|
|
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result sql = Cerebrospinal fluid matrix metalloproteinase-9 increases during treatment of recurrent malignant gliomas.
Cerebrospinal fluid matrix metalloproteinase-9 increases during treatment of recurrent malignant gliomas.char = <;code = 60
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char = y;code = 121
char = l;code = 108
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = d;code = 100
char = e;code = 101
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char = g;code = 103
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = e;code = 101
char = l;code = 108
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = p;code = 112
char = h;code = 104
char = o;code = 111
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = S;code = 83
char = D;code = 68
char = S;code = 83
char = -;code = 45
char = P;code = 80
char = A;code = 65
char = G;code = 71
char = E;code = 69
char = );code = 41
char = ;code = 32
char = z;code = 122
char = y;code = 121
char = m;code = 109
char = o;code = 111
char = g;code = 103
char = r;code = 114
char = a;code = 97
char = p;code = 112
char = h;code = 104
char = y;code = 121
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char = ;code = 32
char = I;code = 73
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = d;code = 100
char = d;code = 100
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = o;code = 111
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char = ,;code = 44
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = e;code = 101
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char = t;code = 116
char = s;code = 115
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char = u;code = 117
char = n;code = 110
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = w;code = 119
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = l;code = 108
char = u;code = 117
char = m;code = 109
char = b;code = 98
char = a;code = 97
char = r;code = 114
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char = p;code = 112
char = u;code = 117
char = n;code = 110
char = c;code = 99
char = t;code = 116
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = C;code = 67
char = S;code = 83
char = F;code = 70
char = ;code = 32
char = s;code = 115
char = a;code = 97
char = m;code = 109
char = p;code = 112
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = g;code = 103
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char = a;code = 97
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char = ;code = 32
char = b;code = 98
char = a;code = 97
char = s;code = 115
char = e;code = 101
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char = i;code = 105
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char = ;code = 32
char = a;code = 97
char = f;code = 102
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = 6;code = 54
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = s;code = 115
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char = (;code = 40
char = 1;code = 49
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 = 41
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = f;code = 102
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = 1;code = 49
char = 2;code = 50
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = 2;code = 50
char = ;code = 32
char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
char = e;code = 101
char = s;code = 115
char = );code = 41
char = ,;code = 44
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char = w;code = 119
char = h;code = 104
char = i;code = 105
char = l;code = 108
char = e;code = 101
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char = b;code = 98
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = v;code = 118
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = m;code = 109
char = o;code = 111
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 = y;code = 121
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = g;code = 103
char = i;code = 105
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = i;code = 105
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = l;code = 108
char = i;code = 105
char = d;code = 100
char = o;code = 111
char = m;code = 109
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = x;code = 120
char = y;code = 121
char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = e;code = 101
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char = d;code = 100
char = e;code = 101
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char = g;code = 103
char = n;code = 110
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = b;code = 98
char = l;code = 108
char = o;code = 111
char = c;code = 99
char = k;code = 107
char = ;code = 32
char = g;code = 103
char = r;code = 114
char = o;code = 111
char = w;code = 119
char = t;code = 116
char = h;code = 104
char = /;code = 47
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
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char = i;code = 105
char = o;code = 111
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char = ,;code = 44
char = ;code = 32
char = a;code = 97
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char = g;code = 103
char = i;code = 105
char = o;code = 111
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char = e;code = 101
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char = e;code = 101
char = s;code = 115
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char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = a;code = 97
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char = d;code = 100
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char = i;code = 105
char = n;code = 110
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char = a;code = 97
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = .;code = 46
char = ;code = 32
char = I;code = 73
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = g;code = 103
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = 1;code = 49
char = 2;code = 50
char = 5;code = 53
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = m;code = 109
char = 2;code = 50
char = /;code = 47
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = 4;code = 52
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = s;code = 115
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char = i;code = 105
char = n;code = 110
char = ;code = 32
char = 6;code = 54
char = -;code = 45
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
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char = c;code = 99
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char = c;code = 99
char = l;code = 108
char = e;code = 101
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char = ,;code = 44
char = ;code = 32
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char = e;code = 101
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
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char = t;code = 116
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char = c;code = 99
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char = n;code = 110
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char = u;code = 117
char = o;code = 111
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char = s;code = 115
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char = d;code = 100
char = o;code = 111
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char = c;code = 99
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = e;code = 101
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char = a;code = 97
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char = 1;code = 49
char = 0;code = 48
char = 0;code = 48
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char = g;code = 103
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char = d;code = 100
char = a;code = 97
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char = l;code = 108
char = y;code = 121
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char = o;code = 111
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char = ;code = 32
char = D;code = 68
char = a;code = 97
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char = ;code = 32
char = 1;code = 49
char = ;code = 32
char = a;code = 97
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char = d;code = 100
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char = 5;code = 53
char = 0;code = 48
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char = m;code = 109
