%PDF-1.6
%
1 0 obj
<>
endobj
2 0 obj
<>stream
Claire J. Cairney, Lauren S. Godwin, Alan E. Bilsland, Sharon Burns, Katrina H. Stevenson, Lynn McGarry, John Revie, Jon D. Moore, Ceri M. Wiggins, Rebecca S. Collinson, Clare Mudd, Elpida Tsonou, Mahito Sadaie, Dorothy C. Bennett, Masashi Narita, Christopher J. Torrance, W. Nicol Keith
A ‘synthetic-sickness’ screen for senescence re-engagement targets in mutant cancer backgrounds
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]
endobj
16 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref001)>>
endobj
17 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref002)>>
endobj
18 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref003)>>
endobj
19 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref004)>>
endobj
20 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref005)>>
endobj
21 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref006)>>
endobj
22 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref007)>>
endobj
23 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref003)>>
endobj
24 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref006)>>
endobj
25 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref008)>>
endobj
26 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref009)>>
endobj
27 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref010)>>
endobj
28 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref011)>>
endobj
29 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref004)>>
endobj
30 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref012)>>
endobj
31 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref013)>>
endobj
32 0 obj
<>/Border[0 0 0]/A 33 0 R>>
endobj
33 0 obj
<>
endobj
15 0 obj
[34 0 R 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
34 0 obj
<>stream
q
0.955 g
0 w
199.9998 713.9999 m
575.9997 713.9999 l
575.9997 488.0004 l
199.9998 488.0004 l
f*
0.83 0.64 0.02 0 k
324.8504 419.9244 m
329.6126 419.9244 l
h
f*
334.0346 419.9244 m
338.7969 419.9244 l
h
f*
437.6126 393.9024 m
442.3748 393.9024 l
h
f*
446.8535 393.9024 m
451.6157 393.9024 l
h
f*
367.1433 380.9197 m
371.9055 380.9197 l
h
f*
340.5543 341.915 m
345.3165 341.915 l
h
f*
448.9512 328.9323 m
453.7134 328.9323 l
h
f*
455.7543 276.9449 m
460.5165 276.9449 l
h
f*
464.9953 276.9449 m
469.7575 276.9449 l
h
f*
474.1795 276.9449 m
478.9417 276.9449 l
h
f*
487.5024 224.9008 m
492.2646 224.9008 l
h
f*
258.1795 172.9134 m
267.7039 172.9134 l
h
f*
272.126 172.9134 m
281.6504 172.9134 l
h
f*
429.5055 159.9307 m
434.2677 159.9307 l
h
f*
300.6425 146.948 m
310.1669 146.948 l
h
f*
494.6457 133.9087 m
504.1134 133.9087 l
h
f*
0 g
1 j
1 J
11.9999 0 0 11.9999 209.9905 696.0188 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Author)Tj
3.137 0 Td
(summary)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 209.9905 677.9905 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Cellular)Tj
3.3788 0 Td
(senescence)Tj
4.5808 0 Td
(is)Tj
0.8504 0 Td
(an)Tj
1.2019 0 Td
(irreversible)Tj
4.7054 0 Td
(arrest)Tj
2.4775 0 Td
(of)Tj
1.0148 0 Td
(cell)Tj
1.559 0 Td
(proliferation.)Tj
5.4936 0 Td
(Senescence)Tj
4.6941 0 Td
(is)Tj
0.8504 0 Td
(understood)Tj
-30.8067 -1.2982 Td
(to)Tj
1.0261 0 Td
(be)Tj
1.1508 0 Td
(a)Tj
0.652 0 Td
(universal)Tj
3.8551 0 Td
(barrier)Tj
2.965 0 Td
(that)Tj
1.7802 0 Td
(all)Tj
1.1452 0 Td
(cancers)Tj
3.2031 0 Td
(must)Tj
2.228 0 Td
(overcome)Tj
4.1499 0 Td
(during)Tj
2.931 0 Td
(their)Tj
2.109 0 Td
(evolution.)Tj
4.2236 0 Td
(Develop-)Tj
-31.419 -1.2983 Td
(ing)Tj
1.5023 0 Td
(ways)Tj
2.1543 0 Td
(to)Tj
1.0262 0 Td
(induce)Tj
2.9366 0 Td
(senescence)Tj
4.5808 0 Td
(in)Tj
1.0318 0 Td
(cancer)Tj
2.846 0 Td
(cells)Tj
1.9218 0 Td
(is)Tj
0.8504 0 Td
(therefore)Tj
3.8494 0 Td
(an)Tj
1.2019 0 Td
(attractive)Tj
3.9232 0 Td
(strategy)Tj
3.3278 0 Td
(to)Tj
1.0261 0 Td
(identify)Tj
-32.1786 -1.3039 Td
(targets)Tj
2.8743 0 Td
(for)Tj
1.3833 0 Td
(cancer)Tj
2.8459 0 Td
(therapy.)Tj
3.4696 0 Td
(However,)Tj
4.0819 0 Td
(a)Tj
0.6519 0 Td
(lack)Tj
1.8199 0 Td
(of)Tj
1.0148 0 Td
(understanding)Tj
6.0717 0 Td
(of)Tj
1.0148 0 Td
(this)Tj
1.6725 0 Td
(complex)Tj
3.6226 0 Td
(process)Tj
3.1861 0 Td
(has)Tj
-33.7093 -1.2983 Td
(meant)Tj
2.7439 0 Td
(that)Tj
1.7801 0 Td
(little)Tj
2.0013 0 Td
(progress)Tj
3.5943 0 Td
(has)Tj
1.542 0 Td
(been)Tj
2.126 0 Td
(made)Tj
2.4208 0 Td
(in)Tj
1.0374 0 Td
(translating)Tj
4.4957 0 Td
(senescence)Tj
4.5751 0 Td
(induction)Tj
4.1386 0 Td
(into)Tj
1.8425 0 Td
(the)Tj
-32.2977 -1.2982 Td
(clinic.)Tj
2.6248 0 Td
(Here)Tj
2.2054 0 Td
(we)Tj
1.3266 0 Td
(describe)Tj
3.5262 0 Td
(the)Tj
1.4684 0 Td
(identification)Tj
5.5842 0 Td
(and)Tj
1.7291 0 Td
(validation)Tj
4.2066 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.652 0 Td
(panel)Tj
2.3924 0 Td
(of)Tj
1.0148 0 Td
(inducers)Tj
3.668 0 Td
(of)Tj
1.0148 0 Td
(senes-)Tj
-32.4281 -1.3039 Td
(cence)Tj
2.4661 0 Td
(phenotypes)Tj
4.7962 0 Td
(from)Tj
2.2053 0 Td
(a)Tj
0.652 0 Td
(large-scale)Tj
4.3993 0 Td
(siRNA)Tj
2.8913 0 Td
(screen.)Tj
2.9991 0 Td
(We)Tj
1.61 0 Td
(show)Tj
2.2961 0 Td
(that)Tj
1.7801 0 Td
(the)Tj
1.4684 0 Td
(senescence)Tj
4.5807 0 Td
(response)Tj
-32.1446 -1.2983 Td
(can)Tj
1.627 0 Td
(be)Tj
1.1509 0 Td
(induced)Tj
3.4639 0 Td
(to)Tj
1.0261 0 Td
(varying)Tj
3.2145 0 Td
(degrees)Tj
3.2201 0 Td
(in)Tj
1.0318 0 Td
(genetic)Tj
3.0728 0 Td
(backgrounds)Tj
5.3858 0 Td
(mimicking)Tj
4.5977 0 Td
(common)Tj
3.8438 0 Td
(cancer)Tj
-31.6344 -1.2983 Td
(mutations,)Tj
4.507 0 Td
(allowing)Tj
3.617 0 Td
(for)Tj
1.389 0 Td
(a)Tj
0.6519 0 Td
(prioritisation)Tj
5.5049 0 Td
(of)Tj
1.0148 0 Td
(approaches.)Tj
4.9606 0 Td
(We)Tj
1.61 0 Td
(also)Tj
1.7688 0 Td
(show)Tj
2.2961 0 Td
(that)Tj
1.7801 0 Td
(partial)Tj
2.7893 0 Td
(senes-)Tj
-31.8895 -1.3039 Td
(cence)Tj
2.4661 0 Td
(responses)Tj
4.0932 0 Td
(can)Tj
1.6214 0 Td
(be)Tj
1.1508 0 Td
(triggered)Tj
3.8381 0 Td
(in)Tj
1.0318 0 Td
(cancer)Tj
2.846 0 Td
(cells)Tj
1.9219 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.474 0 Td
(absence)Tj
3.3392 0 Td
(of)Tj
1.0148 0 Td
(genes)Tj
2.4434 0 Td
(considered)Tj
4.5978 0 Td
(by)Tj
-32.8703 -1.2983 Td
(some)Tj
2.33 0 Td
(to)Tj
1.0261 0 Td
(be)Tj
1.1509 0 Td
(essential)Tj
3.583 0 Td
(for)Tj
1.3889 0 Td
(a)Tj
0.652 0 Td
(senescence)Tj
4.5808 0 Td
(response.)Tj
3.9571 0 Td
(However,)Tj
4.0762 0 Td
(distinct)Tj
3.2145 0 Td
(differences)Tj
4.5637 0 Td
(in)Tj
1.0375 0 Td
(prolifera-)Tj
-31.5607 -1.2982 Td
(tion)Tj
1.8425 0 Td
(arrest)Tj
2.4774 0 Td
(are)Tj
1.4514 0 Td
(observed)Tj
3.7927 0 Td
(different)Tj
3.6567 0 Td
(backgrounds.)Tj
5.6182 0 Td
(These)Tj
2.5625 0 Td
(results)Tj
2.8119 0 Td
(advance)Tj
3.464 0 Td
(our)Tj
1.627 0 Td
(understanding)Tj
-29.3043 -1.2983 Td
(of)Tj
1.0147 0 Td
(the)Tj
1.4684 0 Td
(complexity)Tj
4.6431 0 Td
(of)Tj
1.0148 0 Td
(senescence)Tj
4.5808 0 Td
(biology.)Tj
3.4015 0 Td
(This)Tj
1.9843 0 Td
(study)Tj
2.3924 0 Td
(has)Tj
1.542 0 Td
(identified)Tj
4.0592 0 Td
(several)Tj
2.931 0 Td
(potential)Tj
3.7644 0 Td
(targets)Tj
-32.7966 -1.3039 Td
(for)Tj
1.3889 0 Td
(drug)Tj
2.109 0 Td
(discovery.)Tj
4.2349 0 Td
(Interestingly,)Tj
5.4935 0 Td
(our)Tj
1.6271 0 Td
(results)Tj
2.8063 0 Td
(show)Tj
2.3017 0 Td
(the)Tj
1.4683 0 Td
(potential)Tj
3.7644 0 Td
(for)Tj
1.3833 0 Td
(therapeutic)Tj
4.7338 0 Td
(interven-)Tj
-31.3112 -1.2983 Td
(tion)Tj
1.8425 0 Td
(in)Tj
1.0374 0 Td
(some)Tj
2.3301 0 Td
(backgrounds)Tj
5.3858 0 Td
(which)Tj
2.6532 0 Td
(are)Tj
1.4457 0 Td
(so)Tj
1.0885 0 Td
(far)Tj
1.3152 0 Td
(refractory)Tj
4.1613 0 Td
(to)Tj
1.0261 0 Td
(current)Tj
3.1861 0 Td
(treatments.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 450.9921 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 433.9842 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Cellular)Tj
3.3788 0 Td
(senescence,)Tj
4.8019 0 Td
(often)Tj
2.2847 0 Td
(described)Tj
4.0535 0 Td
(as)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(irreversible)Tj
4.7112 0 Td
(arrest)Tj
2.4775 0 Td
(of)Tj
1.0148 0 Td
(cell)Tj
1.559 0 Td
(proliferation,)Tj
5.4935 0 Td
(can)Tj
1.6271 0 Td
(be)Tj
-33.8851 -1.2982 Td
(induced)Tj
3.4639 0 Td
(by)Tj
1.1848 0 Td
(a)Tj
0.652 0 Td
(variety)Tj
2.9253 0 Td
(of)Tj
1.0148 0 Td
(signals)Tj
2.9027 0 Td
([)Tj
0.83 0.64 0.02 0 k
(1)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2586 0 Td
(2)Tj
0 g
(].)Tj
1.2642 0 Td
(It)Tj
0.8561 0 Td
(is)Tj
0.8504 0 Td
(a)Tj
0.6519 0 Td
(complex)Tj
3.6227 0 Td
(phenotype,)Tj
4.6601 0 Td
(consisting)Tj
4.269 0 Td
(of)Tj
1.0148 0 Td
(various)Tj
3.1407 0 Td
(effector)Tj
-33.732 -1.2983 Td
(mechanisms)Tj
5.2043 0 Td
(including)Tj
4.0422 0 Td
(the)Tj
1.4683 0 Td
(DNA)Tj
2.3755 0 Td
(damage)Tj
3.3278 0 Td
(response)Tj
3.7304 0 Td
(\(DDR\),)Tj
3.2201 0 Td
(chromatin)Tj
4.4164 0 Td
(modification,)Tj
5.6012 0 Td
(autophagy)Tj
-33.3862 -1.3039 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.4683 0 Td
(senescence)Tj
4.5808 0 Td
(associated)Tj
4.2576 0 Td
(secretory)Tj
3.8551 0 Td
(phenotype)Tj
4.439 0 Td
(\(SASP\))Tj
3.0897 0 Td
([)Tj
0.83 0.64 0.02 0 k
(3)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2643 0 Td
(4)Tj
0 g
(].)Tj
1.2586 0 Td
(Understanding)Tj
6.2815 0 Td
(collective)Tj
-32.224 -1.2983 Td
(control)Tj
3.118 0 Td
(of)Tj
1.0148 0 Td
(these)Tj
2.2564 0 Td
(mechanisms)Tj
5.2044 0 Td
(is)Tj
0.8504 0 Td
(a)Tj
0.6519 0 Td
(priority)Tj
3.2769 0 Td
([)Tj
0.83 0.64 0.02 0 k
(5)Tj
0 g
(])Tj
1.3719 0 Td
(and)Tj
1.7348 0 Td
(screening)Tj
4.0479 0 Td
(approaches)Tj
4.7395 0 Td
(might)Tj
2.5965 0 Td
(help)Tj
1.9332 0 Td
(to)Tj
1.0261 0 Td
(deconvo-)Tj
-33.8227 -1.2982 Td
(lute)Tj
1.7121 0 Td
(senescence)Tj
4.5807 0 Td
(pathways.)Tj
4.1556 0 Td
(However,)Tj
4.0819 0 Td
(the)Tj
1.4683 0 Td
(senescence)Tj
4.5807 0 Td
(response)Tj
3.7304 0 Td
(involves)Tj
3.4866 0 Td
(the)Tj
1.4683 0 Td
(expression)Tj
4.4618 0 Td
(of)Tj
1.0147 0 Td
(many)Tj
-34.7411 -1.3039 Td
(biomarkers)Tj
4.7791 0 Td
(linked)Tj
2.7269 0 Td
(to)Tj
1.0262 0 Td
(these)Tj
2.2563 0 Td
(effector)Tj
3.2429 0 Td
(mechanisms,)Tj
5.4311 0 Td
(including)Tj
4.0365 0 Td
(cell)Tj
1.5647 0 Td
(cycle)Tj
2.1884 0 Td
(inhibitors)Tj
4.1442 0 Td
(such)Tj
2.0579 0 Td
(as)Tj
1.0148 0 Td
(p16)Tj
-34.469 -1.2983 Td
(and)Tj
1.7291 0 Td
(p21,)Tj
1.9162 0 Td
(components)Tj
5.1703 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(SASP)Tj
2.4095 0 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(])Tj
1.3776 0 Td
(and)Tj
1.7291 0 Td
(in)Tj
1.0375 0 Td
(some)Tj
2.3301 0 Td
(contexts)Tj
3.5433 0 Td
(senescence-associat)Tj
7.8008 0 Td
(ed)Tj
1.1679 0 Td
(heterochro-)Tj
-32.7002 -1.2983 Td
(matic)Tj
2.4604 0 Td
(foci)Tj
1.7065 0 Td
(\(SAHF\),)Tj
3.5829 0 Td
(which)Tj
2.6476 0 Td
(are)Tj
1.4513 0 Td
(associated)Tj
4.2519 0 Td
(with)Tj
2.0013 0 Td
(gene)Tj
2.0806 0 Td
(repression)Tj
