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char = i;code = 105
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = ;code = 32
char = v;code = 118
char = a;code = 97
char = r;code = 114
char = i;code = 105
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = m;code = 109
char = o;code = 111
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = 5;code = 53
char = 0;code = 48
char = %;code = 37
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = g;code = 103
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = f;code = 102
char = r;code = 114
char = o;code = 111
char = m;code = 109
char = ;code = 32
char = 2;code = 50
char = -;code = 45
char = f;code = 102
char = o;code = 111
char = l;code = 108
char = d;code = 100
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = o;code = 111
char = x;code = 120
char = a;code = 97
char = l;code = 108
char = i;code = 105
char = p;code = 112
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 1;code = 49
char = 4;code = 52
char = -;code = 45
char = f;code = 102
char = o;code = 111
char = l;code = 108
char = d;code = 100
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = l;code = 108
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = l;code = 108
char = a;code = 97
char = n;code = 110
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = d;code = 100
char = r;code = 114
char = u;code = 117
char = g;code = 103
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = f;code = 102
char = r;code = 114
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = s;code = 115
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = N;code = 78
char = o;code = 111
char = ;code = 32
char = h;code = 104
char = y;code = 121
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = b;code = 98
char = s;code = 115
char = e;code = 101
char = r;code = 114
char = v;code = 118
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = g;code = 103
char = e;code = 101
char = m;code = 109
char = c;code = 99
char = i;code = 105
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = e;code = 101
char = t;code = 116
char = o;code = 111
char = p;code = 112
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = 3;code = 51
char = -;code = 45
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = b;code = 98
char = e;code = 101
char = n;code = 110
char = z;code = 122
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = N;code = 78
char = U;code = 85
char = 1;code = 49
char = 0;code = 48
char = 2;code = 50
char = 5;code = 53
char = ,;code = 44
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = h;code = 104
char = y;code = 121
char = d;code = 100
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = .;code = 46
char = ;code = 32
char = F;code = 70
char = A;code = 65
char = N;code = 78
char = C;code = 67
char = C;code = 67
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = F;code = 70
char = A;code = 65
char = N;code = 78
char = C;code = 67
char = G;code = 71
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = s;code = 115
char = r;code = 114
char = u;code = 117
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = o;code = 111
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = u;code = 117
char = l;code = 108
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = c;code = 99
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = a;code = 97
char = s;code = 115
char = t;code = 116
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = m;code = 109
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = r;code = 114
char = r;code = 114
char = a;code = 97
char = d;code = 100
char = i;code = 105
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ,;code = 44
char = ;code = 32
char = b;code = 98
char = u;code = 117
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = F;code = 70
char = A;code = 65
char = N;code = 78
char = C;code = 67
char = G;code = 71
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = s;code = 115
char = r;code = 114
char = u;code = 117
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = b;code = 98
char = s;code = 115
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = c;code = 99
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = v;code = 118
char = i;code = 105
char = v;code = 118
char = a;code = 97
char = l;code = 108
char = .;code = 46
char = ;code = 32
char = F;code = 70
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ,;code = 44
char = ;code = 32
char = F;code = 70
char = A;code = 65
char = N;code = 78
char = C;code = 67
char = C;code = 67
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = F;code = 70
char = A;code = 65
char = N;code = 78
char = C;code = 67
char = G;code = 71
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = s;code = 115
char = r;code = 114
char = u;code = 117
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = c;code = 99
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = p;code = 112
char = o;code = 111
char = n;code = 110
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = e;code = 101
char = o;code = 111
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = c;code = 99
char = h;code = 104
char = r;code = 114
char = o;code = 111
char = m;code = 109
char = o;code = 111
char = s;code = 115
char = o;code = 111
char = m;code = 109
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = b;code = 98
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = k;code = 107
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = p;code = 112
char = p;code = 112
char = o;code = 111
char = r;code = 114
