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0.271 0.235 0.243 scn
0 Tc 2.153 0 Td
(, )Tj
0.122 0.09 0.098 scn
0.0298 Tc 0.503 0 Td
(\311dition )Tj
0.0168 Tc 3.408 0 Td
(Maloine. )Tj
0.0273 Tc -21.811 -2.464 Td
(Un, )Tj
0 Tc 2.182 0 Td
(F)Tj
0.271 0.235 0.243 scn
0.648 0 Td
(. )Tj
0.122 0.09 0.098 scn
0.0136 Tc 0.823 0 Td
(\(2007\). )Tj
0.0445 Tc 3.7 0 Td
("G )Tj
0 Tc 1.27 0 Td
(1 )Tj
0.0258 Tc 1.054 0 Td
(arrest )Tj
0.0231 Tc 2.959 0 Td
(induction )Tj
0.0238 Tc 4.592 0 Td
(represents )Tj
0.212 0.176 0.184 scn
0 Tc 4.921 0 Td
(a )Tj
0.122 0.09 0.098 scn
0.0204 Tc 1.071 0 Td
(critical )Tj
0.0253 Tc 3.579 0 Td
(determinant )Tj
0.0074 Tc 5.678 0 Td
(for )Tj
0.027 Tc 1.844 0 Td
(cisplatin )Tj
0.0278 Tc -34.307 -1.242 Td
(cytotoxicity )Tj
0.0106 Tc 5.423 0 Td
(in )Tj
0.05 Tc 11.4501 0 0 11.2 185.64 422.17 Tm
(GI )Tj
0.0295 Tc 11.2 0 0 11.2 203.89 422.17 Tm
(checkpoint)Tj
0.02 0 0.008 scn
0 Tc 4.67 0 Td
(-)Tj
0.122 0.09 0.098 scn
0.0224 Tc 0.331 0 Td
(retaining )Tj
0.0281 Tc 4.114 0 Td
(human )Tj
0.0258 Tc 3.228 0 Td
(cancers)Tj
0.271 0.235 0.243 scn
0 Tc 3.246 0 Td
(.)Tj
0.122 0.09 0.098 scn
0.237 0 Td
(" )Tj
0.0329 Tc 0.746 0 Td
(Anticancer )Tj
0.0174 Tc 5.012 0 Td
(Drugs. )Tj
0.0185 Tc 3.205 0 Td
(18\(4\): )Tj
0.037 Tc 2.945 0 Td
(411-)Tj
/T1_1 1 Tf
-0.035 Tc 9.9734 0 0 11.5 111.7 408 Tm
(7. )Tj
/T1_0 1 Tf
0.0303 Tc 11.2 0 0 11.2 111.56 380.65 Tm
(Walker, )Tj
-0.0056 Tc 3.856 0 Td
(K. )Tj
0 Tc 1.551 0 Td
(S)Tj
0.271 0.235 0.243 scn
-0.035 Tc 10.7956 0 0 11.2 178.82 380.65 Tm
(., )Tj
0.122 0.09 0.098 scn
0.0254 Tc 11.2 0 0 11.2 189.55 380.65 Tm
(Deak, )Tj
0.0179 Tc 2.979 0 Td
(M., )Tj
0.0254 Tc 1.928 0 Td
(Paterson, )Tj
-0.035 Tc 11.0826 0 0 11.2 293.98 380.65 Tm
(A.)Tj
0.271 0.235 0.243 scn
0 Tc 11.2 0 0 11.2 305.58 380.65 Tm
(, )Tj
0.122 0.09 0.098 scn
0.031 Tc 0.697 0 Td
(Hudson, )Tj
-0.027 Tc 4.05 0 Td
(K.)Tj
0.271 0.235 0.243 scn
0 Tc 1.06 0 Td
(, )Tj
0.122 0.09 0.098 scn
0.0282 Tc 0.712 0 Td
(Cohen, )Tj
0.0154 Tc 3.5 0 Td