4.371 0 Td
([)Tj
0.83 0.64 0.02 0 k
(7)Tj
0 g
(].)Tj
1.5987 0 Td
(There)Tj
2.5795 0 Td
(are)Tj
1.4457 0 Td
(also)Tj
1.7688 0 Td
(some)Tj
2.3301 0 Td
(key)Tj
-34.2763 -1.2982 Td
(morphological)Tj
6.0604 0 Td
(changes)Tj
3.4015 0 Td
(that)Tj
1.7802 0 Td
(occur,)Tj
2.6985 0 Td
(including)Tj
4.0366 0 Td
(a)Tj
0.6576 0 Td
(large)Tj
2.16 0 Td
(flattened)Tj
3.7077 0 Td
(morphology,)Tj
5.3688 0 Td
(enlarged)Tj
3.6566 0 Td
(nucleus)Tj
-33.5279 -1.304 Td
(and)Tj
1.7291 0 Td
(expression)Tj
4.4673 0 Td
(of)Tj
1.0148 0 Td
(senescence)Tj
4.5751 0 Td
(associated)Tj
4.2576 0 Td
(beta-galactosidase)Tj
7.4154 0 Td
(\(SA)Tj
/F11 1 Tf
()Tj
/F7 1 Tf
(Gal\).)Tj
4.1669 0 Td
(Expression)Tj
4.6148 0 Td
(of)Tj
1.0148 0 Td
(these)Tj
2.2507 0 Td
(bio-)Tj
-35.5065 -1.2982 Td
(markers)Tj
3.4865 0 Td
(is)Tj
0.8391 0 Td
(context)Tj
3.1804 0 Td
(dependent)Tj
4.4504 0 Td
(and)Tj
1.7235 0 Td
(few)Tj
1.6044 0 Td
(specifically)Tj
4.5637 0 Td
(define)Tj
2.6929 0 Td
(senescence,)Tj
4.7962 0 Td
(therefore)Tj
3.8438 0 Td
(various)Tj
3.1351 0 Td
(markers)Tj
-34.316 -1.2983 Td
(should)Tj
2.9139 0 Td
(be)Tj
1.1509 0 Td
(investigated)Tj
4.989 0 Td
(in)Tj
1.0374 0 Td
(parallel)Tj
3.1408 0 Td
(to)Tj
1.0205 0 Td
(confirm)Tj
3.4469 0 Td
(the)Tj
1.4683 0 Td
(senescent)Tj
4.0308 0 Td
(state)Tj
2.0353 0 Td
([)Tj
0.83 0.64 0.02 0 k
(3)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2643 0 Td
(6)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
0.9184 0 Td
(8)Tj
0 g
(].)Tj
-26.2203 -1.3039 Td
(Senescence)Tj
4.6998 0 Td
(markers)Tj
3.4922 0 Td
(and)Tj
1.7348 0 Td
(effectors)Tj
3.6 0 Td
(are)Tj
1.4513 0 Td
(evident)Tj
3.1635 0 Td
(in)Tj
1.0375 0 Td
(various)Tj
3.1407 0 Td
(premalignant)Tj
5.5956 0 Td
(tissues)Tj
/F12 1 Tf
2.8176 0 Td
[()12()]TJ
1.0148 0 Td
[()-13()15()3()]TJ
/F7 1 Tf
(,)Tj
2.0466 0 Td
(con-)Tj
-34.9906 -1.2983 Td
(sistent)Tj
2.7779 0 Td
(with)Tj
1.9956 0 Td
(a)Tj
0.6519 0 Td
(role)Tj
1.7688 0 Td
(for)Tj
1.389 0 Td
(senescence)Tj
4.5808 0 Td
(as)Tj
1.0148 0 Td
(a)Tj
0.6519 0 Td
(universal)Tj
3.8551 0 Td
(barrier)Tj
2.965 0 Td
(to)Tj
1.0262 0 Td
(tumorigenesis.)Tj
6.0831 0 Td
(In)Tj
1.1112 0 Td
(mouse)Tj
2.8573 0 Td
(models)Tj
3.1067 0 Td
(of)Tj
/F12 1 Tf
-35.8353 -1.2982 Td
[()-16()22()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 223.4267 243.4393 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[( \n)]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 235.3322 239.0173 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(-dependent)Tj
4.8075 0 Td
(lung)Tj
2.0069 0 Td
(adenocarcinoma)Tj
6.8938 0 Td
(and)Tj
1.7291 0 Td
(pancreatic)Tj
4.3597 0 Td
(ductal)Tj
2.6759 0 Td
(carcinoma,)Tj
4.6771 0 Td
(p16)Tj
1.6895 0 Td
(and)Tj
1.7291 0 Td
(SA)Tj
/F11 1 Tf
()Tj
/F7 1 Tf
(Gal)Tj
-34.1005 -1.3039 Td
(were)Tj
2.1203 0 Td
(detected)Tj
3.5659 0 Td
(in)Tj
1.0374 0 Td
(premalignant)Tj
5.5956 0 Td
(lesions,)Tj
3.1578 0 Td
(but)Tj
1.5533 0 Td
(not)Tj
1.5704 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(malignant)Tj
4.286 0 Td
(disease)Tj
3.016 0 Td
([)Tj
0.83 0.64 0.02 0 k
(9)Tj
0 g
(].)Tj
1.5988 0 Td
(Similarly,)Tj
4.0308 0 Td
(onco-)Tj
-34.0381 -1.2982 Td
(genic)Tj
/F12 1 Tf
2.3471 0 Td
[()-16(\r)]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 246.7842 217.4173 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[( )]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 268.4976 212.9952 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(overexpression)Tj
6.2191 0 Td
(can)Tj
1.6271 0 Td
(induce)Tj
2.9367 0 Td
(senescence)Tj
4.5807 0 Td
(in)Tj
1.0375 0 Td
(cultured)Tj
3.566 0 Td
(melanocytes;)Tj
5.3858 0 Td
(human)Tj
3.0784 0 Td
(nevi)Tj
-35.2797 -1.2982 Td
(\(moles\),)Tj
3.4809 0 Td
(which)Tj
2.6532 0 Td
(often)Tj
2.2846 0 Td
(carry)Tj
/F12 1 Tf
2.2734 0 Td
[()-16(\r)]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 330.2362 204.4346 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[( )]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 349.7385 200.0125 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(,)Tj
0.4478 0 Td
(express)Tj
3.1408 0 Td
(many)Tj
2.4775 0 Td
(senescence)Tj
4.5807 0 Td
(markers)Tj
3.4979 0 Td
(and)Tj
1.7292 0 Td
(much)Tj
2.5171 0 Td
(evidence)Tj
-33.3635 -1.3039 Td
(supports)Tj
3.6794 0 Td
(a)Tj
0.652 0 Td
(role)Tj
1.7688 0 Td
(for)Tj
1.3889 0 Td
(senescence)Tj
4.5808 0 Td
(in)Tj
1.0318 0 Td
(maintaining)Tj
5.1192 0 Td
(their)Tj
2.109 0 Td
(arrested)Tj
3.4299 0 Td
(state)Tj
2.0353 0 Td
(and)Tj
1.7291 0 Td
(preventing)Tj
4.5411 0 Td
(progression)Tj
-32.0653 -1.2982 Td
(to)Tj
1.0262 0 Td
(melanoma)Tj
4.4503 0 Td
([)Tj
0.83 0.64 0.02 0 k
(10)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7348 0 Td
(11)Tj
0 g
(].)Tj
-6.015 -1.2983 Td
(Senescence)Tj
4.6998 0 Td
(signalling)Tj
4.0648 0 Td
(also)Tj
1.7688 0 Td
(occurs)Tj
2.8347 0 Td
(in)Tj
1.0373 0 Td
(advanced)Tj
3.9912 0 Td
(disease)Tj
3.016 0 Td
([)Tj
0.83 0.64 0.02 0 k
(4)Tj
0 g
(])Tj
1.3777 0 Td
(and)Tj
1.7291 0 Td
(in)Tj
1.0375 0 Td
(response)Tj
3.7303 0 Td
(to)Tj
1.0262 0 Td
(standard)Tj
-31.5097 -1.2983 Td
(chemo-)Tj
3.2712 0 Td
(or)Tj
1.0998 0 Td
(radiotherapy)Tj
5.3518 0 Td
([)Tj
0.83 0.64 0.02 0 k
(12)Tj
0 g
(],)Tj
2.075 0 Td
(where)Tj
2.6532 0 Td
(it)Tj
0.7822 0 Td
(may)Tj
1.9276 0 Td
(aid)Tj
1.4513 0 Td
(therapeutic)Tj
4.7338 0 Td
(activity)Tj
3.1181 0 Td
(of)Tj
1.0148 0 Td
(these)Tj
2.2507 0 Td
(agents)Tj
2.7496 0 Td
(by)Tj
1.1849 0 Td
(acting)Tj
2.6589 0 Td
(as)Tj
-36.3229 -1.3039 Td
(a)Tj
0.652 0 Td
(fail-safe)Tj
3.3109 0 Td
(mechanism)Tj
4.8472 0 Td
(in)Tj
1.0374 0 Td
(cases)Tj
2.2224 0 Td
(where)Tj
2.6475 0 Td
(pro-apoptotic)Tj
5.7372 0 Td
(signalling)Tj
4.0705 0 Td
(is)Tj
0.8448 0 Td
(defective)Tj
3.753 0 Td
([)Tj
0.83 0.64 0.02 0 k
(13)Tj
0 g
(].)Tj
2.075 0 Td
(Furthermore,)Tj
-31.1979 -1.2982 Td
(induction)Tj
4.1329 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(SASP)Tj
2.4151 0 Td
(by)Tj
1.1848 0 Td
(cancer)Tj
2.846 0 Td
(therapeutics)Tj
5.0909 0 Td
(may)Tj
1.9275 0 Td
(also)Tj
1.7689 0 Td
(induce)Tj
2.9366 0 Td
(a)Tj
0.6577 0 Td
(tumour-directed)Tj
6.8824 0 Td
(immune)Tj
-32.326 -1.2983 Td
(response)Tj
3.7304 0 Td
(owing)Tj
2.6929 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4684 0 Td
(release)Tj
2.9026 0 Td
(of)Tj
1.0148 0 Td
(inflammatory)Tj
5.7089 0 Td
(cytokines.)Tj
4.2236 0 Td
(Consistent)Tj
4.5014 0 Td
(with)Tj
1.9955 0 Td
(this,)Tj
1.8992 0 Td
(the)Tj
1.4684 0 Td
(re-expres-)Tj
-32.6322 -1.3039 Td
(sion)Tj
1.9049 0 Td
(of)Tj
1.0148 0 Td
(p53)Tj
1.6838 0 Td
(in)Tj
1.0375 0 Td
(a)Tj
0.6519 0 Td
(p53-deficient)Tj
5.5105 0 Td
(mouse)Tj
2.8573 0 Td
(model)Tj
2.7439 0 Td
(of)Tj
1.0148 0 Td
(liver)Tj
1.9842 0 Td
(carcinoma)Tj
4.4447 0 Td
(expressing)Tj
4.4277 0 Td
(oncogenic)Tj
/F12 1 Tf
4.3313 0 Td
[()39()20()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 555.2503 100.4598 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[( \n)]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 82.9984 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(resulted)Tj
3.3958 0 Td
(in)Tj
1.0375 0 Td
(senescence,)Tj
4.8075 0 Td
(rather)Tj
2.6419 0 Td
(than)Tj
2.0296 0 Td
(apoptosis,)Tj
4.2179 0 Td
(and)Tj
1.7292 0 Td
(tumour)Tj
3.2711 0 Td
(regression)Tj
4.32 0 Td
(by)Tj
1.1792 0 Td
(immune)Tj
3.6283 0 Td
(clearance)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 391.1244 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Screen)Tj
3.111 0 Td
(ing)Tj
1.5236 0 Td
(senescence)Tj
5.4709 0 Td
(targets)Tj
3.2245 0 Td
(in)Tj
0.9779 0 Td
(cancer)Tj
3.1749 0 Td
(backgrou)Tj
4.0394 0 Td
(nds)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
(6942)Tj
0 g
3.1819 0 Td
(August)Tj
3.2882 0 Td
(14,)Tj
1.5804 0 Td
(2017)Tj
32.2939 0 Td
(2)Tj
0.7654 0 Td
(/)Tj
0.496 0 Td
(24)Tj
/F9 1 Tf
-0.025 Tc
-66.402 84.0904 Td
(Institute)Tj
3.2244 0 Td
(Core)Tj
1.9488 0 Td
(Grant)Tj
2.2607 0 Td
(C14303/A17)Tj
4.6205 0 Td
(197.)Tj
1.8638 0 Td
(The)Tj
1.5945 0 Td
(funders)Tj
-15.5127 -1.3748 Td
(had)Tj
1.5874 0 Td
(no)Tj
1.1693 0 Td
(role)Tj
1.6157 0 Td
(in)Tj
0.8859 0 Td
(study)Tj
2.2606 0 Td
(design,)Tj
2.9055 0 Td
(data)Tj
1.793 0 Td
(collecti)Tj
2.5653 0 Td
(on)Tj
1.1693 0 Td
(and)Tj
-15.952 -1.3749 Td
(analysis,)Tj
3.4086 0 Td
(decision)Tj
3.2953 0 Td
(to)Tj
0.9497 0 Td
(publish,)Tj
3.1393 0 Td
(or)Tj
1.0064 0 Td
(prepara)Tj
2.8205 0 Td
(tion)Tj
1.6157 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
-17.1851 -1.3748 Td
(manuscript.)Tj
/F8 1 Tf
0 -2.126 Td
(Competing)Tj
4.3795 0 Td
(interests)Tj
3.3307 0 Td
(:)Tj
/F9 1 Tf
0.4819 0 Td
(JDM,)Tj
2.204 0 Td
(CMW,)Tj
2.5299 0 Td
(CM,)Tj
1.7221 0 Td
(and)Tj
1.5874 0 Td
(ET)Tj
1.1693 0 Td
(are)Tj
-17.4048 -1.3748 Td
(employed)Tj
3.848 0 Td
(by)Tj
1.1197 0 Td
(Horizon)Tj
3.0827 0 Td
(Discovery)Tj
3.8906 0 Td
(Ltd.)Tj
1.6512 0 Td
(CJT)Tj
1.637 0 Td
(is)Tj
-15.2292 -1.3748 Td
(employed)Tj
3.848 0 Td
(by)Tj
1.1197 0 Td
(PhoreMos)Tj
3.8481 0 Td
(t)Tj
ET
endstream
endobj
35 0 obj
<>stream
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
9.2906 75.0903 Td
(Ltd.)Tj
ET
Q
endstream
endobj
50 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 13 0 R/Annots 51 0 R/Contents 52 0 R/TrimBox[0 0 612 792]>>
endobj
51 0 obj
[53 0 R 54 0 R 55 0 R 56 0 R 57 0 R 58 0 R 59 0 R 60 0 R 61 0 R 62 0 R 63 0 R]
endobj
53 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref014)>>
endobj
54 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref015)>>
endobj
55 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref016)>>
endobj
56 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref017)>>
endobj
57 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref018)>>
endobj
58 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref019)>>
endobj
59 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref004)>>
endobj
60 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref006)>>
endobj
61 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref020)>>
endobj
62 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.s007)>>
endobj
63 0 obj
<>/Border[0 0 0]/A 64 0 R>>
endobj
64 0 obj
<>
endobj
52 0 obj
[65 0 R 66 0 R 67 0 R 68 0 R 69 0 R 70 0 R 71 0 R 72 0 R 73 0 R 74 0 R 75 0 R 76 0 R 77 0 R]
endobj
65 0 obj
<>stream
q
0.83 0.64 0.02 0 k
203.4142 706.337 m
212.9386 706.337 l
h
f*
262.0346 693.2976 m
271.5024 693.2976 l
h
f*
251.0362 576.3402 m
260.5606 576.3402 l
h
f*
428.1449 563.3008 m
437.6693 563.3008 l
h
f*
333.2409 524.2961 m
342.7654 524.2961 l
h
f*
347.1874 524.2961 m
356.7118 524.2961 l
h
f*
503.4898 485.348 m
508.252 485.348 l
h
f*
512.7307 485.348 m
517.4362 485.348 l
h
f*
247.0677 146.948 m
256.5921 146.948 l
h
f*
539.8866 107.9433 m
566.2488 107.9433 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 200.0125 707.4141 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