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = o;code = 111
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = k;code = 107
char = e;code = 101
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = p;code = 112
char = l;code = 108
char = a;code = 97
char = i;code = 105
char = n;code = 110
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = u;code = 117
char = t;code = 116
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = s;code = 115
char = p;code = 112
char = o;code = 111
char = r;code = 114
char = a;code = 97
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = r;code = 114
char = .;code = 46
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = >;code = 62
char = C;code = 67
char = O;code = 79
char = N;code = 78
char = C;code = 67
char = L;code = 76
char = U;code = 85
char = S;code = 83
char = I;code = 73
char = O;code = 79
char = N;code = 78
char = S;code = 83
char = ;code = 32
char = :;code = 58
char = ;code = 32
char = <;code = 60
char = /;code = 47
char = b;code = 98
char = >;code = 62
char = O;code = 79
char = u;code = 117
char = r;code = 114
char = ;code = 32
char = h;code = 104
char = u;code = 117
char = m;code = 109
char = a;code = 97
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char = c;code = 99
char = a;code = 97
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char = c;code = 99
char = e;code = 101
char = r;code = 114
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char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = v;code = 118
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = c;code = 99
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char = n;code = 110
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = l;code = 108
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = e;code = 101
char = l;code = 108
char = u;code = 117
char = c;code = 99
char = i;code = 105
char = d;code = 100
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = u;code = 117
char = n;code = 110
char = d;code = 100
char = a;code = 97
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = b;code = 98
char = i;code = 105
char = o;code = 111
char = l;code = 108
char = o;code = 111
char = g;code = 103
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = f;code = 102
char = e;code = 101
char = a;code = 97
char = t;code = 116
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = d;code = 100
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = F;code = 70
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = e;code = 101
char = m;code = 109
char = i;code = 105
char = a;code = 97
char = ;code = 32
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = f;code = 102
char = a;code = 97
char = c;code = 99
char = i;code = 105
char = l;code = 108
char = i;code = 105
char = t;code = 116
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = c;code = 99
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = u;code = 117
char = d;code = 100
char = i;code = 105
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = p;code = 112
char = e;code = 101
char = u;code = 117
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = o;code = 111
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = m;code = 109
char = p;code = 112
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = F;code = 70
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = ;code = 32
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = d;code = 100
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result sql = BACKGROUND & AIMS : How specifically to treat pancreatic and other cancers harboring Fanconi anemia gene mutations has raised great interest recently, yet preclinical studies have been hampered by the lack of well-controlled human cancer models.
METHODS : We endogenously disrupted FANCC and FANCG in a human adenocarcinoma cell line and determined the impact of these genes on drug sensitivity, irradiation sensitivity, and genome maintenance.
RESULTS : FANCC and FANCG disruption abrogated FANCD2 monoubiquitination, confirming an impaired Fanconi anemia pathway function. On treatment with DNA interstrand-cross-linking agents, FANCC and FANCG disruption caused increased clastogenic damage, G2/M arrest, and decreased proliferation. The extent of hypersensitivity varied among agents, with ratios of inhibitory concentration 50% ranging from 2-fold for oxaliplatin to 14-fold for melphalan, a drug infrequently used in solid tumors. No hypersensitivity was observed on gemcitabine, etoposide, 3-aminobenzamide, NU1025, or hydrogen peroxide. FANCC and FANCG disruption also resulted in increased clastogenic damage on irradiation, but only FANCG disruption caused a subsequent decrease in relative survival. Finally, FANCC and FANCG disruption increased spontaneous chromosomal breakage, supporting the role of these genes in genome maintenance and likely explaining why they are mutated in sporadic cancer.
CONCLUSIONS : Our human cancer cell model provides optimal controls to elucidate fundamental biologic features of individual Fanconi anemia gene defects and facilitates preclinical studies of therapeutic options. The impact of Fanconi gene defects on drug and irradiation sensitivity renders these genes promising targets for a specific, genotype-based therapy for individual cancer patients, providing a strong rationale for clinical trials.
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result sql = Targeted disruption of FANCC and FANCG in human cancer provides a preclinical model for specific therapeutic options.
