/F7 1 Tf
-0.004 Tc
(T)Tj
2.4944 0 Td
(mutations)Tj
4.2803 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(host)Tj
1.9163 0 Td
(genome)Tj
3.4072 0 Td
([)Tj
0.83 0.64 0.02 0 k
(5)Tj
0 g
(].)Tj
1.5987 0 Td
(Recently,)Tj
3.8834 0 Td
(several)Tj
2.9367 0 Td
(studies)Tj
2.9877 0 Td
(showed)Tj
3.2485 0 Td
(that)Tj
1.7801 0 Td
(APO-)Tj
-33.2104 -1.3039 Td
(BEC3B)Tj
3.084 0 Td
(is)Tj
0.8504 0 Td
(a)Tj
0.652 0 Td
(common)Tj
3.8494 0 Td
(enzymatic)Tj
4.303 0 Td
(mutagenic)Tj
4.4277 0 Td
(factor)Tj
2.5398 0 Td
(affecting)Tj
3.6567 0 Td
(the)Tj
1.4683 0 Td
(evolution)Tj
4.0025 0 Td
(of)Tj
1.0148 0 Td
(different)Tj
3.6567 0 Td
(cancer)Tj
-33.5053 -1.2982 Td
(types,)Tj
2.5001 0 Td
(including)Tj
4.0422 0 Td
(breast)Tj
2.6135 0 Td
(cancer)Tj
2.846 0 Td
([)Tj
0.83 0.64 0.02 0 k
(5)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(19)Tj
0 g
(].)Tj
-10.8056 -1.2983 Td
(In)Tj
1.1111 0 Td
(breast)Tj
2.6136 0 Td
(cancer,)Tj
/F13 1 Tf
3.0727 0 Td
[()13()]TJ
/F7 1 Tf
4.8869 0 Td
(mRNA)Tj
3.0841 0 Td
(is)Tj
0.8447 0 Td
(substantially)Tj
5.2044 0 Td
(upregulated)Tj
4.9832 0 Td
(in)Tj
1.0375 0 Td
(one)Tj
1.7008 0 Td
(third)Tj
2.211 0 Td
(of)Tj
1.0148 0 Td
(cases)Tj
-32.961 -1.3039 Td
(and)Tj
1.7291 0 Td
(its)Tj
1.1452 0 Td
(expression)Tj
4.4673 0 Td
(is)Tj
0.8448 0 Td
(associated)Tj
4.2576 0 Td
(with)Tj
2.0012 0 Td
(mutational)Tj
4.5978 0 Td
(load,)Tj
2.16 0 Td
(including)Tj
4.0421 0 Td
(certain)Tj
2.9877 0 Td
(driver)Tj
2.6362 0 Td
(mutations)Tj
4.2803 0 Td
(in)Tj
/F13 1 Tf
-35.1493 -1.2983 Td
[()14( )]TJ
/F7 1 Tf
3.4809 0 Td
(and)Tj
/F13 1 Tf
1.7291 0 Td
[(\n)]TJ
/F7 1 Tf
2.2904 0 Td
([)Tj
0.83 0.64 0.02 0 k
(18)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(20)Tj
0 g
(].)Tj
3.2541 0 Td
(Besides,)Tj
3.3846 0 Td
(multiple)Tj
3.5659 0 Td
(studies)Tj
2.9877 0 Td
(have)Tj
2.058 0 Td
(postulated)Tj
4.3653 0 Td
(that)Tj
1.7745 0 Td
(APOBEC3B)Tj
5.0796 0 Td
(influ-)Tj
-33.9701 -1.2983 Td
(ences)Tj
2.398 0 Td
(the)Tj
1.4684 0 Td
(development)Tj
5.4141 0 Td
(of)Tj
1.0148 0 Td
(metastases)Tj
4.4334 0 Td
(and)Tj
1.7291 0 Td
(drug)Tj
2.1146 0 Td
(resistance,)Tj
4.354 0 Td
(especially)Tj
4.0195 0 Td
(in)Tj
1.0318 0 Td
(estrogen)Tj
3.6227 0 Td
(receptor)Tj
3.5546 0 Td
(alpha)Tj
-35.155 -1.2982 Td
(\(ER)Tj
/F14 1 Tf
()Tj
/F7 1 Tf
