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char = o;code = 111
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char = ;code = 32
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char = s;code = 115
char = t;code = 116
char = a;code = 97
char = s;code = 115
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char = t;code = 116
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char = l;code = 108
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char = c;code = 99
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char = r;code = 114
char = b;code = 98
char = i;code = 105
char = n;code = 110
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char = t;code = 116
char = r;code = 114
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char = g;code = 103
char = g;code = 103
char = e;code = 101
char = r;code = 114
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char = ;code = 32
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char = ;code = 32
char = C;code = 67
char = D;code = 68
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char = r;code = 114
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char = g;code = 103
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char = t;code = 116
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char = y;code = 121
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char = a;code = 97
char = s;code = 115
char = c;code = 99
char = a;code = 97
char = d;code = 100
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
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 = s;code = 115
char = ;code = 32
char = N;code = 78
char = F;code = 70
char = -;code = 45
char = k;code = 107
char = a;code = 97
char = p;code = 112
char = p;code = 112
char = a;code = 97
char = B;code = 66
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = s;code = 115
char = c;code = 99
char = r;code = 114
char = i;code = 105
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = c;code = 99
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 = i;code = 105
char = n;code = 110
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 = b;code = 98
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = t;code = 116
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 = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = s;code = 115
char = .;code = 46
result sql = Direct inhibition of elastase activity by indole-3-carbinol triggers a CD40-TRAF regulatory cascade that disrupts NF-kappaB transcriptional activity in human breast cancer cells.
Direct inhibition of elastase activity by indole-3-carbinol triggers a CD40-TRAF regulatory cascade that disrupts NF-kappaB transcriptional activity in human breast cancer cells.
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char = m;code = 109
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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 = i;code = 105
char = g;code = 103
char = h;code = 104
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = u;code = 117
char = m;code = 109
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char = r;code = 114
char = i;code = 105
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = M;code = 77
char = D;code = 68
char = A;code = 65
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char = M;code = 77
char = B;code = 66
char = -;code = 45
char = 2;code = 50
char = 3;code = 51
char = 1;code = 49
char = ;code = 32
char = h;code = 104
char = u;code = 117
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char = a;code = 97
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char = e;code = 101
char = a;code = 97
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char = ;code = 32
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char = a;code = 97
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char = c;code = 99
char = e;code = 101
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char = c;code = 99
char = e;code = 101
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char = l;code = 108
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char = -;code = 45
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char = b;code = 98
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char = C;code = 67
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char = d;code = 100
char = i;code = 105
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char = c;code = 99
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char = ;code = 32
char = e;code = 101
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char = l;code = 108
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char = t;code = 116
char = a;code = 97
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char = m;code = 109
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char = s;code = 115
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char = a;code = 97
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char = (;code = 40
char = T;code = 84
char = N;code = 78
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char = );code = 41
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char = a;code = 97
char = B;code = 66
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = s;code = 115
char = c;code = 99
char = r;code = 114
char = i;code = 105
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = f;code = 102
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = a;code = 97
char = c;code = 99
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 = 46
char = ;code = 32
char = B;code = 66
char = e;code = 101
char = c;code = 99
char = a;code = 97
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = T;code = 84
char = R;code = 82
char = A;code = 65
char = F;code = 70
char = 1;code = 49
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = s;code = 115
char = c;code = 99
char = r;code = 114
char = i;code = 105
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = a;code = 97
char = r;code = 114
char = g;code = 103
char = e;code = 101
char = t;code = 116
char = ;code = 32
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = N;code = 78
char = F;code = 70
char = -;code = 45
char = k;code = 107
char = a;code = 97
char = p;code = 112