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char = i;code = 105
char = m;code = 109
char = p;code = 112
char = a;code = 97
char = i;code = 105
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = F;code = 70
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = e;code = 101
char = m;code = 109
char = i;code = 105
char = a;code = 97
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = h;code = 104
char = w;code = 119
char = a;code = 97
char = y;code = 121
char = ;code = 32
char = f;code = 102
char = u;code = 117
char = n;code = 110
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = .;code = 46
char = ;code = 32
char = O;code = 79
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = t;code = 116
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = D;code = 68
char = N;code = 78
char = A;code = 65
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = -;code = 45
char = c;code = 99
char = r;code = 114
char = o;code = 111
char = s;code = 115
char = s;code = 115
char = -;code = 45
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = F;code = 70
char = A;code = 65
char = N;code = 78
char = C;code = 67
char = C;code = 67
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = F;code = 70
char = A;code = 65
char = N;code = 78
char = C;code = 67
char = G;code = 71
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = s;code = 115
char = r;code = 114
char = u;code = 117
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = c;code = 99
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = a;code = 97
char = s;code = 115
char = t;code = 116
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = m;code = 109
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = G;code = 71
char = 2;code = 50
char = /;code = 47
char = M;code = 77
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = c;code = 99
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = f;code = 102
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = h;code = 104
char = y;code = 121
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = ;code = 32
char = v;code = 118
char = a;code = 97
char = r;code = 114
char = i;code = 105
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = m;code = 109
char = o;code = 111
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = 5;code = 53
char = 0;code = 48
char = %;code = 37
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = g;code = 103
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = f;code = 102
char = r;code = 114
char = o;code = 111
char = m;code = 109
char = ;code = 32
char = 2;code = 50
char = -;code = 45
char = f;code = 102
char = o;code = 111
char = l;code = 108
char = d;code = 100
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = o;code = 111
char = x;code = 120
char = a;code = 97
char = l;code = 108
char = i;code = 105
char = p;code = 112
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 1;code = 49
char = 4;code = 52
char = -;code = 45
char = f;code = 102
char = o;code = 111
char = l;code = 108
char = d;code = 100
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = l;code = 108
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = l;code = 108
char = a;code = 97
char = n;code = 110
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = d;code = 100
char = r;code = 114
char = u;code = 117
char = g;code = 103
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = f;code = 102
char = r;code = 114
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = s;code = 115
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = N;code = 78
char = o;code = 111
char = ;code = 32
char = h;code = 104
char = y;code = 121
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = b;code = 98
char = s;code = 115
char = e;code = 101
char = r;code = 114
char = v;code = 118
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = g;code = 103
char = e;code = 101
char = m;code = 109
char = c;code = 99
char = i;code = 105
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = e;code = 101
char = t;code = 116
char = o;code = 111
char = p;code = 112
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = 3;code = 51
char = -;code = 45
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = b;code = 98
char = e;code = 101
char = n;code = 110
char = z;code = 122
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = N;code = 78
char = U;code = 85
char = 1;code = 49
char = 0;code = 48
char = 2;code = 50
char = 5;code = 53
char = ,;code = 44
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = h;code = 104
char = y;code = 121
char = d;code = 100
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = .;code = 46
char = ;code = 32
char = F;code = 70
char = A;code = 65
char = N;code = 78
char = C;code = 67
char = C;code = 67
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = F;code = 70
char = A;code = 65
char = N;code = 78
char = C;code = 67
char = G;code = 71
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = s;code = 115
char = r;code = 114
char = u;code = 117
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = o;code = 111
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = u;code = 117
char = l;code = 108
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = c;code = 99
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = a;code = 97
char = s;code = 115
char = t;code = 116