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = w;code = 119
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char = c;code = 99
char = e;code = 101
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char = d;code = 100
char = a;code = 97
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char = l;code = 108
char = y;code = 121
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char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = f;code = 102
char = t;code = 116
char = e;code = 101
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char = .;code = 46
char = ;code = 32
char = D;code = 68
char = a;code = 97
char = i;code = 105
char = l;code = 108
char = y;code = 121
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char = t;code = 116
char = h;code = 104
char = a;code = 97
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char = i;code = 105
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char = s;code = 115
char = e;code = 101
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char = i;code = 105
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = u;code = 117
char = r;code = 114
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char = c;code = 99
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char = h;code = 104
char = o;code = 111
char = r;code = 114
char = t;code = 116
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char = w;code = 119
char = a;code = 97
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char = 4;code = 52
char = 0;code = 48
char = 0;code = 48
char = ;code = 32
char = m;code = 109
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char = .;code = 46
char = ;code = 32
char = T;code = 84
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = i;code = 105
char = o;code = 111
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char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
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char = m;code = 109
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char = i;code = 105
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char = e;code = 101
char = d;code = 100
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char = b;code = 98
char = y;code = 121
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char = m;code = 109
char = a;code = 97
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char = n;code = 110
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
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char = r;code = 114
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char = s;code = 115
char = o;code = 111
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char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
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char = i;code = 105
char = m;code = 109
char = a;code = 97
char = g;code = 103
char = i;code = 105
char = n;code = 110
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char = ;code = 32
char = (;code = 40
char = M;code = 77
char = R;code = 82
char = I;code = 73
char = );code = 41
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 = R;code = 82
char = E;code = 69
char = S;code = 83
char = U;code = 85
char = L;code = 76
char = T;code = 84
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 = D;code = 68
char = o;code = 111
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char = y;code = 121
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char = y;code = 121
char = l;code = 108
char = i;code = 105
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char = p;code = 112
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char = s;code = 115
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char = M;code = 77
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char = -;code = 45
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char = a;code = 97
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char = 5;code = 53
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char = g;code = 103
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char = w;code = 119
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char = i;code = 105
char = l;code = 108
char = e;code = 101
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char = t;code = 116
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char = e;code = 101
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char = a;code = 97
char = s;code = 115
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char = o;code = 111
char = n;code = 110
char = l;code = 108
char = y;code = 121
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char = 3;code = 51
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char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 5;code = 53
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char = %;code = 37
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char = i;code = 105
char = n;code = 110
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char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
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char = o;code = 111
char = n;code = 110
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = M;code = 77
char = M;code = 77
char = P;code = 80
char = -;code = 45
char = 2;code = 50
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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 = F;code = 70
char = o;code = 111
char = u;code = 117
char = r;code = 114
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = e;code = 101
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char = t;code = 116
char = s;code = 115
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char = r;code = 114
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char = s;code = 115
char = p;code = 112
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = l;code = 108
char = y;code = 121
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char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = l;code = 108
char = e;code = 101
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = 4;code = 52
char = ,;code = 44
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char = 3;code = 51
char = ,;code = 44
char = ;code = 32
char = 1;code = 49
char = ,;code = 44
char = ;code = 32
char = a;code = 97
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char = d;code = 100
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char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
char = e;code = 101
char = s;code = 115
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = i;code = 105
char = r;code = 114
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char = n;code = 110
char = o;code = 111
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char = e;code = 101
char = c;code = 99
char = a;code = 97
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char = ;code = 32
char = t;code = 116
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char = a;code = 97
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char = i;code = 105
char = d;code = 100
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char = m;code = 109
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = a;code = 97
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char = d;code = 100
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char = d;code = 100
char = o;code = 111
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char = y;code = 121
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char = c;code = 99
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = .;code = 46
char = ;code = 32
char = P;code = 80
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = e;code = 101
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char = t;code = 116
char = ;code = 32
char = e;code = 101
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char = r;code = 114
char = o;code = 111
char = l;code = 108
char = l;code = 108
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
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result sql = BACKGROUND : Matrix metalloproteinases (MMPs) are enzymes that promote tumor invasion and angiogenesis by enzymatically remodeling the extracellular matrix. MMP-2 and MMP-9 are the most abundant forms of MMPs in malignant gliomas, while a 130 kDa MMP is thought to be MMP-9 complexed to other proteinases. This study determined whether doxycycline can block MMP activity in vitro. We also measured MMP-2 and MMP-9 levels in cerebrospinal fluid (CSF) from patients with recurrent malignant gliomas.