char = p;code = 112
char = a;code = 97
char = B;code = 66
char = ,;code = 44
char = ;code = 32
char = I;code = 73
char = 3;code = 51
char = C;code = 67
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 = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = e;code = 101
char = e;code = 101
char = d;code = 100
char = b;code = 98
char = a;code = 97
char = c;code = 99
char = k;code = 107
char = ;code = 32
char = l;code = 108
char = o;code = 111
char = o;code = 111
char = p;code = 112
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = v;code = 118
char = o;code = 111
char = l;code = 108
char = v;code = 118
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 = s;code = 115
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = r;code = 114
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
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 = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = o;code = 111
char = n;code = 110
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = R;code = 82
char = N;code = 78
char = A;code = 65
char = ;code = 32
char = a;code = 97
char = b;code = 98
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = k;code = 107
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = I;code = 73
char = 3;code = 51
char = C;code = 67
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 = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = C;code = 67
char = D;code = 68
char = 4;code = 52
char = 0;code = 48
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = c;code = 99
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = G;code = 71
char = (;code = 40
char = 1;code = 49
char = );code = 41
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = ;code = 32
char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
char = e;code = 101
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 = w;code = 119
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = R;code = 82
char = N;code = 78
char = A;code = 65
char = ;code = 32
char = k;code = 107
char = n;code = 110
char = o;code = 111
char = c;code = 99
char = k;code = 107
char = d;code = 100
char = o;code = 111
char = w;code = 119
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = T;code = 84
char = R;code = 82
char = A;code = 65
char = F;code = 70
char = 3;code = 51
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = N;code = 78
char = F;code = 70
char = -;code = 45
char = k;code = 107
char = a;code = 97
char = p;code = 112
char = p;code = 112
char = a;code = 97
char = B;code = 66
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 = ;code = 32
char = I;code = 73
char = k;code = 107
char = a;code = 97
char = p;code = 112
char = p;code = 112
char = a;code = 97
char = B;code = 66
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = I;code = 73
char = 3;code = 51
char = C;code = 67
char = -;code = 45
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = u;code = 117
char = c;code = 99
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = ;code = 32
char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
char = e;code = 101
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 = 46
char = ;code = 32
char = I;code = 73
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = s;code = 115
char = t;code = 116
char = ,;code = 44
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = R;code = 82
char = N;code = 78
char = A;code = 65
char = ;code = 32
char = k;code = 107
char = n;code = 110
char = o;code = 111
char = c;code = 99
char = k;code = 107
char = d;code = 100
char = o;code = 111
char = w;code = 119
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = P;code = 80
char = T;code = 84
char = E;code = 69
char = N;code = 78
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = d;code = 100
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = I;code = 73
char = 3;code = 51
char = C;code = 67
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = N;code = 78
char = F;code = 70
char = -;code = 45
char = k;code = 107
char = a;code = 97
char = p;code = 112
char = p;code = 112
char = a;code = 97
char = B;code = 66
char = ;code = 32
char = a;code = 97
char = c;code = 99
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 = 44
char = ;code = 32
char = s;code = 115
char = h;code = 104
char = o;code = 111
char = w;code = 119
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 = i;code = 105
char = m;code = 109
char = p;code = 112
char = o;code = 111
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = C;code = 67
char = D;code = 68
char = 4;code = 52
char = 0;code = 48
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = g;code = 103
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = g;code = 103
char = u;code = 117
char = l;code = 108
char = a;code = 97
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 = i;code = 105
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = s;code = 115
char = c;code = 99
char = r;code = 114
char = i;code = 105
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = f;code = 102
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = .;code = 46
char = ;code = 32
char = O;code = 79
char = u;code = 117
char = r;code = 114
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = u;code = 117
char = d;code = 100
char = y;code = 121
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 = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = i;code = 105
char = r;code = 114
char = s;code = 115
char = t;code = 116
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = r;code = 114
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = ;code = 32
char = e;code = 101
char = v;code = 118
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = I;code = 73
char = 3;code = 51
char = C;code = 67
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = r;code = 114
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = l;code = 108
char = y;code = 121
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 = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = -;code = 45
char = m;code = 109
char = e;code = 101
char = d;code = 100
char = i;code = 105
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = o;code = 111
char = l;code = 108
char = y;code = 121