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = m;code = 109
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = r;code = 114
char = r;code = 114
char = a;code = 97
char = d;code = 100
char = i;code = 105
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ,;code = 44
char = ;code = 32
char = b;code = 98
char = u;code = 117
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = F;code = 70
char = A;code = 65
char = N;code = 78
char = C;code = 67
char = G;code = 71
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = s;code = 115
char = r;code = 114
char = u;code = 117
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = b;code = 98
char = s;code = 115
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = c;code = 99
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = v;code = 118
char = i;code = 105
char = v;code = 118
char = a;code = 97
char = l;code = 108
char = .;code = 46
char = ;code = 32
char = F;code = 70
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ,;code = 44
char = ;code = 32
char = F;code = 70
char = A;code = 65
char = N;code = 78
char = C;code = 67
char = C;code = 67
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = F;code = 70
char = A;code = 65
char = N;code = 78
char = C;code = 67
char = G;code = 71
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = s;code = 115
char = r;code = 114
char = u;code = 117
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = c;code = 99
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = p;code = 112
char = o;code = 111
char = n;code = 110
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = e;code = 101
char = o;code = 111
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = c;code = 99
char = h;code = 104
char = r;code = 114
char = o;code = 111
char = m;code = 109
char = o;code = 111
char = s;code = 115
char = o;code = 111
char = m;code = 109
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = b;code = 98
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = k;code = 107
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = p;code = 112
char = p;code = 112
char = o;code = 111
char = r;code = 114
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = o;code = 111
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = k;code = 107
char = e;code = 101
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = p;code = 112
char = l;code = 108
char = a;code = 97
char = i;code = 105
char = n;code = 110
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = u;code = 117
char = t;code = 116
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = s;code = 115
char = p;code = 112
char = o;code = 111
char = r;code = 114
char = a;code = 97
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = r;code = 114
char = .;code = 46
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = >;code = 62
char = C;code = 67
char = O;code = 79
char = N;code = 78
char = C;code = 67
char = L;code = 76
char = U;code = 85
char = S;code = 83
char = I;code = 73
char = O;code = 79
char = N;code = 78
char = S;code = 83
char = ;code = 32
char = :;code = 58
char = ;code = 32
char = <;code = 60
char = /;code = 47
char = b;code = 98
char = >;code = 62
char = O;code = 79
char = u;code = 117
char = r;code = 114
char = ;code = 32
char = h;code = 104
char = u;code = 117
char = m;code = 109
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = c;code = 99
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result sql = BACKGROUND & AIMS : How specifically to treat pancreatic and other cancers harboring Fanconi anemia gene mutations has raised great interest recently, yet preclinical studies have been hampered by the lack of well-controlled human cancer models.
METHODS : We endogenously disrupted FANCC and FANCG in a human adenocarcinoma cell line and determined the impact of these genes on drug sensitivity, irradiation sensitivity, and genome maintenance.
RESULTS : FANCC and FANCG disruption abrogated FANCD2 monoubiquitination, confirming an impaired Fanconi anemia pathway function. On treatment with DNA interstrand-cross-linking agents, FANCC and FANCG disruption caused increased clastogenic damage, G2/M arrest, and decreased proliferation. The extent of hypersensitivity varied among agents, with ratios of inhibitory concentration 50% ranging from 2-fold for oxaliplatin to 14-fold for melphalan, a drug infrequently used in solid tumors. No hypersensitivity was observed on gemcitabine, etoposide, 3-aminobenzamide, NU1025, or hydrogen peroxide. FANCC and FANCG disruption also resulted in increased clastogenic damage on irradiation, but only FANCG disruption caused a subsequent decrease in relative survival. Finally, FANCC and FANCG disruption increased spontaneous chromosomal breakage, supporting the role of these genes in genome maintenance and likely explaining why they are mutated in sporadic cancer.
CONCLUSIONS : Our human cancer cell model provides optimal controls to elucidate fundamental biologic features of individual Fanconi anemia gene defects and facilitates preclinical studies of therapeutic options. The impact of Fanconi gene defects on drug and irradiation sensitivity renders these genes promising targets for a specific, genotype-based therapy for individual cancer patients, providing a strong rationale for clinical trials.
Publication: Gastroenterology 2006 Jun ;130(7)::2145-54.