([)Tj
0.83 0.64 0.02 0 k
(14)Tj
0 g
(].)Tj
2.0749 0 Td
(However,)Tj
4.0762 0 Td
(in)Tj
1.0375 0 Td
(some)Tj
2.33 0 Td
(contexts)Tj
3.5433 0 Td
(SASP)Tj
2.4151 0 Td
(components)Tj
5.176 0 Td
(could)Tj
2.4548 0 Td
(promote)Tj
3.6624 0 Td
(cell)Tj
1.559 0 Td
(proliferation)Tj
5.2668 0 Td
(and)Tj
-33.596 -1.3039 Td
(tumorigenesis)Tj
5.862 0 Td
([)Tj
0.83 0.64 0.02 0 k
(15)Tj
0 g
(].)Tj
-4.6658 -1.2982 Td
(Senescence)Tj
4.6998 0 Td
(induction)Tj
4.1329 0 Td
(is)Tj
0.8504 0 Td
(an)Tj
1.2018 0 Td
(attractive)Tj
3.9232 0 Td
(concept)Tj
3.3618 0 Td
(in)Tj
1.0318 0 Td
(cancer)Tj
2.846 0 Td
(research,)Tj
3.7814 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.4684 0 Td
(idea)Tj
1.8765 0 Td
(of)Tj
1.0148 0 Td
(modulat-)Tj
-33.1141 -1.2983 Td
(ing)Tj
1.5023 0 Td
(the)Tj
1.4683 0 Td
(senescence)Tj
4.5808 0 Td
(response)Tj
3.7304 0 Td
(for)Tj
1.3889 0 Td
(therapeutic)Tj
4.7282 0 Td
(benefit,)Tj
3.2031 0 Td
(either)Tj
2.5342 0 Td
(to)Tj
1.0204 0 Td
(enhance)Tj
3.549 0 Td
(current)Tj
3.1861 0 Td
(treatments)Tj
4.4957 0 Td
(or)Tj
1.0999 0 Td
(as)Tj
-36.4873 -1.2983 Td
(a)Tj
0.6519 0 Td
(tumour)Tj
3.2712 0 Td
(suppressive)Tj
4.8075 0 Td
(therapy)Tj
3.2485 0 Td
(in)Tj
1.0318 0 Td
(its)Tj
1.1452 0 Td
(own)Tj
1.9615 0 Td
(right,)Tj
2.3755 0 Td
(has)Tj
1.542 0 Td
(been)Tj
2.126 0 Td
(gaining)Tj
3.2144 0 Td
(momentum)Tj
4.9833 0 Td
(over)Tj
1.9786 0 Td
(recent)Tj
2.7042 0 Td
(years.)Tj
-35.0416 -1.3039 Td
(However,)Tj
4.0761 0 Td
(cellular)Tj
3.1408 0 Td
(senescence)Tj
4.5751 0 Td
(and)Tj
1.7348 0 Td
(immortality)Tj
5.0003 0 Td
(remain)Tj
3.0841 0 Td
(underserved)Tj
5.1817 0 Td
(areas)Tj
2.245 0 Td
(for)Tj
1.3833 0 Td
(drug)Tj
2.1146 0 Td
(discovery)Tj
-32.5358 -1.2982 Td
(owing)Tj
2.6928 0 Td
(to)Tj
1.0205 0 Td
(a)Tj
0.6576 0 Td
(lack)Tj
1.8199 0 Td
(of)Tj
1.0148 0 Td
(senescence-inducing)Tj
8.5039 0 Td
(agents)Tj
2.7495 0 Td
(and)Tj
1.7348 0 Td
(an)Tj
1.2019 0 Td
(incomplete)Tj
4.6942 0 Td
(knowledge)Tj
4.541 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(complexity)Tj
-33.1141 -1.2983 Td
(of)Tj
1.0147 0 Td
(the)Tj
1.4684 0 Td
(underlying)Tj
4.6034 0 Td
(signalling)Tj
4.0649 0 Td
(events.)Tj
2.9593 0 Td
(To)Tj
1.338 0 Td
(address)Tj
3.2258 0 Td
(the)Tj
1.4683 0 Td
(first)Tj
1.8028 0 Td
(issue,)Tj
2.3868 0 Td
(we)Tj
1.3266 0 Td
(recently)Tj
3.4129 0 Td
(reported)Tj
3.6567 0 Td
(identifica-)Tj
-32.7286 -1.3039 Td
(tion)Tj
1.8425 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.6519 0 Td
(novel)Tj
2.3981 0 Td
(compound,)Tj
4.8246 0 Td
(CB-20903630,)Tj
5.845 0 Td
(through)Tj
3.4469 0 Td
(a)Tj
0.6519 0 Td
(target)Tj
2.9027 0 Td
(agnostic)Tj
3.9174 0 Td
(virtual)Tj
2.8177 0 Td
(screen.)Tj
2.999 0 Td
(The)Tj
1.7801 0 Td
(com-)Tj
-35.0926 -1.2983 Td
(pound)Tj
2.8459 0 Td
(selectively)Tj
4.2463 0 Td
(induces)Tj
3.2938 0 Td
(a)Tj
0.6577 0 Td
(variety)Tj
2.9196 0 Td
(of)Tj
1.0205 0 Td
(senescence)Tj
4.5751 0 Td
(associated)Tj
4.2576 0 Td
(phenotypes)Tj
4.8019 0 Td
(and)Tj
1.7291 0 Td
(G1)Tj
1.4116 0 Td
(blockade)Tj
3.7814 0 Td
(in)Tj
-35.5405 -1.2983 Td
(cancer)Tj
2.8402 0 Td
(cells)Tj
1.9219 0 Td
([)Tj
0.83 0.64 0.02 0 k
(16)Tj
0 g
(].)Tj
2.0806 0 Td
(However,)Tj
4.0762 0 Td
(given)Tj
2.3755 0 Td
(the)Tj
1.474 0 Td
(diversity)Tj
3.6453 0 Td
(of)Tj
1.0148 0 Td
(senescence)Tj
4.5807 0 Td
(triggers,)Tj
3.464 0 Td
(it)Tj
0.788 0 Td
(seems)Tj
2.6078 0 Td
(clear)Tj
2.1203 0 Td
(that)Tj
-32.9893 -1.3039 Td
(engagement)Tj
5.0683 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(response)Tj
3.736 0 Td
(is)Tj
0.8448 0 Td
(under)Tj
2.6192 0 Td
(distributed)Tj
4.5977 0 Td
(control)Tj
3.1238 0 Td
([)Tj
0.83 0.64 0.02 0 k
(17)Tj
0 g
(].)Tj
2.0749 0 Td
(Therefore,)Tj
4.3937 0 Td
(populating)Tj
4.5467 0 Td
(senes-)Tj
-33.4882 -1.2982 Td
(cence)Tj
2.4604 0 Td
(effector)Tj
3.2428 0 Td
(pathways)Tj
3.9345 0 Td
(remains)Tj
3.4412 0 Td
(a)Tj
0.6577 0 Td
(major)Tj
2.6078 0 Td
(aim.)Tj
-15.1482 -1.2983 Td
(Kinome-focused)Tj
6.8711 0 Td
(siRNA)Tj
2.8913 0 Td
(screening)Tj
4.0479 0 Td
(has)Tj
1.5477 0 Td
(previously)Tj
4.3483 0 Td
(been)Tj
2.1203 0 Td
(used)Tj
2.0636 0 Td
(successfully)Tj
4.8642 0 Td
(to)Tj
1.0262 0 Td
(uncover)Tj
3.4752 0 Td
(path-)Tj
-34.452 -1.3039 Td
(ways)Tj
2.1543 0 Td
(regulating)Tj
4.2632 0 Td
(cell)Tj
1.5591 0 Td
(immortality)Tj
5.0059 0 Td
([)Tj
0.83 0.64 0.02 0 k
(18)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7348 0 Td
(19)Tj
0 g
(].)Tj
1.7405 0 Td
(In)Tj
1.1055 0 Td
(the)Tj
1.4683 0 Td
(current)Tj
3.1862 0 Td
(study,)Tj
2.6135 0 Td
(we)Tj
1.3323 0 Td
(undertook)Tj
4.4277 0 Td
(a)Tj
0.6519 0 Td
(large-scale)Tj
-31.2432 -1.2983 Td
(siRNA)Tj
2.8913 0 Td
(screen)Tj
2.7666 0 Td
(combined)Tj
4.2462 0 Td
(with)Tj
1.9956 0 Td
(high-throughput)Tj
6.9278 0 Td
(imaging)Tj
3.4866 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4684 0 Td
(human)Tj
3.0784 0 Td
(melanoma)Tj
4.4503 0 Td
(cell)Tj
1.5591 0 Td
(line)Tj
-33.9078 -1.2982 Td
(A375P)Tj
2.8913 0 Td
(to)Tj
1.0204 0 Td
(identify)Tj
3.2995 0 Td
(senescence)Tj
4.5751 0 Td
(effectors.)Tj
3.8324 0 Td
(Our)Tj
1.8652 0 Td
(results)Tj
2.812 0 Td
(revealed)Tj
3.5206 0 Td
(diversity)Tj
3.6453 0 Td
(in)Tj
1.0375 0 Td
(levels)Tj
2.3754 0 Td
(of)Tj
1.0148 0 Td
(senescence)Tj
-31.8895 -1.2983 Td
(engagement)Tj
5.0683 0 Td
(between)Tj
3.5262 0 Td
(gene)Tj
2.0863 0 Td
(targets)Tj
2.8687 0 Td
(and)Tj
1.7291 0 Td
(cell)Tj
1.559 0 Td
(lines,)Tj
2.2961 0 Td
(consistent)Tj
4.2519 0 Td
(with)Tj
2.0013 0 Td
(recent)Tj
2.7099 0 Td
(data)Tj
1.9105 0 Td
([)Tj
0.83 0.64 0.02 0 k
(4)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2643 0 Td
(6)Tj
0 g
(].)Tj
1.2585 0 Td
(Using)Tj
2.5966 0 Td
(a)Tj
-35.1267 -1.3039 Td
(panel)Tj
2.3867 0 Td
(of)Tj
1.0148 0 Td
(HCT116)Tj
3.6907 0 Td
(isogenic)Tj
3.4809 0 Td
(cell)Tj
1.5591 0 Td
(lines)Tj
2.0692 0 Td
(carrying)Tj
3.5547 0 Td
(common)Tj
3.8437 0 Td
(cancer-relevant)Tj
6.3949 0 Td
(gene)Tj
2.0807 0 Td
(mutations,)Tj
4.507 0 Td
(we)Tj
-34.5824 -1.2983 Td
(show)Tj
2.296 0 Td
(that)Tj
1.7801 0 Td
(some)Tj
2.3301 0 Td
(senescence)Tj
4.5808 0 Td
(phenotypes)Tj
4.8018 0 Td
(can)Tj
1.6214 0 Td
(be)Tj
1.1509 0 Td
(engaged)Tj
3.5093 0 Td
(despite)Tj
3.0387 0 Td
(the)Tj
1.4683 0 Td
(absence)Tj
3.3449 0 Td
(of)Tj
1.0148 0 Td
(known)Tj
3.0047 0 Td
(effectors)Tj
-33.9418 -1.2983 Td
(such)Tj
2.0579 0 Td
(as)Tj
1.0148 0 Td
(p53)Tj
1.6894 0 Td
(or)Tj
1.0999 0 Td
(p21.)Tj
1.9105 0 Td
(However,)Tj
4.0762 0 Td
(distinct)Tj
3.2145 0 Td
(differences)Tj
4.5637 0 Td
(in)Tj
1.0375 0 Td
(proliferation)Tj
5.2667 0 Td
(arrest)Tj
2.4775 0 Td
(engagement)Tj
5.074 0 Td
(are)Tj
1.4456 0 Td
(evi-)Tj
-34.9282 -1.3039 Td
(dent)Tj
2.0182 0 Td
(in)Tj
1.0318 0 Td
(different)Tj
3.6567 0 Td
(genetic)Tj
3.0727 0 Td
(backgrounds.)Tj
5.6126 0 Td
(Finally,)Tj
3.1691 0 Td
(we)Tj
1.3323 0 Td
(show)Tj
2.296 0 Td
(senescence)Tj
4.5808 0 Td
(induction)Tj
4.1385 0 Td
(by)Tj
1.1792 0 Td
(knock-down)Tj
-32.0879 -1.2982 Td
(of)Tj
1.0147 0 Td
(ECT2)Tj
2.5399 0 Td
(in)Tj
1.0318 0 Td
(particular)Tj
4.1159 0 Td
(is)Tj
0.8447 0 Td
(greatly)Tj
2.914 0 Td
(enhanced)Tj
4.0762 0 Td
(in)Tj
1.0374 0 Td
(the)Tj
1.4684 0 Td
(presence)Tj
3.7133 0 Td
(of)Tj
1.0148 0 Td
(oncogenic)Tj
/F12 1 Tf
4.3314 0 Td
[()-16()22()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 504.4535 425.8204 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[(\n)]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 521.6881 421.3984 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(.)Tj
0.4422 0 Td
(These)Tj
2.5681 0 Td
(find-)Tj
-35.1776 -1.2982 Td
(ings)Tj
1.8595 0 Td
(suggest)Tj
3.1238 0 Td
(that)Tj
1.7801 0 Td
(pro-senescence)Tj
6.3212 0 Td
(therapy)Tj
3.2485 0 Td
(may)Tj
1.9276 0 Td
(be)Tj
1.1508 0 Td
(effective)Tj
3.5093 0 Td
(in)Tj
1.0375 0 Td
(various)Tj
3.1407 0 Td
(malignancies,)Tj
5.6862 0 Td
(including)Tj
-32.7852 -1.3039 Td
(those)Tj
2.3357 0 Td
(harbouring)Tj
4.7452 0 Td
(oncogenic)Tj
4.337 0 Td
(RAS)Tj
2.0012 0 Td
(mutations,)Tj
4.5071 0 Td
(which)Tj
2.6475 0 Td
(are)Tj
1.4514 0 Td
(common)Tj
3.8437 0 Td
(and)Tj
1.7291 0 Td
(often)Tj
2.2847 0 Td
(refractory)Tj
4.1668 0 Td
(to)Tj
1.0262 0 Td
(treat-)Tj
-35.0756 -1.2983 Td
(ment.)Tj
2.5342 0 Td
(Furthermore,)Tj
5.6125 0 Td
(by)Tj
1.1849 0 Td
(populating)Tj
4.5467 0 Td
(the)Tj
1.4684 0 Td
(signalling)Tj
4.0705 0 Td
(pathways)Tj
3.9345 0 Td
(that)Tj
1.7744 0 Td
(regulate)Tj
3.4129 0 Td
(the)Tj
1.4684 0 Td
(senescent)Tj
4.0307 0 Td
(pheno-)Tj
-34.0381 -1.2983 Td
(type)Tj
1.9105 0 Td
(with)Tj
2.0013 0 Td
(the)Tj
1.4683 0 Td
(effectors)Tj
3.6057 0 Td
(identified)Tj
4.0592 0 Td
(by)Tj
1.1792 0 Td
(our)Tj
1.627 0 Td
(screen,)Tj
2.9934 0 Td
(a)Tj
0.6576 0 Td
(more)Tj
2.3414 0 Td
(complete)Tj
3.8778 0 Td
(picture)Tj
3.0501 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(senescence)Tj
-31.2546 -1.2982 Td
(response)Tj
3.7304 0 Td
(can)Tj
1.627 0 Td
(be)Tj
1.1509 0 Td
(drawn.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 327.0047 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Results)Tj
/F0 1 Tf
0 -1.5023 Td
(Identification)Tj
5.7591 0 Td
(of)Tj
1.0488 0 Td
(siRNAs)Tj
3.5197 0 Td
(that)Tj
1.8709 0 Td
(induce)Tj
3.1228 0 Td
(a)Tj
0.7701 0 Td
(senescent)Tj
4.7292 0 Td
(morphology)Tj
5.3811 0 Td
(in)Tj
0.9827 0 Td
(A375P)Tj
-27.1844 -1.167 Td
(melanoma)Tj
4.8331 0 Td
(cells)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 278.022 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(To)Tj
1.3379 0 Td
(identify)Tj
3.2938 0 Td
(potential)Tj
3.7587 0 Td
(senescence-inducing)Tj
8.5096 0 Td
(targets)Tj
2.8686 0 Td
(for)Tj
1.389 0 Td
(drug)Tj
2.109 0 Td
(discovery)Tj
4.0138 0 Td
(and)Tj
1.7291 0 Td
(extend)Tj
2.9084 0 Td
(our)Tj
1.6214 0 Td
(knowl-)Tj
-33.5393 -1.3039 Td
(edge)Tj
2.0579 0 Td
(of)Tj
1.0148 0 Td
(senescence)Tj
4.5807 0 Td
(signalling)Tj
4.0706 0 Td
(in)Tj
1.0318 0 Td
(cancer,)Tj
3.0727 0 Td
(we)Tj
1.3266 0 Td
(initially)Tj
3.2485 0 Td
(performed)Tj
4.473 0 Td
(validation)Tj
4.201 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.6576 0 Td
(high-content)Tj
-30.75 -1.2982 Td
(fluorescence)Tj
5.1873 0 Td
(imaging)Tj
3.4866 0 Td
(screen)Tj
2.7723 0 Td
(focused)Tj
3.2768 0 Td
(on)Tj
1.2756 0 Td
(senescence)Tj
4.5807 0 Td
(phenotypes.)Tj
5.023 0 Td
(Using)Tj
2.5965 0 Td
(A375P)Tj
2.8913 0 Td
(cells)Tj
1.9219 0 Td
(treated)Tj
-33.012 -1.2983 Td
(with)Tj
1.9955 0 Td
(etoposide,)Tj
4.2803 0 Td
(we)Tj
1.3266 0 Td
(demonstrated)Tj
5.76 0 Td
(that)Tj
1.7801 0 Td
(stable)Tj
2.4888 0 Td
(growth)Tj
3.0728 0 Td
(arrest)Tj
2.4774 0 Td
(in)Tj
1.0375 0 Td
(this)Tj
1.6724 0 Td
(cell)Tj
1.5591 0 Td
(line,)Tj
1.9332 0 Td
(assessed)Tj
3.4696 0 Td
(by)Tj
1.1849 0 Td
(colony)Tj
-34.0382 -1.3039 Td
(formation)Tj
4.2576 0 Td
(assays)Tj
2.6248 0 Td
(and)Tj
1.7348 0 Td
(cell)Tj
1.5591 0 Td
(growth)Tj
3.0727 0 Td
(kinetics)Tj
3.3052 0 Td
(after)Tj
2.0352 0 Td
(compound)Tj