METHODS : To determine whether doxycycline can block MMP activity, we measured the extent of doxycyline-mediated MMP-2 and MMP-9 inhibition in vitro using epidermal growth factor receptor (EGFR) transfected U251 glioma cell lines. MMP activity was measured using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) zymography. In addition, patients underwent lumbar puncture for CSF sampling at baseline, after 6 weeks (1 cycle), and after 12 weeks (2 cycles), while being treated with a novel chemotherapy regimen of irinotecan, thalidomide, and doxycycline designed to block growth/proliferation, angiogenesis, and invasion. Irinotecan was given at 125 mg/m2/week for 4 weeks in 6-week cycles, together with continuous doxycycline at 100 mg twice daily on Day 1 and 50 mg twice daily thereafter. Daily thalidomide dose in our cohort was 400 mg. Tumor progression was monitored by magnetic resonance imaging (MRI).
RESULTS : Doxycyline in vitro completely abolished MMP-9 activity at 500 mug/ml while there was only 30 to 50% inhibition of MMP-2 activity. Four patients respectively completed 4, 3, 1, and 2 cycles of irinotecan, thalidomide, and doxycycline. Patient enrollment was terminated after one patient developed radiologically defined pulmonary embolism, and another had probable pulmonary embolism. Although CSF MMP-2 and 130 kDa MMP levels were stable, MMP-9 level progressively increased during treatment despite stable MRI.
CONCLUSION : Doxycycline can block MMP-2 and MMP-9 activities from glioma cells in vitro. Increased CSF MMP-9 activity could be a biomarker of disease activity in patients with malignant gliomas, before any changes are detectable on MRI.
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result sql = Cerebrospinal fluid matrix metalloproteinase-9 increases during treatment of recurrent malignant gliomas.
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char = k;code = 107
char = D;code = 68
char = a;code = 97
char = ;code = 32
char = M;code = 77
char = M;code = 77
char = P;code = 80
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = o;code = 111
char = u;code = 117
char = g;code = 103
char = h;code = 104
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = ;code = 32
char = M;code = 77
char = M;code = 77
char = P;code = 80
char = -;code = 45
char = 9;code = 57
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = l;code = 108
char = e;code = 101
char = x;code = 120
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = o;code = 111
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
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 = a;code = 97
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = i;code = 105
char = s;code = 115
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 = d;code = 100
char = e;code = 101
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = x;code = 120
char = y;code = 121
char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = b;code = 98
char = l;code = 108
char = o;code = 111
char = c;code = 99
char = k;code = 107
char = ;code = 32
char = M;code = 77
char = M;code = 77
char = P;code = 80
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 = v;code = 118
char = i;code = 105
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = .;code = 46
char = ;code = 32
char = W;code = 87
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = o;code = 111
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = M;code = 77
char = M;code = 77
char = P;code = 80
char = -;code = 45
char = 2;code = 50
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = M;code = 77
char = M;code = 77
char = P;code = 80
char = -;code = 45
char = 9;code = 57
char = ;code = 32
char = l;code = 108
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = l;code = 108
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = b;code = 98
char = r;code = 114
char = o;code = 111
char = s;code = 115
char = p;code = 112
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = f;code = 102
char = l;code = 108
char = u;code = 117
char = i;code = 105
char = d;code = 100
char = ;code = 32
char = (;code = 40
char = C;code = 67
char = S;code = 83
char = F;code = 70
char = );code = 41
char = ;code = 32
char = f;code = 102
char = r;code = 114
char = o;code = 111
char = m;code = 109
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
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 = e;code = 101
char = c;code = 99
char = u;code = 117
char = r;code = 114
char = r;code = 114
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = l;code = 108
char = i;code = 105
char = g;code = 103
char = n;code = 110
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = g;code = 103
char = l;code = 108
char = i;code = 105
char = o;code = 111
char = m;code = 109
char = a;code = 97
char = s;code = 115
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 = M;code = 77
char = E;code = 69
char = T;code = 84
char = H;code = 72
char = O;code = 79
char = D;code = 68
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 = T;code = 84
char = o;code = 111
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = x;code = 120
char = y;code = 121
char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = b;code = 98
char = l;code = 108
char = o;code = 111
char = c;code = 99
char = k;code = 107
char = ;code = 32
char = M;code = 77
char = M;code = 77
char = P;code = 80
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 = w;code = 119
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = u;code = 117
char = r;code = 114
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 = 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 = d;code = 100
char = o;code = 111
char = x;code = 120
char = y;code = 121
char = c;code = 99
char = y;code = 121
char = l;code = 108
char = i;code = 105
char = n;code = 110
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 = M;code = 77
char = M;code = 77
char = P;code = 80
char = -;code = 45
char = 2;code = 50