Publication Date: 2006 Jun
Study Author(s): Gallmeier, Eike;Calhoun, Eric S;Rago, Carlo;Brody, Jonathan R;Cunningham, Steven C;Hucl, Tomas;Gorospe, Myriam;Kohli, Manu;Lengauer, Christoph;Kern, Scott E;
Institution: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland, USA.
Shortcut link to this study:
Publication Date: 2006 Jun
Study Author(s): Gallmeier, Eike;Calhoun, Eric S;Rago, Carlo;Brody, Jonathan R;Cunningham, Steven C;Hucl, Tomas;Gorospe, Myriam;Kohli, Manu;Lengauer, Christoph;Kern, Scott E;
Institution: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland, USA.
Shortcut link to this study:
BACKGROUND & AIMS : How specifically to treat pancreatic and other cancers harboring Fanconi anemia gene mutations has raised great interest recently, yet preclinical studies have been hampered by the lack of well-controlled human cancer models.
METHODS : We endogenously disrupted FANCC and FANCG in a human adenocarcinoma cell line and determined the impact of these genes on drug sensitivity, irradiation sensitivity, and genome maintenance.
RESULTS : FANCC and FANCG disruption abrogated FANCD2 monoubiquitination, confirming an impaired Fanconi anemia pathway function. On treatment with DNA interstrand-cross-linking agents, FANCC and FANCG disruption caused increased clastogenic damage, G2/M arrest, and decreased proliferation. The extent of hypersensitivity varied among agents, with ratios of inhibitory concentration 50% ranging from 2-fold for oxaliplatin to 14-fold for melphalan, a drug infrequently used in solid tumors. No hypersensitivity was observed on gemcitabine, etoposide, 3-aminobenzamide, NU1025, or hydrogen peroxide. FANCC and FANCG disruption also resulted in increased clastogenic damage on irradiation, but only FANCG disruption caused a subsequent decrease in relative survival. Finally, FANCC and FANCG disruption increased spontaneous chromosomal breakage, supporting the role of these genes in genome maintenance and likely explaining why they are mutated in sporadic cancer.
CONCLUSIONS : Our human cancer cell model provides optimal controls to elucidate fundamental biologic features of individual Fanconi anemia gene defects and facilitates preclinical studies of therapeutic options. The impact of Fanconi gene defects on drug and irradiation sensitivity renders these genes promising targets for a specific, genotype-based therapy for individual cancer patients, providing a strong rationale for clinical trials.
METHODS : We endogenously disrupted FANCC and FANCG in a human adenocarcinoma cell line and determined the impact of these genes on drug sensitivity, irradiation sensitivity, and genome maintenance.
RESULTS : FANCC and FANCG disruption abrogated FANCD2 monoubiquitination, confirming an impaired Fanconi anemia pathway function. On treatment with DNA interstrand-cross-linking agents, FANCC and FANCG disruption caused increased clastogenic damage, G2/M arrest, and decreased proliferation. The extent of hypersensitivity varied among agents, with ratios of inhibitory concentration 50% ranging from 2-fold for oxaliplatin to 14-fold for melphalan, a drug infrequently used in solid tumors. No hypersensitivity was observed on gemcitabine, etoposide, 3-aminobenzamide, NU1025, or hydrogen peroxide. FANCC and FANCG disruption also resulted in increased clastogenic damage on irradiation, but only FANCG disruption caused a subsequent decrease in relative survival. Finally, FANCC and FANCG disruption increased spontaneous chromosomal breakage, supporting the role of these genes in genome maintenance and likely explaining why they are mutated in sporadic cancer.
CONCLUSIONS : Our human cancer cell model provides optimal controls to elucidate fundamental biologic features of individual Fanconi anemia gene defects and facilitates preclinical studies of therapeutic options. The impact of Fanconi gene defects on drug and irradiation sensitivity renders these genes promising targets for a specific, genotype-based therapy for individual cancer patients, providing a strong rationale for clinical trials.
PMID: 16762635
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