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result sql = Determination of minimum effective dose and optimal dosing schedule for liposomal curcumin in a xenograft human pancreatic cancer model.
Determination of minimum effective dose and optimal dosing schedule for liposomal curcumin in a xenograft human pancreatic cancer model.char = <;code = 60
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char = u;code = 117
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 = f;code = 102
char = e;code = 101
char = m;code = 109
char = a;code = 97
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = n;code = 110
char = u;code = 117
char = d;code = 100
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = j;code = 106
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = b;code = 98
char = c;code = 99
char = u;code = 117
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 = l;code = 108
char = y;code = 121
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = M;code = 77
char = i;code = 105
char = a;code = 97
char = P;code = 80
char = a;code = 97
char = C;code = 67
char = a;code = 97
char = -;code = 45
char = 2;code = 50
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
char = ;code = 32
char = D;code = 68
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = i;code = 105
char = t;code = 116
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 = t;code = 116
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = z;code = 122
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = 5;code = 53
char = m;code = 109
char = m;code = 109
char = .;code = 46
char = ;code = 32
char = F;code = 70
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = M;code = 77
char = E;code = 69
char = D;code = 68
char = ,;code = 44
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
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 = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = l;code = 108
char = l;code = 108
char = o;code = 111
char = w;code = 119
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
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 = o;code = 111
char = f;code = 102
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = p;code = 112
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 = c;code = 99
char = u;code = 117
char = r;code = 114
char = c;code = 99
char = u;code = 117
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = :;code = 58
char = ;code = 32
char = n;code = 110
char = o;code = 111
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 = 44
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = p;code = 112
char = o;code = 111
char = s;code = 115
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = l;code = 108
char = y;code = 121
char = ,;code = 44
char = ;code = 32
char = 1;code = 49
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
char = ,;code = 44
char = ;code = 32
char = 2;code = 50
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
char = ,;code = 44
char = ;code = 32
char = 5;code = 53
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
char = ,;code = 44
char = ;code = 32
char = 1;code = 49
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
char = ,;code = 44
char = ;code = 32
char = 2;code = 50
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = 4;code = 52
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
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 = b;code = 98
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = a;code = 97
char = i;code = 105
char = l;code = 108
char = ;code = 32
char = v;code = 118
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = j;code = 106
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = r;code = 114
char = e;code = 101
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = 2;code = 50
char = 8;code = 56
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = y;code = 121
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = F;code = 70
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = u;code = 117
char = m;code = 109
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = s;code = 115
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = r;code = 114
char = e;code = 101
char = e;code = 101
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 = a;code = 97
char = l;code = 108
char = ;code = 32
char = s;code = 115
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = v;code = 118
char = a;code = 97
char = l;code = 108
char = u;code = 117
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 = d;code = 100
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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 = t;code = 116
char = h;code = 104
char = r;code = 114
char = e;code = 101
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = l;code = 108
char = y;code = 121
char = ;;code = 59
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = i;code = 105
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = (;code = 40
char = f;code = 102
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = y;code = 121
char = s;code = 115
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = u;code = 117
char = r;code = 114
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = y;code = 121
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 = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = 2;code = 50
char = 8;code = 56
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = y;code = 121
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = l;code = 108
char = l;code = 108
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = i;code = 105
char = g;code = 103
char = h;code = 104
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = n;code = 110
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 = ;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 = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = a;code = 97
char = k;code = 107
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = r;code = 114
char = e;code = 101
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = e;code = 101
char = v;code = 118
char = a;code = 97
char = l;code = 108
char = u;code = 117
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = c;code = 99
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = c;code = 99
char = y;code = 121
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 = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = 2;code = 50
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
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char = h;code = 104
char = a;code = 97
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = g;code = 103
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = t;code = 116
char = e;code = 101
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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
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char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
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 = a;code = 97
char = t;code = 116
char = ;code = 32
char = 5;code = 53
char = 2;code = 50
char = %;code = 37
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 = t;code = 116
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
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 = w;code = 119
char = h;code = 104
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = n;code = 110
char = o;code = 111
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 = 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 = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
char = .;code = 46
char = ;code = 32
char = M;code = 77
char = E;code = 69
char = D;code = 68
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
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 = t;code = 116
char = o;code = 111
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = ;code = 32
char = 2;code = 50
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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 = d;code = 100
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = s;code = 115
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = e;code = 101
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 = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = .;code = 46
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result sql = BACKGROUND : Curcumin is a food chemical present in tumeric (Curcuma longa) that has pharmacological activity to suppress carcinogenesis and inhibits multiple signaling pathways such as nuclear factor kappaB (NF-kappaB), cyclooxygenase-2 (Cox-2) and interleukin-8 (IL-8). Oral curcumin has poor oral bioavailability limiting its clinical activity; however, a patent pending liposomal formulation of curcumin was developed to improve drug delivery and has demonstrated activity in multiple cancers. This study was designed to determine the minimum effective dose (MED) as well as the optimal dosing schedule of liposomal curcumin in a xenograft mouse model of human pancreatic cancer.