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = M;code = 77
char = M;code = 77
char = P;code = 80
char = -;code = 45
char = 9;code = 57
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 = 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 = u;code = 117
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = e;code = 101
char = p;code = 112
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = g;code = 103
char = r;code = 114
char = o;code = 111
char = w;code = 119
char = t;code = 116
char = h;code = 104
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 = r;code = 114
char = e;code = 101
char = c;code = 99
char = e;code = 101
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = (;code = 40
char = E;code = 69
char = G;code = 71
char = F;code = 70
char = R;code = 82
char = );code = 41
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = s;code = 115
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = U;code = 85
char = 2;code = 50
char = 5;code = 53
char = 1;code = 49
char = ;code = 32
char = g;code = 103
char = l;code = 108
char = i;code = 105
char = o;code = 111
char = m;code = 109
char = a;code = 97
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = M;code = 77
char = M;code = 77
char = P;code = 80
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 = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = u;code = 117
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = s;code = 115
char = o;code = 111
char = d;code = 100
char = i;code = 105
char = u;code = 117
char = m;code = 109
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = c;code = 99
char = y;code = 121
char = l;code = 108
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = l;code = 108
char = f;code = 102
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = -;code = 45
char = p;code = 112
char = o;code = 111
char = l;code = 108
char = y;code = 121
char = a;code = 97
char = c;code = 99
char = r;code = 114
char = y;code = 121
char = l;code = 108
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = ;code = 32
char = g;code = 103
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = e;code = 101
char = l;code = 108
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = p;code = 112
char = h;code = 104
char = o;code = 111
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = S;code = 83
char = D;code = 68
char = S;code = 83
char = -;code = 45
char = P;code = 80
char = A;code = 65
char = G;code = 71
char = E;code = 69
char = );code = 41
char = ;code = 32
char = z;code = 122
char = y;code = 121
char = m;code = 109
char = o;code = 111
char = g;code = 103
char = r;code = 114
char = a;code = 97
char = p;code = 112
char = h;code = 104
char = y;code = 121
char = .;code = 46
char = ;code = 32
char = I;code = 73
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = d;code = 100
char = d;code = 100
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ,;code = 44
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = u;code = 117
char = n;code = 110
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = w;code = 119
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = l;code = 108
char = u;code = 117
char = m;code = 109
char = b;code = 98
char = a;code = 97
char = r;code = 114
char = ;code = 32
char = p;code = 112
char = u;code = 117
char = n;code = 110
char = c;code = 99
char = t;code = 116
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = C;code = 67
char = S;code = 83
char = F;code = 70
char = ;code = 32
char = s;code = 115
char = a;code = 97
char = m;code = 109
char = p;code = 112
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = b;code = 98
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = f;code = 102
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = 6;code = 54
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = 1;code = 49
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 = 41
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = f;code = 102
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = 1;code = 49
char = 2;code = 50
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = 2;code = 50
char = ;code = 32
char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
char = e;code = 101
char = s;code = 115
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = i;code = 105
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = v;code = 118
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = m;code = 109
char = o;code = 111
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 = y;code = 121
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = g;code = 103
char = i;code = 105
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = i;code = 105
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = l;code = 108
char = i;code = 105
char = d;code = 100
char = o;code = 111
char = m;code = 109
char = i;code = 105
char = d;code = 100
char = e;code = 101
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 = o;code = 111
char = x;code = 120
char = y;code = 121
char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = s;code = 115
char = i;code = 105
char = g;code = 103
char = n;code = 110
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = b;code = 98
char = l;code = 108
char = o;code = 111
char = c;code = 99
char = k;code = 107
char = ;code = 32
char = g;code = 103
char = r;code = 114
char = o;code = 111
char = w;code = 119
char = t;code = 116
char = h;code = 104
char = /;code = 47
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 = 44
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = g;code = 103
char = i;code = 105
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = e;code = 101
char = s;code = 115
char = i;code = 105
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = v;code = 118
char = a;code = 97
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = .;code = 46
char = ;code = 32
char = I;code = 73
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = c;code = 99