4.5978 0 Td
(washout,)Tj
3.7871 0 Td
(was)Tj
1.6951 0 Td
(accompanied)Tj
5.5502 0 Td
(by)Tj
-34.2196 -1.2983 Td
(induction)Tj
4.1328 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.6577 0 Td
(range)Tj
2.4604 0 Td
(of)Tj
1.0148 0 Td
(senescence)Tj
4.5808 0 Td
(markers.)Tj
3.7247 0 Td
(These)Tj
2.5625 0 Td
(included)Tj
3.7133 0 Td
(increased)Tj
4.0025 0 Td
(nuclear)Tj
3.1918 0 Td
(area,)Tj
2.109 0 Td
(SA)Tj
/F11 1 Tf
()Tj
/F7 1 Tf
(Gal)Tj
-33.1651 -1.2982 Td
(and)Tj
1.7291 0 Td
(p21)Tj
1.6894 0 Td
(expression,)Tj
4.6885 0 Td
(and)Tj
1.7291 0 Td
(53BP1)Tj
2.7893 0 Td
(and)Tj
1.7291 0 Td
(H2AX)Tj
2.8006 0 Td
(nuclear)Tj
3.1918 0 Td
(foci.)Tj
1.9332 0 Td
(We)Tj
1.6101 0 Td
(next)Tj
1.9559 0 Td
(tested)Tj
2.5512 0 Td
(an)Tj
1.2018 0 Td
(imaging)Tj
3.4866 0 Td
(assay)Tj
-33.0857 -1.304 Td
(based)Tj
2.4717 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.4684 0 Td
(nuclear)Tj
3.1974 0 Td
(area)Tj
1.8822 0 Td
(marker)Tj
3.1351 0 Td
(and)Tj
1.7291 0 Td
(cell)Tj
1.5591 0 Td
(number)Tj
3.4185 0 Td
(in)Tj
1.0375 0 Td
(a)Tj
0.652 0 Td
(small)Tj
2.33 0 Td
(scale)Tj
2.109 0 Td
(screen)Tj
2.7666 0 Td
(of)Tj
1.0148 0 Td
(160)Tj
1.6498 0 Td
(kinase)Tj
2.7495 0 Td
(inhibi-)Tj
-34.4463 -1.2982 Td
(tor)Tj
1.3946 0 Td
(compounds)Tj
4.9606 0 Td
(by)Tj
1.1792 0 Td
(high)Tj
2.0069 0 Td
(content)Tj
3.2712 0 Td
(fluorescence)Tj
5.1873 0 Td
(imaging)Tj
3.4866 0 Td
(using)Tj
2.3868 0 Td
(the)Tj
1.474 0 Td
(Operetta)Tj
3.7304 0 Td
(platform.)Tj
3.9288 0 Td
(We)Tj
1.61 0 Td
(have)Tj
-34.6164 -1.2983 Td
(previously)Tj
4.3483 0 Td
(reported)Tj
3.6623 0 Td
(the)Tj
1.4683 0 Td
(ability)Tj
2.6929 0 Td
(of)Tj
1.0148 0 Td
(some)Tj
2.3301 0 Td
(of)Tj
1.0148 0 Td
(these)Tj
2.2564 0 Td
(compounds)Tj
4.9606 0 Td
(to)Tj
1.0261 0 Td
(induce)Tj
2.9367 0 Td
(senescence)Tj
4.5807 0 Td
(in)Tj
1.0318 0 Td
(normal)Tj
-33.3238 -1.2983 Td
(fibroblasts)Tj
4.3653 0 Td
([)Tj
0.83 0.64 0.02 0 k
(20)Tj
0 g
(].)Tj
2.0749 0 Td
(Four)Tj
2.1543 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(best)Tj
1.8085 0 Td
(hits)Tj
1.6725 0 Td
(from)Tj
2.2053 0 Td
(this)Tj
1.6781 0 Td
(screen)Tj
2.7666 0 Td
(were)Tj
2.126 0 Td
(tested)Tj
2.5511 0 Td
(in)Tj
1.0375 0 Td
(a)Tj
0.652 0 Td
(range)Tj
2.4604 0 Td
(of)Tj
1.0148 0 Td
(secondary)Tj
-31.0561 -1.3039 Td
(assays,)Tj
2.8516 0 Td
(including)Tj
4.0422 0 Td
(colony)Tj
2.9026 0 Td
(formation)Tj
4.2633 0 Td
(assays,)Tj
2.8516 0 Td
(confirming)Tj
4.7225 0 Td
(the)Tj
1.474 0 Td
(ability)Tj
2.6929 0 Td
(of)Tj
1.0148 0 Td
(screening)Tj
4.0535 0 Td
(based)Tj
2.4718 0 Td
(on)Tj
1.2756 0 Td
(these)Tj
-34.6164 -1.2982 Td
(markers)Tj
3.4979 0 Td
(to)Tj
1.0261 0 Td
(identify)Tj
3.2939 0 Td
(chemical)Tj
3.7813 0 Td
(agents)Tj
2.7553 0 Td
(capable)Tj
3.2031 0 Td
(of)Tj
1.0148 0 Td
(causing)Tj
3.2485 0 Td
(a)Tj
0.652 0 Td
(range)Tj
2.4604 0 Td
(of)Tj
1.0148 0 Td
(senescence)Tj
4.5808 0 Td
(phenotypes)Tj
-30.5289 -1.2983 Td
(alongside)Tj
3.9968 0 Td
(stable)Tj
2.4944 0 Td
(proliferation)Tj
5.2668 0 Td
(arrest.)Tj
2.7042 0 Td
(These)Tj
2.5625 0 Td
(validation)Tj
4.2066 0 Td
(experiments)Tj
5.142 0 Td
(are)Tj
1.4457 0 Td
(summarised)Tj
5.1307 0 Td
(in)Tj
0.83 0.64 0.02 0 k
1.0374 0 Td
(S2)Tj
1.1736 0 Td
(File)Tj
0 g
(.)Tj
-33.9645 -1.3039 Td
(We)Tj
1.61 0 Td
(next)Tj
1.9559 0 Td
(used)Tj
2.058 0 Td
(the)Tj
1.4683 0 Td
(validated)Tj
3.8324 0 Td
(imaging)Tj
3.4809 0 Td
(assay)Tj
2.2621 0 Td
(to)Tj
1.0261 0 Td
(perform)Tj
3.5149 0 Td
(a)Tj
0.652 0 Td
(large-scale)Tj
4.3994 0 Td
(screen)Tj
2.7722 0 Td
(of)Tj
1.0091 0 Td
(10,414)Tj
2.8233 0 Td
(gene)Tj
2.0807 0 Td
(tar-)Tj
-36.1415 -1.2983 Td
(gets)Tj
1.7688 0 Td
(using)Tj
2.3867 0 Td
(the)Tj
1.4684 0 Td
(Ambion)Tj
3.5546 0 Td
(Silencer)Tj
3.4015 0 Td
(Select)Tj
2.5115 0 Td
(Druggable)Tj
4.3937 0 Td
(Genome)Tj
3.6567 0 Td
(siRNA)Tj
2.8913 0 Td
(library.)Tj
3.0954 0 Td
(As)Tj
1.2642 0 Td
(quality)Tj
2.9594 0 Td
(controls)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 391.1244 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Screen)Tj
3.111 0 Td
(ing)Tj
1.5236 0 Td
(senescence)Tj
5.4709 0 Td
(targets)Tj
3.2245 0 Td
(in)Tj
0.9779 0 Td
(cancer)Tj
3.1749 0 Td
(backgrou)Tj
4.0394 0 Td
(nds)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
(6942)Tj
0 g
3.1819 0 Td
(August)Tj
3.2882 0 Td
(14,)Tj
1.5804 0 Td
(2017)Tj
32.2939 0 Td
(3)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
66 0 obj
<>stream
endstream
endobj
67 0 obj
<>stream
endstream
endobj
68 0 obj
<>stream
endstream
endobj
69 0 obj
<>stream
endstream
endobj
70 0 obj
<>stream
endstream
endobj
71 0 obj
<>stream
endstream
endobj
72 0 obj
<>stream
endstream
endobj
73 0 obj
<>stream
endstream
endobj
74 0 obj
<>stream
endstream
endobj
75 0 obj
<>stream
endstream
endobj
76 0 obj
<>stream
endstream
endobj
77 0 obj
<>stream
BT
66.402 0 Td
(24)Tj
ET
Q
endstream
endobj
78 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 13 0 R/Annots 79 0 R/Contents 80 0 R/TrimBox[0 0 612 792]>>
endobj
79 0 obj
[81 0 R 82 0 R 83 0 R 84 0 R 85 0 R 86 0 R 87 0 R 88 0 R 89 0 R 90 0 R 91 0 R 92 0 R 93 0 R 94 0 R 95 0 R 96 0 R 97 0 R]
endobj
81 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.s007)>>
endobj
82 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref020)>>
endobj
83 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.s001)>>
endobj
84 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.s001)>>
endobj
85 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.t001)>>
endobj
86 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.g001)>>
endobj
87 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.g002)>>
endobj
88 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.s007)>>
endobj
89 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.g002)>>
endobj
90 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.s007)>>
endobj
91 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.ref021)>>
endobj
92 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.s007)>>
endobj
93 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.g002)>>
endobj
94 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.g002)>>
endobj
95 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.g003)>>
endobj
96 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.g003)>>
endobj
97 0 obj
<>/Border[0 0 0]/A 98 0 R>>
endobj
98 0 obj
<>
endobj
80 0 obj
[99 0 R 100 0 R 101 0 R 102 0 R 103 0 R 104 0 R 105 0 R 106 0 R 107 0 R 108 0 R]
endobj
99 0 obj
<>stream
q
0.83 0.64 0.02 0 k
341.1213 706.337 m
367.4835 706.337 l
h
f*
223.4268 667.3323 m
232.9512 667.3323 l
h
f*
512.5606 667.3323 m
536.8819 667.3323 l
h
f*
449.6315 563.3008 m
479.7354 563.3008 l
h
f*
433.6441 537.3354 m
462.7843 537.3354 l
h
f*
326.0409 459.326 m
345.6 459.326 l
h
f*
289.8709 315.9496 m
316.2898 315.9496 l
h
f*
327.7417 315.9496 m
358.8661 315.9496 l
h
f*
286.526 289.9276 m
312.9449 289.9276 l
h
f*
324.3969 289.9276 m
355.3512 289.9276 l
h
f*
243.9496 250.9228 m
253.4173 250.9228 l
h
f*
473.1591 250.9228 m
539.6598 250.9228 l
h
f*
493.5685 237.9402 m
519.9874 237.9402 l
h
f*
467.0929 159.9307 m
492.4913 159.9307 l
h
f*
463.5213 107.9433 m
483.0803 107.9433 l
h
f*
346.0535 81.9213 m
372.4157 81.9213 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 200.0125 707.4141 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(on)Tj
1.2755 0 Td
(each)Tj
2.0296 0 Td
(screening)Tj
4.0479 0 Td
(plate,)Tj
2.3641 0 Td
(etoposide)Tj
4.0535 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S2)Tj
1.5137 0 Td
(File)Tj
0 g
(\))Tj
2.0239 0 Td
(and)Tj
1.7291 0 Td
(an)Tj
1.2019 0 Td
(independent)Tj
5.2781 0 Td
(siRNA)Tj
2.8856 0 Td
(obtained)Tj
3.7361 0 Td
(from)Tj
2.2053 0 Td
(Qiagen)Tj
-34.3443 -1.3039 Td
(against)Tj
3.0273 0 Td
(CDK1)Tj
2.7666 0 Td
(\(which)Tj
2.9934 0 Td
(is)Tj
0.8447 0 Td
(known)Tj
3.0047 0 Td
(to)Tj
1.0262 0 Td
(be)Tj
1.1508 0 Td
(involved)Tj
3.651 0 Td
(in)Tj
1.0375 0 Td
(senescence\))Tj
4.9152 0 Td
(were)Tj
2.126 0 Td
(included.)Tj
3.9345 0 Td
(Primary)Tj
3.4979 0 Td
(hits)Tj
1.6724 0 Td
(in)Tj
-35.6482 -1.2982 Td
(A375P)Tj
2.8913 0 Td
(cells,)Tj
2.1429 0 Td
(detected)Tj
3.566 0 Td
(by)Tj
1.1849 0 Td
(increased)Tj
3.9968 0 Td
(nuclear)Tj
3.1975 0 Td
(area)Tj
1.8822 0 Td
(and)Tj
1.7291 0 Td
(reduced)Tj
3.4469 0 Td
(proliferation)Tj
5.2667 0 Td
(compared)Tj
4.2406 0 Td
(to)Tj
1.0262 0 Td
(con-)Tj
-34.5711 -1.2983 Td
(trols)Tj
2.0012 0 Td
([)Tj
0.83 0.64 0.02 0 k
(20)Tj
0 g
(],)Tj
2.0806 0 Td
(were)Tj
2.1203 0 Td
(rescreened)Tj
4.5184 0 Td
(and)Tj
1.7291 0 Td
(ranked)Tj
3.0217 0 Td
(by)Tj
1.1793 0 Td
(confidence)Tj
4.6034 0 Td
(\(Materials)Tj
4.2859 0 Td
(and)Tj
1.7348 0 Td
(Methods,)Tj
0.83 0.64 0.02 0 k
3.9799 0 Td
(S1)Tj
1.1735 0 Td
(Fig)Tj
0 g
(\))Tj
1.8198 0 Td
(and)Tj
1.7291 0 Td
(a)Tj
-35.977 -1.2983 Td
(refined)Tj
3.067 0 Td
(hit)Tj
1.3153 0 Td
(list)Tj
1.3946 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(24)Tj
1.1678 0 Td
(most)Tj
2.2054 0 Td
(robust)Tj
2.7949 0 Td
(hits)Tj
1.6724 0 Td
(and)Tj
1.7292 0 Td
(16)Tj
1.1735 0 Td
(others)Tj
2.7099 0 Td
(predicted)Tj
3.9968 0 Td
(to)Tj
1.0262 0 Td
(be)Tj
1.1508 0 Td
(druggable)Tj
4.1896 0 Td
(targets)Tj
2.8686 0 Td
(by)Tj
-34.9452 -1.3039 Td
(functional)Tj
4.3086 0 Td
(analysis)Tj
3.3278 0 Td
(was)Tj
1.6951 0 Td
(generated)Tj
4.1386 0 Td
(for)Tj
1.3833 0 Td
(further)Tj
3.0274 0 Td
(validation.)Tj
4.4333 0 Td
(Criteria)Tj
3.3166 0 Td
(for)Tj
1.3833 0 Td
(the)Tj
1.4683 0 Td
(assessment)Tj
4.6148 0 Td
(of)Tj
1.0148 0 Td
(drug-)Tj
-34.1119 -1.2982 Td
(gable)Tj
2.296 0 Td
(targets)Tj
2.8686 0 Td
(included)Tj
3.7134 0 Td
(previous)Tj
3.651 0 Td
(success)Tj
3.1011 0 Td
(in)Tj
1.0318 0 Td
(targeting)Tj
3.7927 0 Td
(the)Tj
1.4684 0 Td
(encoded)Tj
3.6056 0 Td
(protein)Tj
3.1521 0 Td
(or)Tj
1.0998 0 Td
(another)Tj
3.3279 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
-34.1232 -1.2983 Td
(same)Tj
2.2563 0 Td
(molecular)Tj
4.2179 0 Td
(class)Tj
2.0466 0 Td
(with)Tj
1.9956 0 Td
(a)Tj
0.6577 0 Td
(small)Tj
2.3243 0 Td
(molecule)Tj
3.8381 0 Td
(or)Tj
1.0999 0 Td
(drug-like)Tj
3.8947 0 Td
(compound,)Tj
4.8246 0 Td
(or)Tj
1.0998 0 Td
(the)Tj
1.4684 0 Td
(presence)Tj
3.7133 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
-34.452 -1.3039 Td
(potentially)Tj
4.4617 0 Td
(druggable)Tj
4.1839 0 Td
(site)Tj
1.5703 0 Td
(within)Tj
2.812 0 Td
(the)Tj
1.474 0 Td
(protein)Tj
3.1521 0 Td
(structure.)Tj
4.0479 0 Td
(Many)Tj
2.5511 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(24)Tj
1.1735 0 Td
(highest-confidence)Tj
7.8179 0 Td
(hits)Tj
-35.7276 -1.2983 Td
(were)Tj
2.1203 0 Td
(also)Tj
1.7688 0 Td
(classed)Tj
2.999 0 Td
(as)Tj
1.0148 0 Td
(druggable,)Tj
4.4107 0 Td
(increasing)Tj
4.3313 0 Td
(our)Tj
1.6271 0 Td
(interest)Tj
3.2088 0 Td
(in)Tj
1.0374 0 Td
(them.)Tj
2.5115 0 Td
(The)Tj
1.7858 0 Td
(combined)Tj
4.2406 0 Td
(validation)Tj