MATERIALS AND METHODS : The MED determination and optimal schedule was evaluated in female athymic nude mice injected subcutaneously with MiaPaCa-2 cells. Dosing was initiated at an average tumor size of 5mm. For the MED, mice were treated with the following dose levels of liposomal curcumin: no treatment, liposome only, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg given by tail vein injection three times weekly for 28 days. For the optimum dosing schedule, three additional schedules were evaluated and compared to the control of three times weekly; daily (five days per week), every four days, and weekly for 28 days. All mice were weighed and tumor measurements taken three times weekly to evaluate toxicity and efficacy.
RESULTS : The 20 mg/kg dose had the greatest decrease in tumor growth at 52% decrease in tumor growth when compared to no treatment control mice. MED was determined to be 20 mg/kg and was used for the optimal dosing schedule determination. Daily dosing and three times per week dosing had greater inhibition of tumor growth with no discernable difference than once weekly or every 4 day dosing. No toxicity was observed at any dose or schedule.
CONCLUSION : The MED for liposomal curcumin is 20 mg/kg given once daily three times per week to achieve optimal tumor growth inhibition. This was dose recommended for additional preclinical studies to define safety and tolerability of liposomal curcumin in rat and dog models.
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result sql = Determination of minimum effective dose and optimal dosing schedule for liposomal curcumin in a xenograft human pancreatic cancer model.
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char = e;code = 101
char = n;code = 110
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = -;code = 45
char = 2;code = 50
char = ;code = 32
char = (;code = 40
char = C;code = 67
char = o;code = 111
char = x;code = 120
char = -;code = 45
char = 2;code = 50
char = );code = 41
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 = t;code = 116
char = e;code = 101
char = r;code = 114
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = -;code = 45
char = 8;code = 56
char = ;code = 32
char = (;code = 40
char = I;code = 73
char = L;code = 76
char = -;code = 45
char = 8;code = 56
char = );code = 41
char = .;code = 46
char = ;code = 32
char = O;code = 79
char = r;code = 114
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = c;code = 99
char = u;code = 117
char = r;code = 114
char = c;code = 99
char = u;code = 117
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = b;code = 98
char = i;code = 105
char = o;code = 111
char = a;code = 97
char = v;code = 118
char = a;code = 97
char = i;code = 105
char = l;code = 108
char = a;code = 97
char = b;code = 98
char = i;code = 105
char = l;code = 108
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = m;code = 109
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = i;code = 105
char = t;code = 116
char = s;code = 115
char = ;code = 32
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 = 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 = 59
char = ;code = 32
char = h;code = 104
char = o;code = 111
char = w;code = 119
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = p;code = 112
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 = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = u;code = 117
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 = c;code = 99
char = u;code = 117
char = r;code = 114
char = c;code = 99
char = u;code = 117
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = l;code = 108
char = o;code = 111
char = p;code = 112
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = i;code = 105
char = m;code = 109
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = r;code = 114
char = u;code = 117
char = g;code = 103
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = m;code = 109
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
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 = m;code = 109
char = u;code = 117
char = l;code = 108
char = t;code = 116
char = i;code = 105
char = p;code = 112
char = l;code = 108
char = e;code = 101
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 = 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 = w;code = 119
char = a;code = 97
char = s;code = 115
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 = 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 = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = i;code = 105
char = m;code = 109
char = u;code = 117
char = m;code = 109
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 = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = M;code = 77
char = E;code = 69
char = D;code = 68
char = );code = 41
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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 = d;code = 100
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = s;code = 115
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = p;code = 112
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 = c;code = 99
char = u;code = 117
char = r;code = 114
char = c;code = 99
char = u;code = 117
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = x;code = 120
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = g;code = 103
char = r;code = 114
char = a;code = 97
char = f;code = 102
char = t;code = 116
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = u;code = 117
char = s;code = 115
char = e;code = 101
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 = o;code = 111
char = f;code = 102
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 = p;code = 112
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = t;code = 116
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 = M;code = 77
char = A;code = 65
char = T;code = 84
char = E;code = 69
char = R;code = 82
char = I;code = 73
char = A;code = 65
char = L;code = 76
char = S;code = 83
char = ;code = 32
char = A;code = 65
char = N;code = 78
char = D;code = 68
char = ;code = 32
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 = h;code = 104
char = e;code = 101
char = ;code = 32
char = M;code = 77
char = E;code = 69
char = D;code = 68
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 = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
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 = s;code = 115
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = e;code = 101
char = v;code = 118
char = a;code = 97
char = l;code = 108
char = u;code = 117
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 = f;code = 102
char = e;code = 101
char = m;code = 109
char = a;code = 97
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = n;code = 110
char = u;code = 117
char = d;code = 100
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = j;code = 106
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = b;code = 98
char = c;code = 99
char = u;code = 117
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 = l;code = 108
char = y;code = 121
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = M;code = 77
char = i;code = 105
char = a;code = 97
char = P;code = 80
char = a;code = 97
char = C;code = 67
char = a;code = 97
char = -;code = 45
char = 2;code = 50
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
char = ;code = 32
char = D;code = 68
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = i;code = 105
char = t;code = 116
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 = t;code = 116
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = z;code = 122
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = 5;code = 53
char = m;code = 109
char = m;code = 109
char = .;code = 46
char = ;code = 32
char = F;code = 70
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = M;code = 77
char = E;code = 69
char = D;code = 68
char = ,;code = 44
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = e;code = 101
char = a;code = 97