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char = a;code = 97
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char = 1;code = 49
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char = m;code = 109
char = 2;code = 50
char = /;code = 47
char = w;code = 119
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char = e;code = 101
char = k;code = 107
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char = f;code = 102
char = o;code = 111
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char = ;code = 32
char = 4;code = 52
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = s;code = 115
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char = i;code = 105
char = n;code = 110
char = ;code = 32
char = 6;code = 54
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char = w;code = 119
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char = e;code = 101
char = k;code = 107
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char = c;code = 99
char = l;code = 108
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char = e;code = 101
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
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char = w;code = 119
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char = t;code = 116
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char = n;code = 110
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = u;code = 117
char = o;code = 111
char = u;code = 117
char = s;code = 115
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char = d;code = 100
char = o;code = 111
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char = y;code = 121
char = c;code = 99
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = e;code = 101
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char = a;code = 97
char = t;code = 116
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char = 1;code = 49
char = 0;code = 48
char = 0;code = 48
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char = m;code = 109
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char = t;code = 116
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char = a;code = 97
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char = 1;code = 49
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char = d;code = 100
char = a;code = 97
char = i;code = 105
char = l;code = 108
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char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = f;code = 102
char = t;code = 116
char = e;code = 101
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char = .;code = 46
char = ;code = 32
char = D;code = 68
char = a;code = 97
char = i;code = 105
char = l;code = 108
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char = t;code = 116
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char = a;code = 97
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char = i;code = 105
char = d;code = 100
char = o;code = 111
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char = d;code = 100
char = e;code = 101
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char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
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char = i;code = 105
char = n;code = 110
char = ;code = 32
char = o;code = 111
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char = r;code = 114
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char = c;code = 99
char = o;code = 111
char = h;code = 104
char = o;code = 111
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char = t;code = 116
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char = w;code = 119
char = a;code = 97
char = s;code = 115
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char = 4;code = 52
char = 0;code = 48
char = 0;code = 48
char = ;code = 32
char = m;code = 109
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char = .;code = 46
char = ;code = 32
char = T;code = 84
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = i;code = 105
char = o;code = 111
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char = w;code = 119
char = a;code = 97
char = s;code = 115
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char = m;code = 109
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char = o;code = 111
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char = d;code = 100
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char = b;code = 98
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char = m;code = 109
char = a;code = 97
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char = n;code = 110
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
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char = r;code = 114
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char = s;code = 115
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
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char = i;code = 105
char = m;code = 109
char = a;code = 97
char = g;code = 103
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = (;code = 40
char = M;code = 77
char = R;code = 82
char = I;code = 73
char = );code = 41
char = .;code = 46
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
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char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = >;code = 62
char = R;code = 82
char = E;code = 69
char = S;code = 83
char = U;code = 85
char = L;code = 76
char = T;code = 84
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 = D;code = 68
char = o;code = 111
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char = y;code = 121
char = l;code = 108
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char = e;code = 101
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char = i;code = 105
char = n;code = 110
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char = v;code = 118
char = i;code = 105
char = t;code = 116
char = r;code = 114
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char = c;code = 99