(\)-positive)Tj
6.1057 0 Td
(breast)Tj
2.6136 0 Td
(cancer)Tj
2.8459 0 Td
([)Tj
0.83 0.64 0.02 0 k
(5)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(21)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(22)Tj
0 g
(].)Tj
3.9515 0 Td
(In)Tj
1.1112 0 Td
(line)Tj
1.7064 0 Td
(with)Tj
1.9956 0 Td
(this,)Tj
1.8992 0 Td
(we)Tj
1.3266 0 Td
(previously)Tj
4.354 0 Td
(reported)Tj
3.6567 0 Td
(an)Tj
1.2075 0 Td
(association)Tj
-32.7739 -1.3039 Td
(between)Tj
3.5262 0 Td
(high)Tj
/F13 1 Tf
2.0069 0 Td
[()13()]TJ
/F7 1 Tf
4.8926 0 Td
(mRNA)Tj
3.0784 0 Td
(expression)Tj
4.4674 0 Td
(and)Tj
1.7291 0 Td
(poor)Tj
2.126 0 Td
(outcome)Tj
3.7247 0 Td
(in)Tj
1.0375 0 Td
(a)Tj
0.6519 0 Td
(large)Tj
2.16 0 Td
(cohort)Tj
2.8573 0 Td
(of)Tj
1.0148 0 Td
(patients)Tj
-33.2728 -1.2983 Td
(with)Tj
1.9955 0 Td
(ER)Tj
/F14 1 Tf
()Tj
/F7 1 Tf
(-positive)Tj
5.4255 0 Td
(breast)Tj
2.6192 0 Td
(cancer)Tj
2.8403 0 Td
([)Tj
0.83 0.64 0.02 0 k
(23)Tj
0 g
(].)Tj
-11.6843 -1.2983 Td
(Since)Tj
2.3584 0 Td
(APOBEC3B)Tj
5.0796 0 Td
(is)Tj
0.8504 0 Td
(a)Tj
0.652 0 Td
(gain-of-function)Tj
6.8371 0 Td
(mutagenic)Tj
4.4277 0 Td
(enzyme,)Tj
3.5319 0 Td
(it)Tj
0.7824 0 Td
(may)Tj
1.9332 0 Td
(be)Tj
1.1452 0 Td
(treatable)Tj
3.6567 0 Td
(with)Tj
2.0012 0 Td
(small)Tj
-34.452 -1.3039 Td
(molecules)Tj
4.1952 0 Td
([)Tj
0.83 0.64 0.02 0 k
(5)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(24)Tj
0 g
(],)Tj
2.7723 0 Td
(which)Tj
2.6475 0 Td
(could)Tj
2.4491 0 Td
(have)Tj
2.0523 0 Td
(an)Tj
1.2019 0 Td
(important)Tj
4.2746 0 Td
(role)Tj
1.7631 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.4684 0 Td
(management)Tj
5.4311 0 Td
(of)Tj
1.0092 0 Td
(metastatic)Tj
4.2746 0 Td
(disease.)Tj
-34.5711 -1.2983 Td
(However,)Tj
4.0761 0 Td
(the)Tj
1.4684 0 Td
(expression)Tj
4.4674 0 Td
(of)Tj
/F13 1 Tf
1.0148 0 Td
[()13()]TJ
/F7 1 Tf
4.8869 0 Td
(in)Tj
1.0374 0 Td
(breast)Tj
2.6136 0 Td
(cancer)Tj
2.8459 0 Td
(metastases)Tj
4.4334 0 Td
(remained)Tj
4.0365 0 Td
(to)Tj
1.0261 0 Td
(be)Tj
1.1509 0 Td
(elucidated.)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 107.1496 23.6976 re
W* n
q
107.0929 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 301.4929 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Progressive)Tj
5.4142 0 Td
(APOBE)Tj