(P., )Tj
0.0203 Tc 1.588 0 Td
(Alessi)Tj
0.271 0.235 0.243 scn
0 Tc 2.686 0 Td
(, )Tj
0.122 0.09 0.098 scn
0.0262 Tc 0.697 0 Td
(D.R. )Tj
0.0207 Tc 2.521 0 Td
(\(1998\). )Tj
0.0258 Tc -34.786 -1.243 Td
("Activation )Tj
0.05 Tc 12.5203 0 0 11.2 171 366.73 Tm
(of )Tj
0.0301 Tc 11.2 0 0 11.2 184.58 366.73 Tm
(prote )Tj
-0.0109 Tc 2.24 0 Td
(in )Tj
0.0298 Tc 1.121 0 Td
(kinase )Tj
0 Tc 3.083 0 Td
(B )Tj
0.0346 Tc 1.077 0 Td
(beta )Tj
0.0233 Tc 2.132 0 Td
(and )Tj
0.0455 Tc 1.887 0 Td
(gamma )Tj
0.023 Tc 3.494 0 Td
(isoforms )Tj
0.0382 Tc 4.037 0 Td
(by )Tj
0.0244 Tc 1.448 0 Td
(insulin )Tj
-0.0323 Tc 3.279 0 Td
(in )Tj
0.212 0.176 0.184 scn
0.0238 Tc 1.163 0 Td
(vivo )Tj
0.034 Tc 2.242 0 Td
(and )Tj
0.122 0.09 0.098 scn
0.05 Tc 11.5341 0 0 11.2 510.49 366.73 Tm
(by )Tj
-0.0032 Tc 11.2 0 0 11.2 526.91 366.73 Tm
(3-)Tj
0.0296 Tc -37.079 -1.244 Td
(phosphoinositide-dependent )Tj
0.0334 Tc 12.3 0 Td
(protein )Tj
0.0255 Tc 3.339 0 Td
(kinase)Tj
0.02 0 0.008 scn
0 Tc 2.754 0 Td
(-)Tj
0.122 0.09 0.098 scn
0.431 0 Td
(l )Tj
-0.0109 Tc 0.751 0 Td
(in )Tj
0.212 0.176 0.184 scn
0.0012 Tc 1.163 0 Td
(vitro: )Tj
0.122 0.09 0.098 scn
0.0342 Tc 2.585 0 Td
(comparison )Tj
0.0238 Tc 5.301 0 Td
(with )Tj
0.0227 Tc 2.189 0 Td
(protein )Tj
0.0255 Tc 3.361 0 Td
(kinase )Tj
0 Tc 3.062 0 Td
(B )Tj
0.212 0.176 0.184 scn
0.0174 Tc -37.205 -1.221 Td
(alpha." )Tj
0.122 0.09 0.098 scn
0.0312 Tc 3.263 0 Td
(Biochem )Tj
0 Tc 4.092 0 Td
(J )Tj
/T1_2 1 Tf
-0.0085 Tc 11.5 0 0 11.5 201.79 339.13 Tm
(331 )Tj
0.05 Tc 13.0522 0 0 11.5 222.81 339.13 Tm
(\(Pt )Tj
/T1_0 1 Tf
-0.005 Tc 11.2 0 0 11.2 243.93 339.13 Tm
(1\): )Tj
0.0174 Tc 1.464 0 Td
(299-308. )Tj
0.0263 Tc -13.262 -2.486 Td
(Weinberg, )Tj
-0.035 Tc 11.3404 0 0 11.4 167.02 311.29 Tm
(A. )Tj
0 Tc 11.2 0 0 11.2 184.27 311.29 Tm
(R)Tj
0.02 0 0.008 scn
0.755 0 Td
(. )Tj
0.122 0.09 0.098 scn
0.0136 Tc 0.738 0 Td
(\(2007\). )Tj
0.0246 Tc 3.581 0 Td
(The )Tj
0.0319 Tc 2.11 0 Td
(biology )Tj