4.2066 0 Td
(list)Tj
1.3947 0 Td
(of)Tj
-36.6574 -1.2983 Td
(40)Tj
1.1678 0 Td
(targets)Tj
2.8743 0 Td
(showed)Tj
3.2485 0 Td
(a)Tj
0.6576 0 Td
(range)Tj
2.4605 0 Td
(of)Tj
1.0148 0 Td
(senescence-like)Tj
6.3666 0 Td
(morphologies)Tj
5.7373 0 Td
(upon)Tj
2.3187 0 Td
(knockdown,)Tj
5.1874 0 Td
(and)Tj
1.7291 0 Td
(included)Tj
-32.7626 -1.3039 Td
(some)Tj
2.33 0 Td
(weaker)Tj
3.0501 0 Td
(hits)Tj
1.6781 0 Td
(with)Tj
1.9956 0 Td
(fewer)Tj
2.4094 0 Td
(siRNAs)Tj
3.2541 0 Td
(passing)Tj
3.1748 0 Td
(the)Tj
1.4684 0 Td
(cut-off)Tj
2.9026 0 Td
(point)Tj
2.3584 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S1B)Tj
2.092 0 Td
(Fig)Tj
0 g
(\).)Tj
2.0409 0 Td
(These)Tj
2.5682 0 Td
(were)Tj
2.126 0 Td
(included)Tj
-33.4486 -1.2982 Td
(from)Tj
2.2053 0 Td
(a)Tj
0.652 0 Td
(drug)Tj
2.1146 0 Td
(development)Tj
5.4085 0 Td
(standpoint)Tj
4.5297 0 Td
(and)Tj
1.7291 0 Td
(also)Tj
1.7688 0 Td
(to)Tj
1.0262 0 Td
(test)Tj
1.5987 0 Td
(a)Tj
0.652 0 Td
(range)Tj
2.4661 0 Td
(of)Tj
1.0148 0 Td
(senescence)Tj
4.5807 0 Td
(responses)Tj
4.0932 0 Td
(in)Tj
1.0318 0 Td
(sec-)Tj
-34.8715 -1.2983 Td
(ondary)Tj
3.0613 0 Td
(validation)Tj
4.2066 0 Td
(assays.)Tj
2.8517 0 Td
(The)Tj
1.7801 0 Td
(siRNAs)Tj
3.2485 0 Td
(selected)Tj
3.3505 0 Td
(are)Tj
1.4457 0 Td
(given)Tj
2.3811 0 Td
(in)Tj
0.83 0.64 0.02 0 k
1.0375 0 Td
(Table)Tj
2.4377 0 Td
(1)Tj
0 g
(,)Tj
0.9241 0 Td
(together)Tj
3.532 0 Td
(with)Tj
2.0012 0 Td
(their)Tj
2.109 0 Td
(prioriti-)Tj
-34.367 -1.3039 Td
(sation)Tj
2.6362 0 Td
(grouping)Tj
3.8891 0 Td
(and)Tj
1.7291 0 Td
(confidence)Tj
4.6034 0 Td
(ranking.)Tj
-11.6616 -1.2983 Td
(Predictably,)Tj
4.9606 0 Td
(the)Tj
1.4683 0 Td
(majority)Tj
3.6283 0 Td
(of)Tj
1.0148 0 Td
(these)Tj
2.2564 0 Td
(40)Tj
1.1678 0 Td
(genes)Tj
2.4435 0 Td
(are)Tj
1.4513 0 Td
(involved)Tj
3.6454 0 Td
(in)Tj
1.0374 0 Td
(cell)Tj
1.5591 0 Td
(cycle)Tj
2.194 0 Td
(regulation,)Tj
4.5354 0 Td
(the)Tj
1.4683 0 Td
(DNA)Tj
-34.0268 -1.2982 Td
(damage)Tj
3.3221 0 Td
(response)Tj
3.7361 0 Td
(and)Tj
1.7291 0 Td
(maintenance)Tj
5.3858 0 Td
(of)Tj
1.0148 0 Td
(DNA)Tj
2.3811 0 Td
(integrity.)Tj
3.8381 0 Td
(However,)Tj
4.0762 0 Td
(several)Tj
2.9366 0 Td
(more)Tj
2.3414 0 Td
(interesting)Tj
4.4901 0 Td
(gene)Tj
-35.2514 -1.2983 Td
(families)Tj
3.3278 0 Td
(emerged,)Tj
3.8948 0 Td
(including)Tj
4.0422 0 Td
(ribonucleoside-diphospha)Tj
10.4484 0 Td
(te)Tj
0.9411 0 Td
(reductase)Tj
4.0082 0 Td
(subunit)Tj
3.2598 0 Td
(genes)Tj
2.4434 0 Td
(RRM1)Tj
2.829 0 Td
(and)Tj
-35.1947 -1.3039 Td
(RRM2,)Tj
3.0557 0 Td
(calpain)Tj
3.0897 0 Td
(cysteine)Tj
3.4186 0 Td
(protease)Tj
3.5603 0 Td
(family)Tj
2.7269 0 Td
(members)Tj
3.9458 0 Td
(CAPN11)Tj
3.8154 0 Td
(and)Tj
1.7291 0 Td
(CAPN9)Tj
3.3392 0 Td
(and)Tj
1.7291 0 Td
(several)Tj
2.9367 0 Td
(protea-)Tj
-33.3465 -1.2983 Td
(some)Tj
2.33 0 Td
(subunit)Tj
3.2598 0 Td
(family)Tj
2.7269 0 Td
(members)Tj
3.9458 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8199 0 Td
(1)Tj
0 g
(\).)Tj
1.2586 0 Td
(Interestingly,)Tj
5.4935 0 Td
(although)Tj
3.753 0 Td
(the)Tj
1.474 0 Td
(Qiagen)Tj
3.1011 0 Td
(positive)Tj
3.3165 0 Td
(control)Tj
-32.4791 -1.2983 Td
(CDK1)Tj
2.7665 0 Td
(siRNA)Tj
2.8914 0 Td
(performed)Tj
4.4673 0 Td
(as)Tj
1.0148 0 Td
(well)Tj
1.8199 0 Td
(as)Tj
1.0148 0 Td
(many)Tj
2.4774 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(top)Tj
1.5421 0 Td
(hits,)Tj
1.8992 0 Td
(the)Tj
1.4683 0 Td
(Ambion)Tj
3.5546 0 Td
(CDK1)Tj
2.7666 0 Td
(siRNAs)Tj
3.2485 0 Td
(from)Tj
2.211 0 Td
(the)Tj
-35.6312 -1.3039 Td
(library)Tj
2.8686 0 Td
(were)Tj
2.126 0 Td
(not)Tj
1.5703 0 Td
(in)Tj
1.0375 0 Td
(our)Tj
1.6271 0 Td
(top)Tj
1.542 0 Td
(40.)Tj
1.3947 0 Td
(We)Tj
1.61 0 Td
(continued)Tj
4.2917 0 Td
(to)Tj
1.0261 0 Td
(use)Tj
1.5307 0 Td
(the)Tj
1.4683 0 Td
(Qiagen)Tj
3.1068 0 Td
(siRNA)Tj
2.8913 0 Td
(in)Tj
1.0375 0 Td
(further)Tj
3.0274 0 Td
(experiments.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 399.0047 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Screen)Tj
3.3543 0 Td
(hits)Tj
1.7575 0 Td
(induce)Tj
3.1229 0 Td
(expression)Tj
4.9937 0 Td
(of)Tj
1.0488 0 Td
(senescence)Tj
5.4946 0 Td
(biomarkers)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 381.9968 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(To)Tj
1.3379 0 Td
(further)Tj
3.0274 0 Td
(investigate)Tj
4.4617 0 Td
(the)Tj
1.4683 0 Td
(40)Tj
1.1736 0 Td
(prioritised)Tj
4.3993 0 Td
(siRNAs)Tj
3.2485 0 Td
(as)Tj
1.0148 0 Td
(senescence)Tj
4.5807 0 Td
(inducers,)Tj
3.8948 0 Td
(a)Tj
0.652 0 Td
(fresh)Tj
2.194 0 Td
(batch)Tj
2.4094 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
-34.8772 -1.2982 Td
(same)Tj
2.2563 0 Td
(siRNAs)Tj
3.2542 0 Td
(was)Tj
1.6951 0 Td
(tested)Tj
2.5511 0 Td
(for)Tj
1.389 0 Td
(the)Tj
1.4683 0 Td
(ability)Tj
2.6929 0 Td
(to)Tj
1.0262 0 Td
(increase)Tj
3.4752 0 Td
(nuclear)Tj
3.1918 0 Td
(area)Tj
1.8822 0 Td
(and)Tj
1.7348 0 Td
(induce)Tj
2.9367 0 Td
(SA)Tj
/F11 1 Tf
()Tj
/F7 1 Tf
(Gal)Tj
3.2598 0 Td
(in)Tj
1.0375 0 Td
(A375P)Tj
-33.8511 -1.3039 Td
(cells)Tj
1.9218 0 Td
(using)Tj
2.3868 0 Td
(a)Tj
0.6519 0 Td
(stricter)Tj
3.0388 0 Td
(cut-off)Tj
2.9026 0 Td
(value)Tj
2.3017 0 Td
(of)Tj
1.0148 0 Td
(control)Tj
3.1238 0 Td
(mean)Tj
2.4491 0 Td
(+)Tj
0.7994 0 Td
(3)Tj
0.6916 0 Td
(standard)Tj
3.7247 0 Td
(deviations)Tj
4.3087 0 Td
(\(SD\))Tj
2.1146 0 Td
(in)Tj
1.0318 0 Td
(at)Tj
0.9524 0 Td
(least)Tj
1.9843 0 Td
(2/3)Tj
-35.3988 -1.2983 Td
(replicate)Tj
3.6169 0 Td
(wells)Tj
2.1714 0 Td
(in)Tj
1.0261 0 Td
(2/3)Tj
1.491 0 Td
(independent)Tj
5.2667 0 Td
(experiments.)Tj
5.3575 0 Td
(Hereafter)Tj
4.0138 0 Td
(an)Tj
1.1962 0 Td
(increase)Tj
4.2463 0 Td
(will)Tj
1.6554 0 Td
(refer)Tj
2.092 0 Td
(to)Tj
1.0148 0 Td
(an)Tj
1.1962 0 Td
(increase)Tj
-34.3443 -1.2983 Td
(passing)Tj
3.1747 0 Td
(this)Tj
1.6725 0 Td
(criterion)Tj
3.6963 0 Td
(unless)Tj
2.6872 0 Td
(otherwise)Tj
4.0876 0 Td
(stated.)Tj
2.7836 0 Td
(All)Tj
1.4003 0 Td
(40)Tj
1.1679 0 Td
(siRNAs)Tj
3.2541 0 Td
(increased)Tj
3.9968 0 Td
(nuclear)Tj
3.1975 0 Td
(area)Tj
1.8822 0 Td
(in)Tj
1.0375 0 Td
(3)Tj
0.6916 0 Td
(inde-)Tj
-34.7298 -1.2982 Td
(pendent)Tj
3.5035 0 Td
(experiments)Tj
5.1421 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(2A)Tj
0 g
1.3776 0 Td
(&)Tj
0.83 0.64 0.02 0 k
0.9298 0 Td
(S2A)Tj
1.8538 0 Td
(Fig)Tj
0 g
(\),)Tj
2.0466 0 Td
(further)Tj
3.0274 0 Td
(validating)Tj
4.1612 0 Td
(the)Tj
1.4684 0 Td
(primary)Tj
3.4582 0 Td
(screen)Tj
2.7723 0 Td
(results.)Tj
3.033 0 Td
(How-)Tj
-34.5937 -1.3039 Td
(ever,)Tj
2.1146 0 Td
(many)Tj
2.4774 0 Td
(gave)Tj
2.0013 0 Td
(SA)Tj
/F11 1 Tf
()Tj
/F7 1 Tf
(Gal)Tj
3.2598 0 Td
(levels)Tj
2.3754 0 Td
(below)Tj
2.5852 0 Td
(the)Tj
1.474 0 Td
(stricter)Tj
3.0331 0 Td
(cut-off,)Tj
3.1294 0 Td
(suggesting)Tj
4.3993 0 Td
(a)Tj
0.6577 0 Td
(partial)Tj
2.7836 0 Td
(or)Tj
1.0998 0 Td
(atypical)Tj
-31.3906 -1.2983 Td
(senescence)Tj
4.5807 0 Td
(response)Tj
3.7304 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(2A)Tj
0 g
1.3833 0 Td
(&)Tj
0.83 0.64 0.02 0 k
0.9241 0 Td
(S2C)Tj
1.8312 0 Td
(Fig)Tj
0 g
(\).)Tj
-13.0733 -1.2983 Td
(Analysis)Tj
3.5773 0 Td
(of)Tj
1.0148 0 Td
(these)Tj
2.2563 0 Td
(40)Tj
1.1736 0 Td
(siRNAs)Tj
3.2484 0 Td
(was)Tj
1.7008 0 Td
(extended)Tj
3.8551 0 Td
(to)Tj
1.0261 0 Td
(HCT116)Tj
3.6907 0 Td
(colorectal)Tj
4.0989 0 Td
(carcinoma)Tj
4.4504 0 Td
(cells,)Tj
2.143 0 Td
(chosen)Tj
-33.4316 -1.3039 Td
(for)Tj
1.3832 0 Td
(the)Tj
1.4741 0 Td
(availability)Tj
4.5297 0 Td
(of)Tj
1.0148 0 Td
(isogenic)Tj
3.4809 0 Td
(derivatives)Tj
4.5014 0 Td
(with)Tj
2.0012 0 Td
(various)Tj
3.1408 0 Td
(oncogenic)Tj
4.3313 0 Td
(genotypes,)Tj
4.4447 0 Td
(previously)Tj
4.354 0 Td
(used)Tj
2.0579 0 Td
(in)Tj
-36.714 -1.2983 Td
(screening)Tj
4.0535 0 Td
([)Tj
0.83 0.64 0.02 0 k
(21)Tj
0 g
(])Tj
1.8481 0 Td
(and)Tj
1.7292 0 Td
(their)Tj
2.1089 0 Td
(ability)Tj
2.6929 0 Td
(to)Tj
1.0262 0 Td
(express)Tj
3.1464 0 Td
(biomarkers)Tj
4.7735 0 Td
(of)Tj
1.0148 0 Td
(senescence)Tj
4.5808 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S2B)Tj
2.0919 0 Td
(and)Tj
1.7291 0 Td
(S2D)Tj
1.9106 0 Td
(Fig)Tj
0 g
(\).)Tj
2.0466 0 Td
(The)Tj
-34.7525 -1.2982 Td
(results)Tj
2.8062 0 Td
(with)Tj
2.0013 0 Td
(parental)Tj
3.4922 0 Td
(HCT116)Tj
3.6851 0 Td
(cells)Tj
1.9218 0 Td
(further)Tj
3.0274 0 Td
(corroborated)Tj
5.4708 0 Td
(those)Tj
2.3358 0 Td
(for)Tj
1.3889 0 Td
(A375P)Tj
2.8857 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8255 0 Td
(2A)Tj
0 g
(\).)Tj
1.9446 0 Td
(Many)Tj
2.5455 0 Td
(of)Tj
-35.3308 -1.3039 Td
(the)Tj
1.4683 0 Td
(strongest)Tj
3.8551 0 Td
(inducers)Tj
3.668 0 Td
(of)Tj
1.0148 0 Td
(senescence)Tj
4.5807 0 Td
(in)Tj
1.0375 0 Td
(A375P)Tj
2.8913 0 Td
(also)Tj
1.7632 0 Td
(came)Tj
2.3244 0 Td
(out)Tj
1.5533 0 Td
(top)Tj
1.5421 0 Td
(in)Tj
1.0375 0 Td
(HCT116,)Tj
3.9117 0 Td
(while)Tj
2.3698 0 Td
(those)Tj
2.3357 0 Td
(that)Tj
-35.3534 -1.2983 Td
(were)Tj
2.1203 0 Td
(negative)Tj
3.5376 0 Td
(for)Tj
1.3833 0 Td
(SA)Tj
/F11 1 Tf
()Tj
/F7 1 Tf
(Gal)Tj
3.2598 0 Td
(in)Tj
1.0375 0 Td
(A375P)Tj
2.8913 0 Td
(were)Tj
2.1203 0 Td
(also)Tj
1.7688 0 Td
(negative)Tj
3.5376 0 Td
(for)Tj
1.3833 0 Td
(increased)Tj
4.0025 0 Td
(nuclear)Tj
3.1918 0 Td
(area)Tj
1.8822 0 Td
(and)Tj
1.7348 0 Td
(SA)Tj
/F11 1 Tf
()Tj
/F7 1 Tf
(Gal)Tj
-33.8511 -1.2983 Td
(in)Tj
1.0318 0 Td
(HCT116.)Tj
3.9174 0 Td
(Based)Tj
2.5455 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.4683 0 Td
(SA)Tj
/F11 1 Tf
()Tj
/F7 1 Tf
(Gal)Tj
3.2598 0 Td
(results)Tj
2.812 0 Td
(for)Tj
1.3833 0 Td
(A375P,)Tj
3.1181 0 Td
(the)Tj
1.4683 0 Td
(nuclear)Tj
3.1975 0 Td
(area)Tj
1.8822 0 Td
(and)Tj
1.7291 0 Td
(SA)Tj
/F11 1 Tf
()Tj
/F7 1 Tf
(Gal)Tj
3.2598 0 Td
(for)Tj
1.389 0 Td
(HCT116,)Tj
-33.7377 -1.3039 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.4683 0 Td
(assessment)Tj
4.6148 0 Td
(of)Tj
1.0148 0 Td
(druggability,)Tj
5.2724 0 Td
(the)Tj
1.474 0 Td
(list)Tj
1.389 0 Td
(was)Tj
1.7007 0 Td
(refined)Tj
3.0671 0 Td
(to)Tj
1.0261 0 Td
(16)Tj
1.1736 0 Td
(siRNA)Tj
2.8913 0 Td
(targets)Tj
2.8686 0 Td
(for)Tj
1.389 0 Td
(further)Tj
3.0274 0 Td
(analysis.)Tj
-34.1062 -1.2982 Td
(This)Tj
1.9842 0 Td
(refined)Tj
3.0727 0 Td
(list)Tj
1.389 0 Td
(encompassed)Tj
5.5672 0 Td
(many)Tj
2.4775 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(strongest)Tj
3.8551 0 Td
(hits)Tj
1.6781 0 Td
(from)Tj
2.2053 0 Td
(the)Tj
1.4684 0 Td
(siRNA)Tj
2.8913 0 Td
(screen.)Tj
2.9934 0 Td
(We)Tj
1.61 0 Td
(contin-)Tj
-33.6753 -1.2983 Td
(ued)Tj
1.6951 0 Td
(to)Tj
1.0261 0 Td
(include)Tj
3.1861 0 Td
(the)Tj
1.4684 0 Td
(Qiagen)Tj
3.1067 0 Td
(positive)Tj
3.3165 0 Td
(control)Tj
3.1181 0 Td
(siRNA)Tj
2.8913 0 Td
(targeting)Tj
3.7928 0 Td
(CDK1)Tj
2.7666 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(2B)Tj
0 g
(\).)Tj
-26.9913 -1.2983 Td
(Two)Tj
2.0239 0 Td
(additional)Tj