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char = m;code = 109
char = p;code = 112
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char = e;code = 101
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char = e;code = 101
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char = a;code = 97
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char = o;code = 111
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char = i;code = 105
char = s;code = 115
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char = e;code = 101
char = d;code = 100
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char = M;code = 77
char = M;code = 77
char = P;code = 80
char = -;code = 45
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char = a;code = 97
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char = t;code = 116
char = i;code = 105
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char = i;code = 105
char = t;code = 116
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char = a;code = 97
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char = ;code = 32
char = 5;code = 53
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char = 0;code = 48
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char = g;code = 103
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char = w;code = 119
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char = i;code = 105
char = l;code = 108
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char = e;code = 101
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char = a;code = 97
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char = 5;code = 53
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char = i;code = 105
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char = f;code = 102
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char = M;code = 77
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char = a;code = 97
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char = i;code = 105
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char = ,;code = 44
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char = ,;code = 44
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char = P;code = 80
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char = l;code = 108
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char = a;code = 97
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char = C;code = 67
char = S;code = 83
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char = M;code = 77
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char = .;code = 46
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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 = ;code = 32
char = :;code = 58
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char = <;code = 60
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char = >;code = 62
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char = c;code = 99
char = k;code = 107
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char = M;code = 77
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char = -;code = 45
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char = i;code = 105
char = n;code = 110
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char = v;code = 118
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result sql = BACKGROUND : Matrix metalloproteinases (MMPs) are enzymes that promote tumor invasion and angiogenesis by enzymatically remodeling the extracellular matrix. MMP-2 and MMP-9 are the most abundant forms of MMPs in malignant gliomas, while a 130 kDa MMP is thought to be MMP-9 complexed to other proteinases. This study determined whether doxycycline can block MMP activity in vitro. We also measured MMP-2 and MMP-9 levels in cerebrospinal fluid (CSF) from patients with recurrent malignant gliomas.
METHODS : To determine whether doxycycline can block MMP activity, we measured the extent of doxycyline-mediated MMP-2 and MMP-9 inhibition in vitro using epidermal growth factor receptor (EGFR) transfected U251 glioma cell lines. MMP activity was measured using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) zymography. In addition, patients underwent lumbar puncture for CSF sampling at baseline, after 6 weeks (1 cycle), and after 12 weeks (2 cycles), while being treated with a novel chemotherapy regimen of irinotecan, thalidomide, and doxycycline designed to block growth/proliferation, angiogenesis, and invasion. Irinotecan was given at 125 mg/m2/week for 4 weeks in 6-week cycles, together with continuous doxycycline at 100 mg twice daily on Day 1 and 50 mg twice daily thereafter. Daily thalidomide dose in our cohort was 400 mg. Tumor progression was monitored by magnetic resonance imaging (MRI).
RESULTS : Doxycyline in vitro completely abolished MMP-9 activity at 500 mug/ml while there was only 30 to 50% inhibition of MMP-2 activity. Four patients respectively completed 4, 3, 1, and 2 cycles of irinotecan, thalidomide, and doxycycline. Patient enrollment was terminated after one patient developed radiologically defined pulmonary embolism, and another had probable pulmonary embolism. Although CSF MMP-2 and 130 kDa MMP levels were stable, MMP-9 level progressively increased during treatment despite stable MRI.
CONCLUSION : Doxycycline can block MMP-2 and MMP-9 activities from glioma cells in vitro. Increased CSF MMP-9 activity could be a biomarker of disease activity in patients with malignant gliomas, before any changes are detectable on MRI.
Publication: Cerebrospinal Fluid Res 2008 ;5:1. :doi: 10.1186/1743-8454-5-1.
Publication Date: 2008
Study Author(s): Wong, Eric T;Alsop, David;Lee, Diana;Tam, Angela;Barron, Loretta;Bloom, Julianne;Gautam, Shiva;Wu, Julian K;
Institution: Beth Israel Deaconess Medical Center, Brain Tumor Center & Neuro-Oncology Unit, Boston, MA 02215, USA. ewong@bidmc.harvard.edu.