0.05 Tc 12.2421 0 0 11.2 306.84 311.29 Tm
(of )Tj
0.0239 Tc 11.2 0 0 11.2 322.21 311.29 Tm
(cancer, )Tj
0.0269 Tc 3.536 0 Td
(Garland )Tj
0.0257 Tc 3.917 0 Td
(science, )Tj
0.0278 Tc 3.905 0 Td
(Taylor )Tj
/T1_1 1 Tf
0 Tc 10.9 0 0 10.9 486.58 311.29 Tm
(& )Tj
/T1_0 1 Tf
0.0305 Tc 11.2 0 0 11.2 501.31 311.29 Tm
(Francis )Tj
0.0263 Tc -34.783 -1.221 Td
(group, )Tj
0.0064 Tc 3.046 0 Td
(LLC. )Tj
0.0237 Tc -3.041 -2.486 Td
(Williams, )Tj
0 Tc 4.538 0 Td
(l )Tj
0.0211 Tc 1.055 0 Td
(W., )Tj
0.0299 Tc 1.928 0 Td
(Duggleby, )Tj
0.05 Tc 12.2612 0 0 11.2 250.26 269.77 Tm
(RG., )Tj
0.0174 Tc 11.2 0 0 11.2 280.44 269.77 Tm
(Cutler, )Tj
0.05 Tc 13.6972 0 0 11.2 317.21 269.77 Tm
(R, )Tj
0.0332 Tc 11.2 0 0 11.2 335.23 269.77 Tm
(Morrison)Tj
0.271 0.235 0.243 scn
0 Tc 4.017 0 Td
(, )Tj
0.122 0.09 0.098 scn
0.05 Tc 13.7701 0 0 11.2 387.24 269.77 Tm
(lF. )Tj
0.0136 Tc 11.2 0 0 11.2 409.07 269.77 Tm
(\(1980\). )Tj
0.0164 Tc 3.529 0 Td
("The )Tj
0.0273 Tc 2.432 0 Td
(inhibition )Tj
0.05 Tc 12.5203 0 0 11.2 526.92 269.77 Tm
(of )Tj
0.0254 Tc 11.2 0 0 11.2 111.73 255.85 Tm
(dihydrofolate )Tj
0.0242 Tc 6.051 0 Td
(reductase )Tj
0.05 Tc 11.3034 0 0 11.2 227.77 255.85 Tm
(by )Tj
0.013 Tc 11.2 0 0 11.2 243.48 255.85 Tm
(folate )Tj
0.0147 Tc 2.744 0 Td
(analogues: )Tj
0.0218 Tc 4.838 0 Td
(structural )Tj
0.0266 Tc 4.32 0 Td
(requirements )Tj
0.0181 Tc 5.862 0 Td
(for )Tj
0.0243 Tc 1.561 0 Td
(slow-)Tj
0.212 0.176 0.184 scn
0.034 Tc 2.683 0 Td
(and )Tj
0.122 0.09 0.098 scn
0.022 Tc 1.85 0 Td
(tight\255)Tj
0.0355 Tc -35.632 -1.201 Td
(binding )Tj
0.0151 Tc 3.591 0 Td
(inhibition." )Tj
0.0347 Tc 5.039 0 Td
(Biochem )Tj
0.0363 Tc 4.114 0 Td
(PharmacoI29\(4\): )Tj
0.0171 Tc 7.683 0 Td
(589)Tj
0.02 0 0.008 scn
0 Tc 1.61 0 Td
(-)Tj
0.122 0.09 0.098 scn
-0.0125 Tc 0.343 0 Td
(95. )Tj
0.0284 Tc -22.385 -2.506 Td
(Wilson, )Tj
-0.0292 Tc 3.643 0 Td
(W. )Tj
0.016 Tc 1.542 0 Td
(H., )Tj
0.0253 Tc 1.607 0 Td
(Berg, )Tj
-0.0081 Tc 2.664 0 Td
(S.L.)Tj
0.271 0.235 0.243 scn
0 Tc 1.76 0 Td