4.2803 0 Td
(biomarkers)Tj
4.7735 0 Td
(of)Tj
1.0148 0 Td
(senescence)Tj
4.5807 0 Td
(are)Tj
1.4514 0 Td
(p21)Tj
1.6894 0 Td
(\(CDKN1A\))Tj
4.8699 0 Td
(and)Tj
1.7291 0 Td
(recruitment)Tj
4.9946 0 Td
(of)Tj
1.0148 0 Td
(53BP1)Tj
2.7836 0 Td
(to)Tj
-36.4022 -1.3039 Td
(sites)Tj
1.9275 0 Td
(of)Tj
1.0148 0 Td
(DNA)Tj
2.3811 0 Td
(damage)Tj
3.3222 0 Td
(\(nuclear)Tj
3.5319 0 Td
(foci\).)Tj
2.2734 0 Td
(To)Tj
1.3379 0 Td
(further)Tj
3.0274 0 Td
(characterise)Tj
4.9776 0 Td
(the)Tj
1.474 0 Td
(response)Tj
3.7304 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(refined)Tj
3.0728 0 Td
(siRNAs)Tj
-34.5541 -1.2983 Td
(we)Tj
1.3266 0 Td
(analysed)Tj
3.651 0 Td
(induction)Tj
4.1328 0 Td
(of)Tj
1.0148 0 Td
(p21)Tj
1.6895 0 Td
(and)Tj
1.7291 0 Td
(formation)Tj
4.2633 0 Td
(of)Tj
1.0148 0 Td
(53BP1)Tj
2.7836 0 Td
(foci)Tj
1.7064 0 Td
(by)Tj
1.1792 0 Td
(immunofluorescence)Tj
8.6797 0 Td
(in)Tj
1.0374 0 Td
(A375P)Tj
-34.2082 -1.2982 Td
(and)Tj
1.7291 0 Td
(HCT116)Tj
3.6907 0 Td
(cells)Tj
1.9162 0 Td
(transfected)Tj
4.6204 0 Td
(with)Tj
1.9956 0 Td
(the)Tj
1.4683 0 Td
(16)Tj
1.1736 0 Td
(hit)Tj
1.3152 0 Td
(and)Tj
1.7292 0 Td
(control)Tj
3.1237 0 Td
(siRNAs)Tj
3.2485 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(3)Tj
0 g
(\).)Tj
1.2586 0 Td
(Consistent)Tj
4.5014 0 Td
(with)Tj
1.9956 0 Td
(the)Tj
-35.5859 -1.3039 Td
(results)Tj
2.8062 0 Td
(for)Tj
1.389 0 Td
(nuclear)Tj
3.1918 0 Td
(area)Tj
1.8822 0 Td
(and)Tj
1.7348 0 Td
(SA)Tj
/F11 1 Tf
()Tj
/F7 1 Tf
(Gal,)Tj
3.4866 0 Td
(all)Tj
1.1452 0 Td
(16)Tj
1.1678 0 Td
(test)Tj
1.6044 0 Td
(siRNAs)Tj
3.2485 0 Td
(induced)Tj
3.4696 0 Td
(expression)Tj
4.4617 0 Td
(of)Tj
1.0148 0 Td
(p21)Tj
1.6894 0 Td
(greater)Tj
3.0104 0 Td
(than)Tj
-35.3024 -1.2983 Td
(the)Tj
1.4683 0 Td
(non-targeting)Tj
5.7486 0 Td
(control)Tj
3.1181 0 Td
(in)Tj
1.0375 0 Td
(A375P)Tj
2.8913 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(3A)Tj
0 g
(\).)Tj
1.9446 0 Td
(In)Tj
1.1055 0 Td
(HCT116)Tj
3.6907 0 Td
(cells,)Tj
2.1486 0 Td
(p21)Tj
1.6838 0 Td
(expression)Tj
4.4674 0 Td
(was)Tj
1.7007 0 Td
(also)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 391.1244 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Screen)Tj
3.111 0 Td
(ing)Tj
1.5236 0 Td
(senescence)Tj
5.4709 0 Td
(targets)Tj
3.2245 0 Td
(in)Tj
0.9779 0 Td
(cancer)Tj
3.1749 0 Td
(backgrou)Tj
4.0394 0 Td
(nds)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
(6942)Tj
0 g
3.1819 0 Td
(August)Tj
3.2882 0 Td
(14,)Tj
1.5804 0 Td
(2017)Tj
32.2939 0 Td
(4)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
100 0 obj
<>stream
endstream
endobj
101 0 obj
<>stream
endstream
endobj
102 0 obj
<>stream
endstream
endobj
103 0 obj
<>stream
endstream
endobj
104 0 obj
<>stream
endstream
endobj
105 0 obj
<>stream
endstream
endobj
106 0 obj
<>stream
endstream
endobj
107 0 obj
<>stream
endstream
endobj
108 0 obj
<>stream
BT
66.402 0 Td
(24)Tj
ET
Q
endstream
endobj
109 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 13 0 R/Annots 110 0 R/Contents 111 0 R/TrimBox[0 0 612 792]>>
endobj
110 0 obj
[112 0 R 113 0 R 114 0 R 115 0 R 116 0 R 117 0 R 118 0 R]
endobj
112 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.g003)>>
endobj
113 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.g002)>>
endobj
114 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.g003)>>
endobj
115 0 obj
<>/Border[0 0 0]/Dest(Rpgen.1006942.g003)>>
endobj
116 0 obj
<>/Border[0 0 0]/Dest(Lpgen.1006942.t001)>>
endobj
117 0 obj
<>/Border[0 0 0]/A 119 0 R>>
endobj
119 0 obj
<>
endobj
118 0 obj
<>/Border[0 0 0]/A 120 0 R>>
endobj
120 0 obj
<>
endobj
111 0 obj
[121 0 R 122 0 R 123 0 R 124 0 R]
endobj
121 0 obj
<>stream
q
0.83 0.64 0.02 0 k
416.9764 121.7197 m
443.1685 121.7197 l
h
f*
330.463 108.737 m
350.022 108.737 l
h
f*
476.2772 108.737 m
503.2063 108.737 l
h
f*
375.6472 82.715 m
424.5732 82.715 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 200.0125 122.7968 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(increased)Tj
3.9968 0 Td
(by)Tj
1.1848 0 Td
(all)Tj
1.1452 0 Td
(test)Tj
1.5988 0 Td
(siRNAs)Tj
3.2541 0 Td
(except)Tj
2.7723 0 Td
(that)Tj
1.7745 0 Td
(targeting)Tj
3.7927 0 Td
(CIT)Tj
1.8368 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8199 0 Td
(3C)Tj
0 g
(\).)Tj
1.9218 0 Td
(Likewise,)Tj
3.9062 0 Td
(CIT)Tj
1.8368 0 Td
(siRNA)Tj
2.8913 0 Td
(failed)Tj
2.4038 0 Td
(to)Tj
-36.1358 -1.2982 Td
(increase)Tj
3.4695 0 Td
(SA)Tj
/F11 1 Tf
()Tj
/F7 1 Tf
(Gal)Tj
3.2655 0 Td
(in)Tj
1.0318 0 Td
(this)Tj
1.6781 0 Td
(cell)Tj
1.5591 0 Td
(line)Tj
1.7008 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(2)Tj
0 g
(\),)Tj
1.2642 0 Td
(and)Tj
1.7291 0 Td
(formation)Tj
4.2633 0 Td
(of)Tj
1.0148 0 Td
(53BP1)Tj
2.7836 0 Td
(foci)Tj
1.7065 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(3D)Tj
0 g
(\),)Tj
1.9956 0 Td
(suggesting)Tj
4.405 0 Td
(that)Tj
-35.5065 -1.3039 Td
(knockdown)Tj
4.9492 0 Td
(of)Tj
1.0035 0 Td
(CIT)Tj
1.8255 0 Td
(does)Tj
2.0296 0 Td
(not)Tj
1.5703 0 Td
(induce)Tj
2.9254 0 Td
(senescence)Tj
4.5694 0 Td
(in)Tj
1.0318 0 Td
(HCT116)Tj
3.6794 0 Td
(cells.)Tj
2.1373 0 Td
(Generally,)Tj
4.2973 0 Td
(only)Tj
1.9672 0 Td
(a)Tj
0.6463 0 Td
(small)Tj
2.3187 0 Td
(induc-)Tj
-34.9509 -1.2983 Td
(tion)Tj
1.8425 0 Td
(of)Tj
1.0148 0 Td
(53BP1)Tj
2.7836 0 Td
(was)Tj
1.7007 0 Td
(evident)Tj
3.1635 0 Td
(in)Tj
1.0318 0 Td
(both)Tj
2.0636 0 Td
(cell)Tj
1.559 0 Td
(lines)Tj
2.0636 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8199 0 Td
(3B)Tj
1.2756 0 Td
(&)Tj
0.9241 0 Td
(3D)Tj
0 g
(\),)Tj
2.0012 0 Td
(however)Tj
3.6113 0 Td
(many)Tj
2.4775 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(top)Tj
1.5421 0 Td
(hits)Tj
1.6724 0 Td
(for)Tj
ET
Q
q
0.45 0.36 0.35 0.01 k
1 j
1 J
0 w
199.9998 684.8892 m
575.9997 684.8892 l
575.9997 684.3892 l
199.9998 684.3892 l
f*
284.1021 684.3892 m
284.1021 671.8893 l
283.602 671.8893 l
283.602 684.3892 l
f*
283.602 671.8893 m
199.9998 671.8893 l
199.9998 672.3893 l
283.602 672.3893 l
f*
392.8156 684.3892 m
392.8156 671.8893 l
392.3155 671.8893 l
392.3155 684.3892 l
f*
392.3155 671.8893 m
284.1021 671.8893 l
284.1021 672.3893 l
392.3155 672.3893 l
f*
575.9997 671.8893 m
392.8156 671.8893 l
392.8156 672.3893 l
575.9997 672.3893 l
f*
284.1021 671.8893 m
284.1021 659.3893 l
283.602 659.3893 l
283.602 671.8893 l
f*
283.602 659.3893 m
199.9998 659.3893 l
199.9998 659.8894 l
283.602 659.8894 l
f*
392.8156 671.8893 m
392.8156 659.3893 l
392.3155 659.3893 l
392.3155 671.8893 l
f*
392.3155 659.3893 m
284.1021 659.3893 l
284.1021 659.8894 l
392.3155 659.8894 l
f*
575.9997 659.3893 m
392.8156 659.3893 l
392.8156 659.8894 l
575.9997 659.8894 l
f*
284.1021 659.3893 m
284.1021 646.8894 l
283.602 646.8894 l
283.602 659.3893 l
f*
283.602 646.8894 m
199.9998 646.8894 l
199.9998 647.3894 l
283.602 647.3894 l
f*
392.8156 659.3893 m
392.8156 646.8894 l
392.3155 646.8894 l
392.3155 659.3893 l
f*
392.3155 646.8894 m
284.1021 646.8894 l
284.1021 647.3894 l
392.3155 647.3894 l
f*
575.9997 646.8894 m
392.8156 646.8894 l
392.8156 647.3894 l
575.9997 647.3894 l
f*
284.1021 646.8894 m
284.1021 634.3894 l
283.602 634.3894 l
283.602 646.8894 l
f*
283.602 634.3894 m
199.9998 634.3894 l
199.9998 634.8895 l
283.602 634.8895 l
f*
392.8156 646.8894 m
392.8156 634.3894 l
392.3155 634.3894 l
392.3155 646.8894 l
f*
392.3155 634.3894 m
284.1021 634.3894 l
284.1021 634.8895 l
392.3155 634.8895 l
f*
575.9997 634.3894 m
392.8156 634.3894 l
392.8156 634.8895 l
575.9997 634.8895 l
f*
284.1021 634.3894 m
284.1021 621.8895 l
283.602 621.8895 l
283.602 634.3894 l
f*
283.602 621.8895 m
199.9998 621.8895 l
199.9998 622.3895 l
283.602 622.3895 l
f*
392.8156 634.3894 m
392.8156 621.8895 l
392.3155 621.8895 l
392.3155 634.3894 l
f*
392.3155 621.8895 m
284.1021 621.8895 l
284.1021 622.3895 l
392.3155 622.3895 l
f*
575.9997 621.8895 m
392.8156 621.8895 l
392.8156 622.3895 l
575.9997 622.3895 l
f*
284.1021 621.8895 m
284.1021 609.3896 l
283.602 609.3896 l
283.602 621.8895 l
f*
283.602 609.3896 m
199.9998 609.3896 l
199.9998 609.8896 l
283.602 609.8896 l
f*
392.8156 621.8895 m
392.8156 609.3896 l
392.3155 609.3896 l
392.3155 621.8895 l
f*
392.3155 609.3896 m
284.1021 609.3896 l
284.1021 609.8896 l
392.3155 609.8896 l
f*
575.9997 609.3896 m
392.8156 609.3896 l
392.8156 609.8896 l
575.9997 609.8896 l
f*
284.1021 609.3896 m
284.1021 596.8896 l
283.602 596.8896 l
283.602 609.3896 l
f*
283.602 596.8896 m
199.9998 596.8896 l
199.9998 597.3897 l
283.602 597.3897 l
f*
392.8156 609.3896 m
392.8156 596.8896 l
392.3155 596.8896 l
392.3155 609.3896 l
f*
392.3155 596.8896 m
284.1021 596.8896 l
284.1021 597.3897 l
392.3155 597.3897 l
f*
575.9997 596.8896 m
392.8156 596.8896 l
392.8156 597.3897 l
575.9997 597.3897 l
f*
284.1021 596.8896 m
284.1021 584.3897 l
283.602 584.3897 l
283.602 596.8896 l
f*
283.602 584.3897 m
199.9998 584.3897 l
199.9998 584.8897 l
283.602 584.8897 l
f*
392.8156 596.8896 m
392.8156 584.3897 l
392.3155 584.3897 l
392.3155 596.8896 l
f*
392.3155 584.3897 m
284.1021 584.3897 l
284.1021 584.8897 l
392.3155 584.8897 l
f*
575.9997 584.3897 m
392.8156 584.3897 l
392.8156 584.8897 l
575.9997 584.8897 l
f*
284.1021 584.3897 m
284.1021 571.8898 l
283.602 571.8898 l
283.602 584.3897 l
f*
283.602 571.8898 m
199.9998 571.8898 l
199.9998 572.3898 l
283.602 572.3898 l
f*
392.8156 584.3897 m
392.8156 571.8898 l
392.3155 571.8898 l
392.3155 584.3897 l
f*
392.3155 571.8898 m
284.1021 571.8898 l
284.1021 572.3898 l
392.3155 572.3898 l
f*
575.9997 571.8898 m
392.8156 571.8898 l
392.8156 572.3898 l
575.9997 572.3898 l
f*
284.1021 571.8898 m
284.1021 559.3898 l
283.602 559.3898 l
283.602 571.8898 l
f*
283.602 559.3898 m
199.9998 559.3898 l
199.9998 559.8899 l
283.602 559.8899 l
f*
392.8156 571.8898 m
392.8156 559.3898 l
392.3155 559.3898 l
392.3155 571.8898 l
f*
392.3155 559.3898 m
284.1021 559.3898 l
284.1021 559.8899 l
392.3155 559.8899 l
f*
575.9997 559.3898 m
392.8156 559.3898 l
392.8156 559.8899 l
575.9997 559.8899 l
f*
284.1021 559.3898 m
284.1021 546.8899 l
283.602 546.8899 l
283.602 559.3898 l
f*
283.602 546.8899 m
199.9998 546.8899 l
199.9998 547.3899 l
283.602 547.3899 l
f*
392.8156 559.3898 m
392.8156 546.8899 l
392.3155 546.8899 l
392.3155 559.3898 l
f*
392.3155 546.8899 m
284.1021 546.8899 l
284.1021 547.3899 l
392.3155 547.3899 l
f*
575.9997 546.8899 m
392.8156 546.8899 l
392.8156 547.3899 l
575.9997 547.3899 l
f*
284.1021 546.8899 m
284.1021 534.39 l
283.602 534.39 l
283.602 546.8899 l
f*
283.602 534.39 m
199.9998 534.39 l
199.9998 534.89 l
283.602 534.89 l
f*
392.8156 546.8899 m
392.8156 534.39 l
392.3155 534.39 l
392.3155 546.8899 l
f*
392.3155 534.39 m
284.1021 534.39 l
284.1021 534.89 l
392.3155 534.89 l
f*
575.9997 534.39 m
392.8156 534.39 l
392.8156 534.89 l
