Chromosome segregation errors: a double-edged sword - TI Pharma

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Table I. Overview of (Pre-)clinical mitotic targets currently being evaluated. Target Clinically used inhibitors Cell cycle effect Mouse model Eg5 Ispinesib, SB743921, MK- Mitotic delay 0731,AZD-4877, ARRY-520, (monopolar LY2523355 spindle) Plk1 BI2536, BI6727, GSK-461363,ON 01910.Na, HMN-241, NMS-1286937, TAK-960, TKM-080301 (RNAi) Aurora A MLN8054, MLN8237, ENMD- 2076 Aurora B AZD1152, GSK1070916A Mitotic delay (monopolar spindle) CENP-E Lonafarnib, GSK923295A Mitotic delay (chromosome misalignment) Future target APC/C (Cdc20) Mps1 (mitotic checkpoint) Clinical Trials Refs Xenografts I,II 542,543 and reviewed in 471 Xenografts I,II 544,545 and reviewed in 184,546 , 547 Mitotic delay Xenografts I,II 548 , (monopolar reviewed in spindle) 184,504 549 Polyploidy Xenografts I,II Reviewed in Xenografts, conditional mouse model Inhibitors (pre-clinical) Cell cycle effect Mouse model I Clinical trials 184,504,506,549 397,482,483 and reviewed in 471 References TAME Mitotic delay Conditional knock out model None 499,501 Mps1 IN-1, Reversine, <strong>Chromosome</strong> Xenografts None 176,550 123 , NMS-P715 mis<strong>segregation</strong>s 85 Mitosis as an anti-cancer target 4
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Chromosome segregation errors: a do
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Chromosome segregation errors: a do
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Get up, stand up, stand up for your
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Chapter 1 General Introduction Anie
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cytoplasms and pinches off the memb
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which sister-chromatids are not pro
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Non-MCC members, but important mito
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completely separated. Following cle
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Two striking features of cancer cel
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predisposition at a very young age,
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that aberrant spindle formation inc
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(Fig.7C). As discussed in section 4
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Thesis outline Chromosome segregati
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286,395,407,408 Increase (thymus) I
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2 Abstract Various types of chromos
Page 35 and 36: 2 34 A C D E % of cells Control 100
Page 37 and 38: 2 assess whether cytokinesis induce
Page 39 and 40: 2 A Asynchronous Monastrol release
Page 41 and 42: 2 for 14 hours (unless indicated ot
Page 43 and 44: 2 Immuno Blotting Cells were lysed
Page 45 and 46: 2 Supplemental figures 44 A B C % o
Page 47 and 48: 2 A MCF7 B C 53BP1 foci/cell 46 % o
Page 49 and 50: 2 A siLuc siATM C 48 p-S1981 ATM me
Page 51 and 52: 2 50 A B C % of EdU positive cells
Page 54 and 55: Chapter 3 Studying Chromosomal inst
Page 56 and 57: Introduction Aneuploidy is a common
Page 58 and 59: activity by ~80% 170-172 . With the
Page 60 and 61: A WT/CiMKi T649A Embryo’s: Figure
Page 62 and 63: control treated MEFs (unpaired t te
Page 64 and 65: Materials and Methods Cloning targe
Page 66 and 67: - Loop out BamHI site with site-dir
Page 68 and 69: Primers: pGH_pA_FW#2: TCTATGGCTTCTG
Page 70 and 71: was prepared using standard procedu
Page 72: 71 Cre-inducible Mps1 knock-in mous
Page 75 and 76: 4 Abstract Most of the current drug
Page 77 and 78: 4 Two other interesting mitotic tar
Page 79 and 80: 4 inhibition of the anti-apoptotic
Page 81 and 82: 4 cluster their centrosomes. This
Page 83 and 84: 4 of checkpoint function can be ach
Page 85: 4 4.5 Disadvantages of exploiting m
Page 89 and 90: 5 Abstract The mitotic checkpoint h
Page 91 and 92: 5 increase in cell death (18% vs. 4
Page 93 and 94: A U2OS-TetR Mps1 B relative colony
Page 95 and 96: 5 A Mad2 U2OS-TetR MAD2 100 30 B U2
Page 97 and 98: 5 however, this amount was not enha
Page 99 and 100: 5 Cells were grown in 96 wells plat
Page 101 and 102: 5 A B DIC Propidium Iodide C D 100
Page 103 and 104: 5 A C 102 relative colony formation
Page 105 and 106: 5 (+SEM). B) Quantification of time
Page 107 and 108: 5 106 Addendum Targeting the mitoti
Page 109 and 110: 5 Introduction Chromosomal instabil
Page 111 and 112: 5 110 A B percentage of cells 100 8
Page 113 and 114: 5 Flow Cytometry Flow cytometry sam
Page 115 and 116: 5 114
Page 117 and 118: 6 Abstract Developing anti-tumor th
Page 119 and 120: 6 Results Search for a potent and s
Page 121 and 122: 6 120 A B 50 40 30 20 RPE-1 Compoun
Page 123 and 124: 6 severe missegregations in either
Page 125 and 126: 6 these cells with E1A virus 584 .
Page 127 and 128: 6 when compared to diploid untransf
Page 129 and 130: 6 with 400mg/ml Hygromycin. U2OS ce
Page 131 and 132: 6 Supplemental data Supplemental fi
Page 134 and 135: Chapter 7 Docetaxel affects in vivo
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Introduction Taxanes are among the
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Simultaneously imaging mitotic prog
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treatment respectively. In line wit
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C % abnormal nuclei D E % of cells
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(reviewed in 447) and might explain
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Tissues were isolated and fixed in
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147 Intravital imaging of Docetaxel
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Chapter 8 Summary & Discussion 149
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Discussion 1. Chromosome segregatio
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Since it has been shown that replic
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2.2 Benefits of being CIN Generally
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opportunities for the development o
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& References 1. Pines, J., The cell
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& 22(6): p. 1321-9. 84. Hwang, L.H.
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& Oncogene, 2009. 28(10): p. 1366-7
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& p. 1749-53. 256. Miki, Y., et al.
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& of telomeres. EMBO J, 2012. 31(9)
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& 426. Giunta, S., R. Belotserkovsk
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& 511. Andreassen, P.R., et al., Te
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& 4610-7. 601. Beerling, E., et al.
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& Toch balanceren chromosoom instab
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& Curriculum Vitae Aniek Janssen we
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& Dankwoord En dan nu eindelijk het
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& period. Tania, congratulations wi
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& gezelligheid bij borrels en in he
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Chromosome segregation errors: a double-edged sword - TI Pharma

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