(, )Tj
0.122 0.09 0.098 scn
0.0348 Tc 0.526 0 Td
(Bryant)Tj
0.271 0.235 0.243 scn
0 Tc 2.924 0 Td
(, )Tj
0.122 0.09 0.098 scn
0.542 0 Td
(G)Tj
0.271 0.235 0.243 scn
-0.035 Tc 10.7956 0 0 11.2 290.66 214.33 Tm
(., )Tj
0.122 0.09 0.098 scn
0.0144 Tc 11.2 0 0 11.2 299.72 214.33 Tm
(Wittes, )Tj
0.0191 Tc 3.299 0 Td
(R.E., )Tj
0.025 Tc 2.443 0 Td
(Bates, )Tj
0.0036 Tc 2.944 0 Td
(S., )Tj
0.0246 Tc 1.385 0 Td
(Fojo, )Tj
-0.035 Tc 11.3404 0 0 11.4 440.62 214.33 Tm
(A.)Tj
0.271 0.235 0.243 scn
0 Tc 11.4 0 0 11.4 452.7 214.33 Tm
(, )Tj
0.122 0.09 0.098 scn
0.0266 Tc 11.2 0 0 11.2 458.68 214.33 Tm
(Steinberg)Tj
0.271 0.235 0.243 scn
0 Tc 4.095 0 Td
(, )Tj
0.122 0.09 0.098 scn
0.0269 Tc 0.555 0 Td
(S.M)Tj
0.271 0.235 0.243 scn
-0.035 Tc 10.7956 0 0 11.2 531.62 214.33 Tm
(., )Tj
0.122 0.09 0.098 scn
0.0232 Tc 11.2 0 0 11.2 111.73 200.89 Tm
(Goldspiel, )Tj
0.05 Tc 12.3649 0 0 11.2 168.66 200.89 Tm
(B.R, )Tj
0.0244 Tc 11.2 0 0 11.2 201.07 200.89 Tm
(Herdt, )Tj
0.05 Tc 17.5167 0 0 11.2 238.89 200.89 Tm
(l, )Tj
0.0258 Tc 11.2 0 0 11.2 257.41 200.89 Tm
(O'Shaughnessy, )Tj
0 Tc 7.437 0 Td
(l )Tj
0.0136 Tc 1.39 0 Td
(\(1994\). )Tj
0.0238 Tc 3.807 0 Td
("Paclitaxel )Tj
0.0106 Tc 5.282 0 Td
(in )Tj
0.0321 Tc 1.498 0 Td
(doxorubicin\255)Tj
0.0244 Tc -32.413 -1.243 Td
(refractory )Tj
0.0445 Tc 4.878 0 Td
(or )Tj
0.0246 Tc 1.572 0 Td
(mitoxantrone-refractory )Tj
0.0263 Tc 10.888 0 Td
(breast )Tj
0.0159 Tc 3.204 0 Td
(cancer: )Tj
0 Tc 3.75 0 Td
(a )Tj
0.0335 Tc 1.147 0 Td
(phase )Tj
0.0153 Tc 3.12 0 Td
(IIiI )Tj
0.006 Tc 2.04 0 Td
(trial )Tj
0.05 Tc 12.5203 0 0 11.2 481.32 186.97 Tm
(of )Tj
0.0372 Tc 11.2 0 0 11.2 499.07 186.97 Tm
(96-hour )Tj
0.0302 Tc -34.582 -1.244 Td
(infusion)Tj
0.271 0.235 0.243 scn
0 Tc 3.545 0 Td
(.)Tj
0.122 0.09 0.098 scn
0.237 0 Td
(" )Tj
/T1_1 1 Tf
0.675 0 Td
(J )Tj
/T1_0 1 Tf
0.0267 Tc 0.683 0 Td
(Clin )Tj
0.0473 Tc 2.101 0 Td
(Oncol12\(8\): )Tj
0.0048 Tc 5.846 0 Td
(1621-9)Tj
0.02 0 0.008 scn
0 Tc 2.929 0 Td
(. )Tj