575.9997 534.89 l
f*
284.1021 534.39 m
284.1021 521.89 l
283.602 521.89 l
283.602 534.39 l
f*
283.602 521.89 m
199.9998 521.89 l
199.9998 522.39 l
283.602 522.39 l
f*
392.8156 534.39 m
392.8156 521.89 l
392.3155 521.89 l
392.3155 534.39 l
f*
392.3155 521.89 m
284.1021 521.89 l
284.1021 522.39 l
392.3155 522.39 l
f*
575.9997 521.89 m
392.8156 521.89 l
392.8156 522.39 l
575.9997 522.39 l
f*
284.1021 521.89 m
284.1021 509.3901 l
283.602 509.3901 l
283.602 521.89 l
f*
283.602 509.3901 m
199.9998 509.3901 l
199.9998 509.8901 l
283.602 509.8901 l
f*
392.8156 521.89 m
392.8156 509.3901 l
392.3155 509.3901 l
392.3155 521.89 l
f*
392.3155 509.3901 m
284.1021 509.3901 l
284.1021 509.8901 l
392.3155 509.8901 l
f*
575.9997 509.3901 m
392.8156 509.3901 l
392.8156 509.8901 l
575.9997 509.8901 l
f*
284.1021 509.3901 m
284.1021 496.8901 l
283.602 496.8901 l
283.602 509.3901 l
f*
283.602 496.8901 m
199.9998 496.8901 l
199.9998 497.3902 l
283.602 497.3902 l
f*
392.8156 509.3901 m
392.8156 496.8901 l
392.3155 496.8901 l
392.3155 509.3901 l
f*
392.3155 496.8901 m
284.1021 496.8901 l
284.1021 497.3902 l
392.3155 497.3902 l
f*
575.9997 496.8901 m
392.8156 496.8901 l
392.8156 497.3902 l
575.9997 497.3902 l
f*
284.1021 496.8901 m
284.1021 484.3902 l
283.602 484.3902 l
283.602 496.8901 l
f*
283.602 484.3902 m
199.9998 484.3902 l
199.9998 484.8902 l
283.602 484.8902 l
f*
392.8156 496.8901 m
392.8156 484.3902 l
392.3155 484.3902 l
392.3155 496.8901 l
f*
392.3155 484.3902 m
284.1021 484.3902 l
284.1021 484.8902 l
392.3155 484.8902 l
f*
575.9997 484.3902 m
392.8156 484.3902 l
392.8156 484.8902 l
575.9997 484.8902 l
f*
284.1021 484.3902 m
284.1021 471.8903 l
283.602 471.8903 l
283.602 484.3902 l
f*
283.602 471.8903 m
199.9998 471.8903 l
199.9998 472.3903 l
283.602 472.3903 l
f*
392.8156 484.3902 m
392.8156 471.8903 l
392.3155 471.8903 l
392.3155 484.3902 l
f*
392.3155 471.8903 m
284.1021 471.8903 l
284.1021 472.3903 l
392.3155 472.3903 l
f*
575.9997 471.8903 m
392.8156 471.8903 l
392.8156 472.3903 l
575.9997 472.3903 l
f*
284.1021 471.8903 m
284.1021 459.3903 l
283.602 459.3903 l
283.602 471.8903 l
f*
283.602 459.3903 m
199.9998 459.3903 l
199.9998 459.8904 l
283.602 459.8904 l
f*
392.8156 471.8903 m
392.8156 459.3903 l
392.3155 459.3903 l
392.3155 471.8903 l
f*
392.3155 459.3903 m
284.1021 459.3903 l
284.1021 459.8904 l
392.3155 459.8904 l
f*
575.9997 459.3903 m
392.8156 459.3903 l
392.8156 459.8904 l
575.9997 459.8904 l
f*
284.1021 459.3903 m
284.1021 446.8904 l
283.602 446.8904 l
283.602 459.3903 l
f*
283.602 446.8904 m
199.9998 446.8904 l
199.9998 447.3904 l
283.602 447.3904 l
f*
392.8156 459.3903 m
392.8156 446.8904 l
392.3155 446.8904 l
392.3155 459.3903 l
f*
392.3155 446.8904 m
284.1021 446.8904 l
284.1021 447.3904 l
392.3155 447.3904 l
f*
575.9997 446.8904 m
392.8156 446.8904 l
392.8156 447.3904 l
575.9997 447.3904 l
f*
284.1021 446.8904 m
284.1021 434.3905 l
283.602 434.3905 l
283.602 446.8904 l
f*
283.602 434.3905 m
199.9998 434.3905 l
199.9998 434.8905 l
283.602 434.8905 l
f*
392.8156 446.8904 m
392.8156 434.3905 l
392.3155 434.3905 l
392.3155 446.8904 l
f*
392.3155 434.3905 m
284.1021 434.3905 l
284.1021 434.8905 l
392.3155 434.8905 l
f*
575.9997 434.3905 m
392.8156 434.3905 l
392.8156 434.8905 l
575.9997 434.8905 l
f*
284.1021 434.3905 m
284.1021 421.8905 l
283.602 421.8905 l
283.602 434.3905 l
f*
283.602 421.8905 m
199.9998 421.8905 l
199.9998 422.3906 l
283.602 422.3906 l
f*
392.8156 434.3905 m
392.8156 421.8905 l
392.3155 421.8905 l
392.3155 434.3905 l
f*
392.3155 421.8905 m
284.1021 421.8905 l
284.1021 422.3906 l
392.3155 422.3906 l
f*
575.9997 421.8905 m
392.8156 421.8905 l
392.8156 422.3906 l
575.9997 422.3906 l
f*
284.1021 421.8905 m
284.1021 409.3906 l
283.602 409.3906 l
283.602 421.8905 l
f*
283.602 409.3906 m
199.9998 409.3906 l
199.9998 409.8906 l
283.602 409.8906 l
f*
392.8156 421.8905 m
392.8156 409.3906 l
392.3155 409.3906 l
392.3155 421.8905 l
f*
392.3155 409.3906 m
284.1021 409.3906 l
284.1021 409.8906 l
392.3155 409.8906 l
f*
575.9997 409.3906 m
392.8156 409.3906 l
392.8156 409.8906 l
575.9997 409.8906 l
f*
284.1021 409.3906 m
284.1021 396.8906 l
283.602 396.8906 l
283.602 409.3906 l
f*
283.602 396.8906 m
199.9998 396.8906 l
199.9998 397.3907 l
283.602 397.3907 l
f*
392.8156 409.3906 m
392.8156 396.8906 l
392.3155 396.8906 l
392.3155 409.3906 l
f*
392.3155 396.8906 m
284.1021 396.8906 l
284.1021 397.3907 l
392.3155 397.3907 l
f*
575.9997 396.8906 m
392.8156 396.8906 l
392.8156 397.3907 l
575.9997 397.3907 l
f*
284.1021 396.8906 m
284.1021 384.3907 l
283.602 384.3907 l
283.602 396.8906 l
f*
283.602 384.3907 m
199.9998 384.3907 l
199.9998 384.8907 l
283.602 384.8907 l
f*
392.8156 396.8906 m
392.8156 384.3907 l
392.3155 384.3907 l
392.3155 396.8906 l
f*
392.3155 384.3907 m
284.1021 384.3907 l
284.1021 384.8907 l
392.3155 384.8907 l
f*
575.9997 384.3907 m
392.8156 384.3907 l
392.8156 384.8907 l
575.9997 384.8907 l
f*
284.1021 384.3907 m
284.1021 371.8908 l
283.602 371.8908 l
283.602 384.3907 l
f*
283.602 371.8908 m
199.9998 371.8908 l
199.9998 372.3908 l
283.602 372.3908 l
f*
392.8156 384.3907 m
392.8156 371.8908 l
392.3155 371.8908 l
392.3155 384.3907 l
f*
392.3155 371.8908 m
284.1021 371.8908 l
284.1021 372.3908 l
392.3155 372.3908 l
f*
575.9997 371.8908 m
392.8156 371.8908 l
392.8156 372.3908 l
575.9997 372.3908 l
f*
284.1021 371.8908 m
284.1021 359.3908 l
283.602 359.3908 l
283.602 371.8908 l
f*
283.602 359.3908 m
199.9998 359.3908 l
199.9998 359.8909 l
283.602 359.8909 l
f*
392.8156 371.8908 m
392.8156 359.3908 l
392.3155 359.3908 l
392.3155 371.8908 l
f*
392.3155 359.3908 m
284.1021 359.3908 l
284.1021 359.8909 l
392.3155 359.8909 l
f*
575.9997 359.3908 m
392.8156 359.3908 l
392.8156 359.8909 l
575.9997 359.8909 l
f*
284.1021 359.3908 m
284.1021 346.8909 l
283.602 346.8909 l
283.602 359.3908 l
f*
283.602 346.8909 m
199.9998 346.8909 l
199.9998 347.3909 l
283.602 347.3909 l
f*
392.8156 359.3908 m
392.8156 346.8909 l
392.3155 346.8909 l
392.3155 359.3908 l
f*
392.3155 346.8909 m
284.1021 346.8909 l
284.1021 347.3909 l
392.3155 347.3909 l
f*
575.9997 346.8909 m
392.8156 346.8909 l
392.8156 347.3909 l
575.9997 347.3909 l
f*
284.1021 346.8909 m
284.1021 334.391 l
283.602 334.391 l
283.602 346.8909 l
f*
283.602 334.391 m
199.9998 334.391 l
199.9998 334.891 l
283.602 334.891 l
f*
392.8156 346.8909 m
392.8156 334.391 l
392.3155 334.391 l
392.3155 346.8909 l
f*
392.3155 334.391 m
284.1021 334.391 l
284.1021 334.891 l
392.3155 334.891 l
f*
575.9997 334.391 m
392.8156 334.391 l
392.8156 334.891 l
575.9997 334.891 l
f*
284.1021 334.391 m
284.1021 321.891 l
283.602 321.891 l
283.602 334.391 l
f*
283.602 321.891 m
199.9998 321.891 l
199.9998 322.3911 l
283.602 322.3911 l
f*
392.8156 334.391 m
392.8156 321.891 l
392.3155 321.891 l
392.3155 334.391 l
f*
392.3155 321.891 m
284.1021 321.891 l
284.1021 322.3911 l
392.3155 322.3911 l
f*
575.9997 321.891 m
392.8156 321.891 l
392.8156 322.3911 l
575.9997 322.3911 l
f*
284.1021 321.891 m
284.1021 309.3911 l
283.602 309.3911 l
283.602 321.891 l
f*
283.602 309.3911 m
199.9998 309.3911 l
199.9998 309.8911 l
283.602 309.8911 l
f*
392.8156 321.891 m
392.8156 309.3911 l
392.3155 309.3911 l
392.3155 321.891 l
f*
392.3155 309.3911 m
284.1021 309.3911 l
284.1021 309.8911 l
392.3155 309.8911 l
f*
575.9997 309.3911 m
392.8156 309.3911 l
392.8156 309.8911 l
575.9997 309.8911 l
f*
284.1021 309.3911 m
284.1021 296.8911 l
283.602 296.8911 l
283.602 309.3911 l
f*
283.602 296.8911 m
199.9998 296.8911 l
199.9998 297.3912 l
283.602 297.3912 l
f*
392.8156 309.3911 m
392.8156 296.8911 l
392.3155 296.8911 l
392.3155 309.3911 l
f*
392.3155 296.8911 m
284.1021 296.8911 l
284.1021 297.3912 l
392.3155 297.3912 l
f*
575.9997 296.8911 m
392.8156 296.8911 l
392.8156 297.3912 l
575.9997 297.3912 l
f*
284.1021 296.8911 m
284.1021 284.3912 l
283.602 284.3912 l
283.602 296.8911 l
f*
283.602 284.3912 m
199.9998 284.3912 l
199.9998 284.8912 l
283.602 284.8912 l
f*
392.8156 296.8911 m
392.8156 284.3912 l
392.3155 284.3912 l
392.3155 296.8911 l
f*
392.3155 284.3912 m
284.1021 284.3912 l
284.1021 284.8912 l
392.3155 284.8912 l
f*
575.9997 284.3912 m
392.8156 284.3912 l
392.8156 284.8912 l
575.9997 284.8912 l
f*
284.1021 284.3912 m
284.1021 271.8913 l
283.602 271.8913 l
283.602 284.3912 l
f*
283.602 271.8913 m
199.9998 271.8913 l
199.9998 272.3913 l
283.602 272.3913 l
f*
392.8156 284.3912 m
392.8156 271.8913 l
392.3155 271.8913 l
392.3155 284.3912 l
f*
392.3155 271.8913 m
284.1021 271.8913 l
284.1021 272.3913 l
392.3155 272.3913 l
f*
575.9997 271.8913 m
392.8156 271.8913 l
392.8156 272.3913 l
575.9997 272.3913 l
f*
284.1021 271.8913 m
284.1021 259.3913 l
283.602 259.3913 l
283.602 271.8913 l
f*
283.602 259.3913 m
199.9998 259.3913 l
199.9998 259.8914 l
283.602 259.8914 l
f*
392.8156 271.8913 m
392.8156 259.3913 l
392.3155 259.3913 l
392.3155 271.8913 l
f*
392.3155 259.3913 m
284.1021 259.3913 l
284.1021 259.8914 l
392.3155 259.8914 l
f*
575.9997 259.3913 m
392.8156 259.3913 l
392.8156 259.8914 l
575.9997 259.8914 l
f*
284.1021 259.3913 m
284.1021 246.8914 l
283.602 246.8914 l
283.602 259.3913 l
f*
283.602 246.8914 m
199.9998 246.8914 l
199.9998 247.3914 l
283.602 247.3914 l
f*
392.8156 259.3913 m
392.8156 246.8914 l
392.3155 246.8914 l
392.3155 259.3913 l
f*
392.3155 246.8914 m
284.1021 246.8914 l
284.1021 247.3914 l
392.3155 247.3914 l
f*
575.9997 246.8914 m
392.8156 246.8914 l
392.8156 247.3914 l
575.9997 247.3914 l
f*
284.1021 246.8914 m
284.1021 234.3915 l
283.602 234.3915 l
283.602 246.8914 l
f*
283.602 234.3915 m
199.9998 234.3915 l
199.9998 234.8915 l
283.602 234.8915 l
f*
392.8156 246.8914 m
392.8156 234.3915 l
392.3155 234.3915 l
392.3155 246.8914 l
f*
392.3155 234.3915 m
284.1021 234.3915 l
284.1021 234.8915 l
392.3155 234.8915 l
f*
575.9997 234.3915 m
392.8156 234.3915 l
392.8156 234.8915 l
575.9997 234.8915 l
f*
284.1021 234.3915 m
284.1021 221.8915 l
283.602 221.8915 l
283.602 234.3915 l
f*
283.602 221.8915 m
199.9998 221.8915 l
199.9998 222.3916 l
283.602 222.3916 l
f*
392.8156 234.3915 m
392.8156 221.8915 l
392.3155 221.8915 l
392.3155 234.3915 l
f*
392.3155 221.8915 m
284.1021 221.8915 l
284.1021 222.3916 l
392.3155 222.3916 l
f*
575.9997 221.8915 m
392.8156 221.8915 l
392.8156 222.3916 l
575.9997 222.3916 l
f*
284.1021 221.8915 m
284.1021 209.3916 l
283.602 209.3916 l
283.602 221.8915 l
f*
283.602 209.3916 m
199.9998 209.3916 l
199.9998 209.8916 l
283.602 209.8916 l
f*
392.8156 221.8915 m
392.8156 209.3916 l
392.3155 209.3916 l
392.3155 221.8915 l
f*
392.3155 209.3916 m
284.1021 209.3916 l
284.1021 209.8916 l
392.3155 209.8916 l
f*
575.9997 209.3916 m
392.8156 209.3916 l
392.8156 209.8916 l
575.9997 209.8916 l