3.4087 0 Td
(C3B)Tj
2.1401 0 Td
(mRNA)Tj
3.1252 0 Td
(expression)Tj
4.9678 0 Td
(in)Tj
0.978 0 Td
(distant)Tj
3.111 0 Td
(breast)Tj
2.9552 0 Td
(cancer)Tj
3.1677 0 Td
(metastases)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*
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
(ONE)Tj
2.3669 0 Td
(|)Tj
0.4748 0 Td
(DOI:10.137)Tj
5.0387 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.0171)Tj
3.5434 0 Td
(343)Tj
2.6362 0 Td
(January)Tj
3.7134 0 Td
(31,)Tj
1.5874 0 Td
(2017)Tj
37.8003 0 Td
(2)Tj
0.7654 0 Td
(/)Tj
0.496 0 Td
(12)Tj
/F9 1 Tf
-0.025 Tc
-66.402 84.0904 Td
(Abbreviati)Tj
3.9118 0 Td
(ons:)Tj
/F10 1 Tf
1.8425 0 Td
(APOBEC3B,)Tj
4.6064 0 Td
(Apolipoprotein)Tj
5.6268 0 Td
(B)Tj
-15.9875 -1.3748 Td
(mRNA)Tj
2.6716 0 Td
(Editing)Tj
2.7567 0 Td
(Enzyme,)Tj
3.3449 0 Td
(Catalytic)Tj
3.3308 0 Td
(Polypeptide)Tj
4.3229 0 Td
(-Like)Tj
-16.4269 -1.3749 Td
(3B;)Tj
1.4456 0 Td
(AVG,)Tj
2.0764 0 Td
(average;)Tj
3.3378 0 Td
(Cq,)Tj
1.4386 0 Td
(quantitative)Tj
4.4788 0 Td
(threshold)Tj
3.7134 0 Td
(cycle;)Tj
-16.4906 -1.3748 Td
(dCq,)Tj
1.9134 0 Td
(delta)Tj
1.9842 0 Td
(quantitative)Tj
4.4788 0 Td
(threshold)Tj
3.7134 0 Td
(cycle;)Tj
2.3244 0 Td
(ER/ESR1,)Tj
-14.4142 -1.3748 Td
(estrogen)Tj
3.4653 0 Td
(receptor;)Tj
3.5292 0 Td
(ER)Tj
/F11 1 Tf
[(.)]TJ
/F10 1 Tf
(,)Tj
1.963 0 Td
(estrogen)Tj
3.4725 0 Td
(receptor)Tj
3.3024 0 Td
(alpha;)Tj
-15.7324 -1.3748 Td
(FFPE,)Tj
2.2889 0 Td
(formalin-)Tj
3.3733 0 Td
(fixed)Tj
1.9843 0 Td
(paraffin-embe)Tj
5.1803 0 Td
(dded;)Tj
2.289 0 Td
(HER2/)Tj
-15.1158 -1.3748 Td
(ERBB2,)Tj
3.026 0 Td
(human)Tj
2.8205 0 Td
(epidermal)Tj
3.8764 0 Td
(growth)Tj
2.8417 0 Td
(factor)Tj
2.3528 0 Td
(receptor)Tj
3.3024 0 Td
(2;)Tj
-18.2198 -1.3748 Td
(NWO,)Tj
2.4236 0 Td
(Netherlands)Tj
4.6701 0 Td
(Organization)Tj
4.8544 0 Td
(of)Tj
0.9496 0 Td
(Scientifi)Tj
2.9268 0 Td
(c)Tj
-15.8245 -1.3748 Td
(Research)Tj
3.4724 0 Td
(;)Tj
0.4465 0 Td
(PTPRC,)Tj
3.0827 0 Td
(gene)Tj
2.0126 0 Td
(for)Tj
1.2543 0 Td
(the)Tj
1.3678 0 Td
(common)Tj
3.5716 0 Td
(leukocyte)Tj
-15.2079 -1.3748 Td
(antigen)Tj
2.9338 0 Td
(CD45;)Tj
2.5016 0 Td
(RT-qPCR,)Tj
3.926 0 Td
(quantita)Tj
2.9623 0 Td
(tive)Tj
1.5165 0 Td
(reverse)Tj
-13.8402 -1.3749 Td
(transcriptas)Tj
4.3724 0 Td
(e)Tj
0.6449 0 Td