0.122 0.09 0.098 scn
0.028 Tc -16.032 -2.463 Td
(Yamaguchi, )Tj
0.0133 Tc 5.508 0 Td
(A., )Tj
0.0246 Tc 1.643 0 Td
(Tamatani, )Tj
0.0179 Tc 4.59 0 Td
(M., )Tj
0.0276 Tc 1.8 0 Td
(Matsuzaki)Tj
0.271 0.235 0.243 scn
0 Tc 4.467 0 Td
(, )Tj
0.122 0.09 0.098 scn
-0.018 Tc 0.569 0 Td
(H.)Tj
0.271 0.235 0.243 scn
0 Tc 1.06 0 Td
(, )Tj
0.122 0.09 0.098 scn
0.0359 Tc 0.535 0 Td
(Namikawa, )Tj
0 Tc 5.241 0 Td
(K)Tj
0.271 0.235 0.243 scn
-0.035 Tc 10.7956 0 0 11.2 405.38 145.45 Tm
(., )Tj
0.122 0.09 0.098 scn
0.0452 Tc 11.2 0 0 11.2 414.43 145.45 Tm
(Kiyama)Tj
0.271 0.235 0.243 scn
0 Tc 3.396 0 Td
(, )Tj
0.122 0.09 0.098 scn
0.0267 Tc 0.547 0 Td
(H., )Tj
0.0261 Tc 1.653 0 Td
(Vitek, )Tj
0.0123 Tc 2.997 0 Td
(M.P.)Tj
0.271 0.235 0.243 scn
0 Tc 2.11 0 Td
(, )Tj
0.122 0.09 0.098 scn
0.0275 Tc -37.746 -1.243 Td
(Mitsuda, )Tj
0.0318 Tc 4.102 0 Td
(N., )Tj
0.0276 Tc 1.722 0 Td
(Tohyama, )Tj
-0.0142 Tc 4.654 0 Td
(M. )Tj
0.0136 Tc 1.601 0 Td
(\(2001\). )Tj
0.0273 Tc 3.486 0 Td
("Akt )Tj
0.0233 Tc 2.388 0 Td
(activation )Tj
0.0271 Tc 4.533 0 Td
(protects )Tj
0.0308 Tc 3.768 0 Td
(hippocampal )Tj
0.0302 Tc 5.894 0 Td
(neurons )Tj
0.0245 Tc 3.783 0 Td
(from )Tj
0.0224 Tc -35.913 -1.265 Td
(apoptosis )Tj
0.0382 Tc 4.254 0 Td
(by )Tj
0.0249 Tc 1.362 0 Td
(inhibiting )Tj
0.0228 Tc 4.398 0 Td
(transcriptional )Tj
0.0208 Tc 6.421 0 Td
(activity )Tj
0.05 Tc 11.5209 0 0 11.2 334.45 117.36 Tm
(ofp53." )Tj
0 Tc 11.5 0 0 11.5 376.01 117.36 Tm
(J )Tj
0.0267 Tc 11.2 0 0 11.2 383.47 117.36 Tm
(Biol )Tj
0.0476 Tc 2.115 0 Td
(Chem )Tj
0.0162 Tc 2.812 0 Td
(276\(7\): )Tj
0.0304 Tc 3.421 0 Td
(5256)Tj
0.02 0 0.008 scn
0 Tc 2.146 0 Td
(-)Tj
0.122 0.09 0.098 scn
-0.002 Tc 0.363 0 Td
(64. )Tj
ET
q
/CS0 cs 0.159 0.159 0.159 scn
433.9199982 0 0 648.9600067 107.5200043 112.1040039 cm
/Im0 Do
Q
endstream
endobj
1450 0 obj
<>/Filter/JBIG2Decode/Height 2704/ImageMask true/Length 4873/Subtype/Image/Width 1808>>stream
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