Shortcut link to this study:
Publication Date: 2008
Study Author(s): Wong, Eric T;Alsop, David;Lee, Diana;Tam, Angela;Barron, Loretta;Bloom, Julianne;Gautam, Shiva;Wu, Julian K;
Institution: Beth Israel Deaconess Medical Center, Brain Tumor Center & Neuro-Oncology Unit, Boston, MA 02215, USA. ewong@bidmc.harvard.edu.
Shortcut link to this study:
BACKGROUND : Matrix metalloproteinases (MMPs) are enzymes that promote tumor invasion and angiogenesis by enzymatically remodeling the extracellular matrix. MMP-2 and MMP-9 are the most abundant forms of MMPs in malignant gliomas, while a 130 kDa MMP is thought to be MMP-9 complexed to other proteinases. This study determined whether doxycycline can block MMP activity in vitro. We also measured MMP-2 and MMP-9 levels in cerebrospinal fluid (CSF) from patients with recurrent malignant gliomas.
METHODS : To determine whether doxycycline can block MMP activity, we measured the extent of doxycyline-mediated MMP-2 and MMP-9 inhibition in vitro using epidermal growth factor receptor (EGFR) transfected U251 glioma cell lines. MMP activity was measured using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) zymography. In addition, patients underwent lumbar puncture for CSF sampling at baseline, after 6 weeks (1 cycle), and after 12 weeks (2 cycles), while being treated with a novel chemotherapy regimen of irinotecan, thalidomide, and doxycycline designed to block growth/proliferation, angiogenesis, and invasion. Irinotecan was given at 125 mg/m2/week for 4 weeks in 6-week cycles, together with continuous doxycycline at 100 mg twice daily on Day 1 and 50 mg twice daily thereafter. Daily thalidomide dose in our cohort was 400 mg. Tumor progression was monitored by magnetic resonance imaging (MRI).
RESULTS : Doxycyline in vitro completely abolished MMP-9 activity at 500 mug/ml while there was only 30 to 50% inhibition of MMP-2 activity. Four patients respectively completed 4, 3, 1, and 2 cycles of irinotecan, thalidomide, and doxycycline. Patient enrollment was terminated after one patient developed radiologically defined pulmonary embolism, and another had probable pulmonary embolism. Although CSF MMP-2 and 130 kDa MMP levels were stable, MMP-9 level progressively increased during treatment despite stable MRI.
CONCLUSION : Doxycycline can block MMP-2 and MMP-9 activities from glioma cells in vitro. Increased CSF MMP-9 activity could be a biomarker of disease activity in patients with malignant gliomas, before any changes are detectable on MRI.
METHODS : To determine whether doxycycline can block MMP activity, we measured the extent of doxycyline-mediated MMP-2 and MMP-9 inhibition in vitro using epidermal growth factor receptor (EGFR) transfected U251 glioma cell lines. MMP activity was measured using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) zymography. In addition, patients underwent lumbar puncture for CSF sampling at baseline, after 6 weeks (1 cycle), and after 12 weeks (2 cycles), while being treated with a novel chemotherapy regimen of irinotecan, thalidomide, and doxycycline designed to block growth/proliferation, angiogenesis, and invasion. Irinotecan was given at 125 mg/m2/week for 4 weeks in 6-week cycles, together with continuous doxycycline at 100 mg twice daily on Day 1 and 50 mg twice daily thereafter. Daily thalidomide dose in our cohort was 400 mg. Tumor progression was monitored by magnetic resonance imaging (MRI).
RESULTS : Doxycyline in vitro completely abolished MMP-9 activity at 500 mug/ml while there was only 30 to 50% inhibition of MMP-2 activity. Four patients respectively completed 4, 3, 1, and 2 cycles of irinotecan, thalidomide, and doxycycline. Patient enrollment was terminated after one patient developed radiologically defined pulmonary embolism, and another had probable pulmonary embolism. Although CSF MMP-2 and 130 kDa MMP levels were stable, MMP-9 level progressively increased during treatment despite stable MRI.
CONCLUSION : Doxycycline can block MMP-2 and MMP-9 activities from glioma cells in vitro. Increased CSF MMP-9 activity could be a biomarker of disease activity in patients with malignant gliomas, before any changes are detectable on MRI.
PMID: 18186943
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