(polymeras)Tj
3.8835 0 Td
(e)Tj
0.6449 0 Td
(chain)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
BT
11.7426 70.3422 Td
(reaction.)Tj
ET
Q
endstream
endobj
50 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 16 0 R/Annots 52 0 R/Contents 53 0 R/TrimBox[0 0 612 792]>>
endobj
51 0 obj
<>
endobj
54 0 obj
<>
endobj
57 0 obj
<>stream
MinionPro-Regular 6 )
H? HD H\ ' - 3 > H N T Z ` j q t { +2=CIU[cnz~
"(.9CIOU[elov|&-8>DPV^iuy &+/49@DGLPU[]_ahjmru|
&-4;BIPW^elsz
")07>ELSZahov} %,3:AHOV]dkry#/;JTey ! ( / 6 = D K R Y ` g n u |
$
+
2
9
@
G
N
U
\
c
j
q
x
'.5<CJQX_fmt{ #*18?FMT[bkry
"
)
0
7
>
E
J
O
W
d
q
v
$+29@GNU\cjqx '.5<CJQX_fmt{ #*18?FMT[bipw~
&-4;BIPW^elsz !(/6=DOVcpuz-B\v$<Tdy*5@Tanz!2>O_fmt{ $-6?HQZclu~ )2;DMV^gpy $-6?HQZclu~ )2;DM\enwcommaaccentAbreveAmacronAogonekAEacuteCacuteCcaronCcircumflexCdotaccentDcaronDcroatEbreveEcaronEdotaccentEmacronEngEogonekGbreveGcircumflexGcommaaccentGdotaccentHbarHcircumflexIbreveIJImacronIogonekItildeJcircumflexKcommaaccentLacuteLcaronLcommaaccentLdotNacuteNcaronNcommaaccentObreveOhungarumlautOmacronOslashacuteRacuteRcaronRcommaaccentSacuteScedillaScircumflexScommaaccentTbarTcaronTcommaaccentUbreveUhungarumlautUmacronUogonekUringUtildeWacuteWcircumflexWdieresisWgraveYcircumflexYgraveZacuteZdotaccentIdotaccentabreveamacronaogonekaeacutecacuteccaronccircumflexcdotaccentdcarondcroatebreveecaronedotaccentemacronengeogonekgbrevegcircumflexgcommaaccentgdotaccenthbarhcircumflexibreveijimacroniogonekitildejcircumflexkcommaaccentlacutelcaronlcommaaccentldotnacutencaronncommaaccentobreveohungarumlautomacronoslashacuteracutercaronrcommaaccentsacutescedillascircumflexscommaaccenttbartcarontcommaaccentubreveuhungarumlautumacronuogonekuringutildewacutewcircumflexwdieresiswgraveycircumflexygravezacutezdotaccentkgreenlandiclongsnapostrophetonosdieresistonosAlphaBetaGammaDeltaEpsilonZetaEtaThetaIotaKappaLambdaMuNuXiOmicronPiRhoSigmaTauUpsilonPhiChiPsiOmegaAlphatonosEpsilontonosEtatonosIotatonosIotadieresisOmicrontonosUpsilontonosUpsilondieresisOmegatonosuni1FBBuni1F09uni1F0Duni1F0Buni1F0Funi1FB8uni1FBAuni1FBCuni1F89uni1F8Duni1F8Buni1F8Funi1F88uni1F8Cuni1F8Auni1F8Euni1F08uni1F0Cuni1F0Auni1F0Euni1FB9uni1FC9uni1F19uni1F1Duni1F1Buni1FC8uni1F18uni1F1Cuni1F1Auni1FCBuni1F29uni1F2Duni1F