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = c;code = 99
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = C;code = 67
char = D;code = 68
char = 4;code = 52
char = 0;code = 48
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = i;code = 105
char = c;code = 99
char = h;code = 104
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = w;code = 119
char = n;code = 110
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = m;code = 109
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = g;code = 103
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = o;code = 111
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 = ;code = 32
char = N;code = 78
char = F;code = 70
char = -;code = 45
char = k;code = 107
char = a;code = 97
char = p;code = 112
char = p;code = 112
char = a;code = 97
char = B;code = 66
char = -;code = 45
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = u;code = 117
char = c;code = 99
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
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 = 32
char = a;code = 97
char = n;code = 110
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 = v;code = 118
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = p;code = 112
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = F;code = 70
char = u;code = 117
char = r;code = 114
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = m;code = 109
char = o;code = 111
char = r;code = 114
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = l;code = 108
char = i;code = 105
char = s;code = 115
char = h;code = 104
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = n;code = 110
char = e;code = 101
char = w;code = 119
char = ;code = 32
char = I;code = 73
char = 3;code = 51
char = C;code = 67
char = -;code = 45
char = m;code = 109
char = e;code = 101
char = d;code = 100
char = i;code = 105
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = i;code = 105
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 = v;code = 118
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = s;code = 115
char = c;code = 99
char = a;code = 97
char = d;code = 100
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = s;code = 115
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result sql = Treatment of highly tumorigenic MDA-MB-231 human breast cancer cells with indole-3-carbinol (I3C) directly inhibited the extracellular elastase-dependent cleavage of membrane-associated CD40, a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 signaling has been implicated in regulating cell survival, apoptosis, and proliferation, as well as in sensitizing breast cancer cells to chemotherapy, and is therefore an important potential target of novel breast cancer treatments. The I3C-dependent accumulation of full-length unprocessed CD40 protein caused a shift in CD40 signaling through TNF receptor-associated factors (TRAF), including the TRAF1/TRAF2 positive regulators and TRAF3 negative regulator of NF-kappaB transcription factor activity. Because TRAF1 is a transcriptional target gene of NF-kappaB, I3C disrupted a positive feedback loop involving these critical cell survival components. siRNA ablation of elastase expression mimicked the I3C inhibition of CD40 protein processing and G(1) cell cycle arrest, whereas siRNA knockdown of TRAF3 and the NF-kappaB inhibitor IkappaB prevented the I3C-induced cell cycle arrest. In contrast, siRNA knockdown of PTEN had no effect on the I3C control of NF-kappaB activity, showing the importance of CD40 signaling in regulating this transcription factor. Our study provides the first direct in vitro evidence that I3C directly inhibits the elastase-mediated proteolytic processing of CD40, which alters downstream signaling to disrupt NF-kappaB-induced cell survival and proliferative responses. Furthermore, we have established a new I3C-mediated antiproliferative cascade that has significant therapeutic potential for treatment of human cancers associated with high levels of elastase and its CD40 membrane substrate.

Publication: Cancer Res. 2010 Jun 15 ;70(12)::4961-71. :doi: 10.1158/0008-5472.CAN-09-3349.
Publication Date: 2010 Jun 15
Study Author(s): Aronchik, Ida;Bjeldanes, Leonard F;Firestone, Gary L;
Institution: Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720-3200, USA.
Shortcut link to this study:
Treatment of highly tumorigenic MDA-MB-231 human breast cancer cells with indole-3-carbinol (I3C) directly inhibited the extracellular elastase-dependent cleavage of membrane-associated CD40, a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 signaling has been implicated in regulating cell survival, apoptosis, and proliferation, as well as in sensitizing breast cancer cells to chemotherapy, and is therefore an important potential target of novel breast cancer treatments. The I3C-dependent accumulation of full-length unprocessed CD40 protein caused a shift in CD40 signaling through TNF receptor-associated factors (TRAF), including the TRAF1/TRAF2 positive regulators and TRAF3 negative regulator of NF-kappaB transcription factor activity. Because TRAF1 is a transcriptional target gene of NF-kappaB, I3C disrupted a positive feedback loop involving these critical cell survival components. siRNA ablation of elastase expression mimicked the I3C inhibition of CD40 protein processing and G(1) cell cycle arrest, whereas siRNA knockdown of TRAF3 and the NF-kappaB inhibitor IkappaB prevented the I3C-induced cell cycle arrest. In contrast, siRNA knockdown of PTEN had no effect on the I3C control of NF-kappaB activity, showing the importance of CD40 signaling in regulating this transcription factor. Our study provides the first direct in vitro evidence that I3C directly inhibits the elastase-mediated proteolytic processing of CD40, which alters downstream signaling to disrupt NF-kappaB-induced cell survival and proliferative responses. Furthermore, we have established a new I3C-mediated antiproliferative cascade that has significant therapeutic potential for treatment of human cancers associated with high levels of elastase and its CD40 membrane substrate.
PMID: 20530686

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