f*
284.1021 209.3916 m
284.1021 196.8917 l
283.602 196.8917 l
283.602 209.3916 l
f*
283.602 196.8917 m
199.9998 196.8917 l
199.9998 197.3917 l
283.602 197.3917 l
f*
392.8156 209.3916 m
392.8156 196.8917 l
392.3155 196.8917 l
392.3155 209.3916 l
f*
392.3155 196.8917 m
284.1021 196.8917 l
284.1021 197.3917 l
392.3155 197.3917 l
f*
575.9997 196.8917 m
392.8156 196.8917 l
392.8156 197.3917 l
575.9997 197.3917 l
f*
284.1021 196.8917 m
284.1021 184.3917 l
283.602 184.3917 l
283.602 196.8917 l
f*
283.602 184.3917 m
199.9998 184.3917 l
199.9998 184.8917 l
283.602 184.8917 l
f*
392.8156 196.8917 m
392.8156 184.3917 l
392.3155 184.3917 l
392.3155 196.8917 l
f*
392.3155 184.3917 m
284.1021 184.3917 l
284.1021 184.8917 l
392.3155 184.8917 l
f*
575.9997 184.3917 m
392.8156 184.3917 l
392.8156 184.8917 l
575.9997 184.8917 l
f*
284.1021 184.3917 m
284.1021 171.8918 l
283.602 171.8918 l
283.602 184.3917 l
f*
283.602 171.8918 m
199.9998 171.8918 l
199.9998 172.3918 l
283.602 172.3918 l
f*
392.8156 184.3917 m
392.8156 171.8918 l
392.3155 171.8918 l
392.3155 184.3917 l
f*
392.3155 171.8918 m
284.1021 171.8918 l
284.1021 172.3918 l
392.3155 172.3918 l
f*
575.9997 171.8918 m
392.8156 171.8918 l
392.8156 172.3918 l
575.9997 172.3918 l
f*
284.1021 171.8918 m
284.1021 159.3918 l
283.602 159.3918 l
283.602 171.8918 l
f*
283.602 159.3918 m
199.9998 159.3918 l
199.9998 159.8919 l
283.602 159.8919 l
f*
392.8156 171.8918 m
392.8156 159.3918 l
392.3155 159.3918 l
392.3155 171.8918 l
f*
392.3155 159.3918 m
284.1021 159.3918 l
284.1021 159.8919 l
392.3155 159.8919 l
f*
575.9997 159.3918 m
392.8156 159.3918 l
392.8156 159.8919 l
575.9997 159.8919 l
f*
0.83 0.64 0.02 0 k
200.0126 146.3244 m
350.7591 146.3244 l
h
f*
0 g
7.9999 0 0 7.9999 200.0125 708.7181 cm
BT
/F2 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Table)Tj
2.7992 0 Td
(1.)Tj
1.2614 0 Td
(siRNA)Tj
3.1748 0 Td
(selected)Tj
4.1599 0 Td
(for)Tj
1.5307 0 Td
(further)Tj
3.3946 0 Td
(investiga)Tj
4.2732 0 Td
(tion)Tj
2.041 0 Td
(by)Tj
1.3677 0 Td
(priority)Tj
3.6213 0 Td
(group)Tj
3.026 0 Td
(and)Tj
1.9843 0 Td
(confidence)Tj
5.2158 0 Td
(.)Tj
/F0 1 Tf
0.7157 0 Td
(Confidenc)Tj
4.415 0 Td
(e)Tj
0.7654 0 Td
(ranking)Tj
-43.746 -1.1905 Td
(for)Tj
1.3677 0 Td
(nuclear)Tj
3.437 0 Td
(area)Tj
2.1827 0 Td
(was)Tj
1.9701 0 Td
(based)Tj
2.8914 0 Td
(on)Tj
1.311 0 Td
(number)Tj
3.5575 0 Td
(of)Tj
1.0417 0 Td
(standard)Tj
4.0394 0 Td
(deviation)Tj
3.919 0 Td
(s)Tj
0.7157 0 Td
(above)Tj
2.8985 0 Td
(the)Tj
1.5803 0 Td
(mean)Tj
2.6859 0 Td
(of)Tj
1.0417 0 Td
(plate)Tj
2.3386 0 Td
(negative)Tj
3.9331 0 Td
(controls)Tj
3.6567 0 Td
(and)Tj
-44.568 -1.1835 Td
(the)Tj
1.5874 0 Td
(number)Tj
3.5504 0 Td
(of)Tj
1.0417 0 Td
(library)Tj
2.8843 0 Td
(siRNA)Tj
3.0118 0 Td
(passing)Tj
3.6001 0 Td
(each)Tj
2.3457 0 Td
(threshold.)Tj
/F2 1 Tf
0 Tc
-18.0214 -1.8567 Td
(Target)Tj
10.7646 0 Td
(Priority)Tj
3.7134 0 Td
(group)Tj
9.8717 0 Td
(Confidence)Tj
5.6623 0 Td
(ranking)Tj
/F0 1 Tf
-30.012 -1.5591 Td
(ACCN1)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(1)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(1)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-39.1538 -1.5661 Td
(ALDOA)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(2)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-39.1538 -1.5591 Td
(AURKB)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5661 Td
(BUB1B)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(3)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5591 Td
(CAPN11)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(1)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5662 Td
(CAPN9)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(1)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.559 Td
(CCNA2)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(3)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5662 Td
(CDC45)Tj
3.2456 0 Td
(L)Tj
7.6395 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.559 Td
(CDC7)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5662 Td
(CDK1)Tj
10.8851 0 Td
(Positive)Tj
3.7063 0 Td
(control)Tj
-14.5914 -1.5591 Td
(CHAF1B)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(2)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-39.1538 -1.5661 Td
(CIT)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(3)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5591 Td
(CRKRS)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(1)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(2)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-39.1538 -1.5591 Td
(DDB1)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5661 Td
(ECT2)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(3)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5591 Td
(EFTUD2)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(1)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5661 Td
(ESPL1)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(3)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5591 Td
(GRIA3)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(1)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(2)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-39.1538 -1.5662 Td
(INCEN)Tj
3.0897 0 Td
(P)Tj
7.7954 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(3)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.559 Td
(KCNQ5)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(1)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(2)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-39.1538 -1.5662 Td
(KIF11)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(3)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.559 Td
(METAP2)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(1)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5662 Td
(MMP24)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(1)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5591 Td
(PABPN1)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(2)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-39.1538 -1.5661 Td
(PDE3A)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(1)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(2)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-39.1538 -1.5591 Td
(PSMA2)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5661 Td
(PSMA5)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(2)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-39.1538 -1.5591 Td
(PSMA7)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(2)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-39.1538 -1.5662 Td
(PSMB1)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.559 Td
(PSMB2)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(2)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-39.1538 -1.5662 Td
(PSMB4)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.559 Td
(PSMB5)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(2)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-39.1538 -1.5662 Td
(RRM1)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(3)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(1)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5591 Td
(RRM2)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(1)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5661 Td
(SCN3B)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(1)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(1)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5591 Td
(SMO)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(1)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5661 Td
(TOP2A)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(1)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(1)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-39.1538 -1.5591 Td
(TRRAP)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(2)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-39.1538 -1.5662 Td
(UBL5)Tj
10.8851 0 Td
(Druggable)Tj
4.7977 0 Td
(16)Tj
8.7945 0 Td
(1)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(2)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-39.1538 -1.559 Td
(WEE1)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
-30.8695 -1.5662 Td
(XPO1)Tj
10.8851 0 Td
(Top)Tj
1.9417 0 Td
(24)Tj
11.6505 0 Td
(2)Tj
0.7795 0 Td
(siRNA)Tj
3.0402 0 Td
(at)Tj
1.063 0 Td
(3)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD;)Tj
1.8921 0 Td
(1)Tj
0.7796 0 Td
(siRNA)Tj
3.0472 0 Td
(at)Tj
1.0559 0 Td
(2)Tj
0.7796 0 Td
(x)Tj
0.7299 0 Td
(SD)Tj
0.83 0.64 0.02 0 k
/F9 1 Tf
-0.025 Tc
-39.1538 -1.8709 Td
(https://d)Tj
3.0827 0 Td
(oi.org/10.1371/j)Tj
5.9173 0 Td
(ournal.pge)Tj
3.9331 0 Td
(n.1006942.t00)Tj
5.4355 0 Td
(1)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 391.1244 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Screen)Tj
3.111 0 Td
(ing)Tj
1.5236 0 Td
(senescence)Tj
5.4709 0 Td
(targets)Tj
3.2245 0 Td
(in)Tj
0.9779 0 Td
(cancer)Tj
3.1749 0 Td
(backgrou)Tj
4.0394 0 Td
(nds)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
(6942)Tj
0 g
3.1819 0 Td
(August)Tj
3.2882 0 Td
(14,)Tj
1.5804 0 Td
(2017)Tj
32.2939 0 Td
(5)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
122 0 obj
<>stream
endstream
endobj
123 0 obj
<>stream
endstream
endobj
124 0 obj
<>stream
BT
66.402 0 Td
(24)Tj
ET
Q
endstream
endobj
125 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 13 0 R/Annots 127 0 R/Contents 128 0 R/TrimBox[0 0 612 792]>>
endobj
126 0 obj
<>stream
x]řC9C=X`^eWqw&0J(#9"MK ,fcl<`l?`0C!1xfOjsުzꪫ~Q类@ 9sfΝHK\{..\p @ !T믿>Ri|%>ߕW^{5/$z9'I*MTh=ۯ*],S1! @ hu]j, 6ԧM<^~妼X|y
Ѳe3I^E߉'[˳`[s>}4f*=y7*%KRzF@ @/mG}#=\nO"5{A%נ馛$Բd6-~wq+W_ݪcr/V
rg%C2PdpcUV՛UIaq,]vY}Z E ,Sd\zݏ5#Mkl2w1uy;;eS4JmRѤ&-ض"W\?ⰮYUHa5>5[*0I@ ~³cחP(ƲP0 jQ7v&*X@EKsFbz^"7TGYw)n&o7jL\36}taP53?Xk^kU` P2UyxT1mZS9P]>Ӥ_$0sfL}&U5Ev9<bZxŁիZԳݳ5N?GkXk-Q?lWل L_ACbq:99Qs.\$W
Dw~Z;'2REPRiP[&
~vOrML7'XK*t[c9\2i! @ (MDQj;ѧ~G-.%"p8&g=ޮm=6Vũ˾(GiReY[@;e6U|wVW̬yL;)J'O2,
tWEBz[Uβ@Z𦏦--r8͊ A\%_UbE@O@lZǨ-EE>A#]4'xl+J[% 3<_+f? P[!S[)B6ǵ[`O{1 //7sVQ322FS]-úP"l۶Ru#" 3$ZnR"Q^jKJ>=`Y=fU2+P@=PFHfCH+^+#*ff^jPdK|e-lf`qP\Q|S+_ˀKUaUXg֢20i~L]Zb(\zV'>ԝNR\U`챫%|P yW4RbM%%
6쌰]x\kW|(`Ր܍xB#1!{J>8g_25o;cU,=I졡϶?3`G\Y?CwXnhSnĕHkβb
=G6JmO-Vc kZ[ENڔU)Ȯ6(i*ޒN:8aU~*=aė!Hdi2ʎDCǷpwQGYw[aO*?CUceE5gG׀oGWeJ#-[5Vp->nUh3h)StX`=繮*)j/HzMK?EG37,CVcjg,;1}OYW`CAy\d=lG@4z ȷWvtro/ل uVmUoMo]LIRcZXm!,rP_lͧ m3Wv4gaojJP-(A OvgYmGG.wޱpnm$\u3X6uX2E}Ʒ[BuWA9\[{@\atlij,H|mL"=
OhaK+=/ՒOG=ₛ.Ϭ+'h좪&!(oښ"G2BY)\@Ƶium.hfDZl= "b9,gj<#,JZfBhm`;'W
Q?kft{5,\TԊPԊs`ueک)[ RZUbrC9ʂoY*Gߺ,NYeYZl{tى`*R%gCf":2E;2|pEoM*6JX,zߌk=7֍-|(tRn\?sQ|_yDlgVGraW@UzMXSLȦ_/;;,ScȲSWCȂs& E@U;
;V5gL53bXKITYHԃGǍ
YeQ\'Z,M.=nEݒYLDS37#sg!_xbM~?sמ~9\[ARd>
'JWZl=-!`7]!V뛽w{ͧPT1L]W9F