2Buni1F2Funi1FCAuni1FCCuni1F99uni1F9Duni1F9Buni1F9Funi1F98uni1F9Cuni1F9Auni1F9Euni1F28uni1F2Cuni1F2Auni1F2Euni1FDBuni1F39uni1F3Duni1F3Buni1F3Funi1FD8uni1FDAuni1F38uni1F3Cuni1F3Auni1F3Euni1FD9uni1FFBuni1F69uni1F6Duni1F6Buni1F6Funi1FFAuni1FFCuni1FA9uni1FADuni1FABuni1FAFuni1FA8uni1FACuni1FAAuni1FAEuni1F68uni1F6Cuni1F6Auni1F6Euni1FF9uni1F49uni1F4Duni1F4Buni1FF8uni1F48uni1F4Cuni1F4Auni1FECuni1FEBuni1F59uni1F5Duni1F5Buni1F5Funi1FE8uni1FEAuni1FE9alphabetagammadeltaepsilonzetaetathetaiotakappalambdanuxiomicronpirhosigmatauupsilonphichipsiomegaalphatonosepsilontonosetatonosiotatonosiotadieresisomicrontonosupsilontonosupsilondieresisomegatonosiotadieresistonosupsilondieresistonosuni03C2uni0374uni0375uni037Euni03D0uni03DAuni03DEuni03E0uni03F0uni1FBDuni1FBEuni1FC1uni1FCDuni1FCEuni1FCFuni1FDDuni1FDEuni1FDFuni1FEDuni1FEEuni1FFEuni1F00uni1F01uni1F02uni1F03uni1F04uni1F05uni1F06uni1F07uni1F10uni1F11uni1F12uni1F13uni1F14uni1F15uni1F20uni1F21uni1F22uni1F23uni1F24uni1F25uni1F26uni1F27uni1F30uni1F31uni1F32uni1F33uni1F34uni1F35uni1F36uni1F37uni1F40uni1F41uni1F42uni1F43uni1F44uni1F45uni1F50uni1F51uni1F52uni1F53uni1F54uni1F55uni1F56uni1F57uni1F60uni1F61uni1F62uni1F63uni1F64uni1F65uni1F66uni1F67uni1F70uni1F71uni1F72uni1F73uni1F74uni1F75uni1F76uni1F77uni1F78uni1F79uni1F7Auni1F7Buni1F7Cuni1F7Duni1F80uni1F81uni1F82uni1F83uni1F84uni1F85uni1F86uni1F87uni1F90uni1F91uni1F92uni1F93uni1F94uni1F95uni1F96uni1F97uni1FA0uni1FA1uni1FA2uni1FA3uni1FA4uni1FA5uni1FA6uni1FA7uni1FB0uni1FB1uni1FB2uni1FB3uni1FB6uni1FB7uni1FC2uni1FC3uni1FC4uni1FC6uni1FC7uni1FD0uni1FD1uni1FD2uni1FD3uni1FD6uni1FD7uni1FE0uni1FE1uni1FE2uni1FE3uni1FE4uni1FE5uni1FE6uni1FF2uni1FF3uni1FF4uni1FF6uni1FF7uni1FB4uni1FE7uniEFD5anoteleiauni03D1uni03D5uni03D6franclirapesetaEuroafii61289estimatedpartialdiffproductsummationuni2219radicalinfinityintegralapproxequalnotequallessequalgreaterequallozengeuni02C9uniEFEDuniEFEEuniEFF1uniEFF2uniEFF3uniEFF5uniEFF7AcuteCaronDieresisDieresisAcuteDieresisGraveGraveHungarumlautMacroncyrBrevecyrFlexdblGravecyrbrevecyrflexdblgravedieresisacutedieresisgraveuniF635uniF637uniF638uniF639uniF6DCuniF63AuniF63BuniF63CuniF63DuniF63EuniF63FuniF640uniF641uniF642uniF628uniF643uniF644uniF645uniF646uniF647uniF648uniF649uniF64AuniF64BuniF64CuniF64DuniF64EuniF64FuniF650uniF651uniF652uniF653uniF654uniF655uniF656uniF657uniF658uniF659uniF65AuniF65BuniF65CuniF65DuniF65EuniF65FuniF660uniF629uniF62AuniF62BuniF62CuniF62DuniF661uniF662uniF663uniF664uniF665uniF666uniF667uniF668uniF669uniF66AuniF66BuniF66CuniF62EuniF62FuniF630uniF631uniF632uniF66DuniF66EuniF66FuniF670uniF671uniF672uniF673uniF674uniF675uniF676uniF677uniF678uniF679uniF67AuniF67BuniF67CuniF67DuniF67EuniF67FuniF680uniF681uniF682uniF683uniF684uniF685uniF686uniF687uniF688uniF689uniF68AuniF68BuniF68CuniF68DuniF68EuniF68FuniF690uniF691uniF692uniF693uniF694uniF695uniF696uniF697uniF698uniF699uniF69AuniF69BuniF69CuniF69DuniF69EuniF69FuniF6A0uniF6A1uniF6A2uniF6A3uniF6A4uniF6A5uniF6A6uniF6A7uniF6A8uniF6A9uniF6AAuniF6ABuniF6ACuniF6ADuniF6AEuniF6AFuniF6B0uniF6B1uniF6B2uniF6B3uniF6B4uniF6B5uniF6B6uniF6B7uniF6B8uniF6B9uniF6BAuniF6BBuniF6BCuniF6BDuniF633c_hc_kc_tf_bf_f_bf_f_hf_f_kf_f_tf_hf_jf_f_jf_kf_ts_puniFB06T_hlongs_blongs_hlongs_ilongs_klongs_llongs_longsuniFB05longs_longs_ilongs_longs_la.ende.endm.endn.endr.endK.altR.altk.altcaron.altcommaaccent.altpeseta.altAlphaiotasub.altAlphaiotasubasper.altAlphaiotasubasperacute.altAlphaiotasubaspergrave.altAlphaiotasubaspertilde.altAlphaiotasublenis.altAlphaiotasublenisacute.altAlphaiotasublenisgrave.altAlphaiotasublenistilde.altEtaiotasub.altEtaiotasubasper.altEtaiotasubasperacute.altEtaiotasubaspergrave.altEtaiotasubaspertilde.altEtaiotasublenis.altEtaiotasublenisacute.altEtaiotasublenisgrave.altEtaiotasublenistilde.altOmegaiotasub.altOmegaiotasubasper.altOmegaiotasubasperacute.altOmegaiotasubaspergrave.altOmegaiotasubaspertilde.altOmegaiotasublenis.altOmegaiotasublenisacute.altOmegaiotasublenisgrave.altOmegaiotasublenistilde.altEuro.fittedcent.fittedcolonmonetary.fitteddollar.fittedflorin.fittedfranc.fittedlira.fittednumbersign.fittedsterling.fittedyen.fittedEuro.oldstylecolonmonetary.oldstyleestimated.oldstyleflorin.oldstylefranc.oldstylelira.oldstylenumbersign.oldstylesterling.oldstyleyen.oldstylefranc.taboldstylelira.taboldstyleorn.001orn.002orn.003orn.004orn.005orn.006orn.007orn.008orn.009orn.010orn.011orn.012orn.013orn.014orn.015orn.016orn.017orn.018orn.019orn.020orn.021orn.022orn.023afii10023afii10031afii10022afii10049T_h.caronafii10070afii10196afii10026afii10021afii10846afii10193afii10107afii10024afii10195afii10041afii10037afii10109afii10053afii10045afii10108afii10040afii10104afii10036afii10078afii10074afii10060afii10046afii10052afii10087afii10050afii10145afii10057afii10059afii10146afii10088afii10101afii10054afii10058Rholenisafii10025afii10099afii10068afii10035afii10048afii10089afii10105afii10085afii10020afii10077afii10106afii10019afii10076afii10110afii10100afii10090afii10028afii10095afii10147afii10066afii10098afii10082afii10061afii10103afii10102afii10083afii10027afii10072afii10039afii61352afii10069afii10094afii10038afii10034afii10148afii10032afii10194afii10033afii10075afii10017afii10081afii10056afii10084afii10044afii10030afii10051afii10047afii10018afii10080afii10042afii10071afii10029afii10062afii10065afii10097T_h.commaaccentafii10096afii10079afii10091afii10093afii10064afii10043afii10092uni2215uni021Bafii10073afii10067uni00A0uni021Aafii10086afii10055uni0394uni03BCuni03A9uni00ADCopyright 2000 Adobe Systems Incorporated. All Rights Reserved. U.S. Patent Des. 337,604.Minion is either a registered trademark or a trademark of Adobe Systems Incorporated in the United States and/or other countries.Minion Pro RegularMinion Pro% i WZ5:`v22> % I
/
2
I
o
#3p~U
D
e
!o#]emE %<Jeov~EMfjtFp|,S-AZ0=DK +^&7NQy(/S_dl 5Rk$=Valsz"'-@T_gos{ ) . > N ^ d n v ~ !!!!'!3!?!H!Q!Z!]!c!i!n!s!x!!!!!!!!!!!!!"""#"'"3"?"K"W"c"k"s"{""""""""""""""c&oEr^7 JB@H *W2c~sp&m!1= 4:$kYyywRvzwrZnon?˘iNUddLoLݪ
~}}vywS6vO(Zp^TrǕ؍8x`?NYwUVYWE}zyMhummR~Kfowx}|txcBzuyBpOwTxql[LPҩy}~Bxxhzqlc#T0@9
5/j,X^M8Uruuoquvqiff{bE<H8XUo^bb_rMG'Н=[W}yQSSۚ$P|TzTyT'
ajqyzx||rrpwttozpj`lWHrʥaiqyo
|rqpxt@tpyqjalVHr]yt/m'mDx]pIsn8AgmxpQAz4wv~s}~vstzf|oęgfeoszvwzxu$wny|YgJO-ʆea]>9+ZhchAB_\?#^|m[5v-<<[FL LHHq˂~XxAo4uFabfqaf%f+rrs}ǔcqW "* ڟŇՊvx|po~}wUJN<0o-כtzr[ {"!coч~^o]/6'orsBp0ZlZqRoGt{_Fpq|iiMkTratap`DabuvCICpAϦ{~{lpˇBDDpӐ qoكtYoNU)gI_Z`yӔodžF/INlw71oC
ŸԱȗГnoՆ3$811xrdcQD:0] ;hJjp~djmplXhZfYxnmmyf^#MR:AgszvT]jjZ?_ynZQ{sNHyZdƨ]O틯֯}ޣDyZ{kvumofFMk_VYЄ#ms^@L A_!Z Z|蒯}~rqyg|usqrwgmazԬqbfZBoل5|%69o<3oZMZJuׇ3c T{ddmvrjY_VpŇkrkGpφ}8Fgsmy]pWSy/OBR7WXjfeolw}v84o~}xUGP~72pC
~㿊IK
NϪb98IPq
`y[~XsłI\FL
ދ.R۲vhl_@oۅ8(85oq͗ƫ>(3XOG7]_\i^%"Ba:Jy.}eu}|wzq]is|~ґϐuCDDEp
ؑ~P|xhcMp^},
qkuGuzwv~s}~ust}e{nęgfR5BcH
蠓`
i
`c
v
y
蠚}xsnyvrpyh&T~Y|S|Q4xrqxvrpyhrqVVrm