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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 = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = l;code = 108
char = l;code = 108
char = o;code = 111
char = w;code = 119
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
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 = o;code = 111
char = f;code = 102
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = p;code = 112
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 = c;code = 99
char = u;code = 117
char = r;code = 114
char = c;code = 99
char = u;code = 117
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = :;code = 58
char = ;code = 32
char = n;code = 110
char = o;code = 111
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 = 44
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = p;code = 112
char = o;code = 111
char = s;code = 115
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = l;code = 108
char = y;code = 121
char = ,;code = 44
char = ;code = 32
char = 1;code = 49
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
char = ,;code = 44
char = ;code = 32
char = 2;code = 50
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
char = ,;code = 44
char = ;code = 32
char = 5;code = 53
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
char = ,;code = 44
char = ;code = 32
char = 1;code = 49
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
char = ,;code = 44
char = ;code = 32
char = 2;code = 50
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = 4;code = 52
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
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 = b;code = 98
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = a;code = 97
char = i;code = 105
char = l;code = 108
char = ;code = 32
char = v;code = 118
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = j;code = 106
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = r;code = 114
char = e;code = 101
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = 2;code = 50
char = 8;code = 56
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = y;code = 121
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = F;code = 70
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = u;code = 117
char = m;code = 109
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = s;code = 115
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = r;code = 114
char = e;code = 101
char = e;code = 101
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 = a;code = 97
char = l;code = 108
char = ;code = 32
char = s;code = 115
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = v;code = 118
char = a;code = 97
char = l;code = 108
char = u;code = 117
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 = d;code = 100
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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 = t;code = 116
char = h;code = 104
char = r;code = 114
char = e;code = 101
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = l;code = 108
char = y;code = 121
char = ;;code = 59
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = i;code = 105
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = (;code = 40
char = f;code = 102
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = y;code = 121
char = s;code = 115
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = u;code = 117
char = r;code = 114
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = y;code = 121
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 = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = 2;code = 50
char = 8;code = 56
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = y;code = 121
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = l;code = 108
char = l;code = 108
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = i;code = 105
char = g;code = 103
char = h;code = 104
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = n;code = 110
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 = ;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 = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = a;code = 97
char = k;code = 107
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = r;code = 114
char = e;code = 101
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = e;code = 101
char = v;code = 118
char = a;code = 97
char = l;code = 108
char = u;code = 117
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = c;code = 99
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = c;code = 99
char = y;code = 121
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 = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = 2;code = 50
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = g;code = 103
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
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 = t;code = 116
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
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 = a;code = 97
char = t;code = 116
char = ;code = 32
char = 5;code = 53
char = 2;code = 50
char = %;code = 37
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 = t;code = 116
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
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 = w;code = 119
char = h;code = 104
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = n;code = 110
char = o;code = 111
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 = 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 = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
char = .;code = 46
char = ;code = 32
char = M;code = 77
char = E;code = 69
char = D;code = 68
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
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 = t;code = 116
char = o;code = 111
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = ;code = 32
char = 2;code = 50
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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 = d;code = 100
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = s;code = 115
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = e;code = 101
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 = 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 = D;code = 68
char = a;code = 97
char = i;code = 105
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = d;code = 100
char = o;code = 111
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 = t;code = 116
char = h;code = 104
char = r;code = 114
char = e;code = 101
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = d;code = 100
char = ;code = 32
char = g;code = 103
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = r;code = 114
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 = t;code = 116
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
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 = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = s;code = 115
char = c;code = 99
char = e;code = 101
char = r;code = 114
char = n;code = 110
char = a;code = 97
char = b;code = 98
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = r;code = 114
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 = n;code = 110
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = 4;code = 52
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = y;code = 121
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = .;code = 46
char = ;code = 32
char = N;code = 78
char = o;code = 111
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = c;code = 99
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 = a;code = 97
char = t;code = 116
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = y;code = 121
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = s;code = 115
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = e;code = 101
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 = ;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 = h;code = 104
char = e;code = 101
char = ;code = 32
char = M;code = 77
char = E;code = 69
char = D;code = 68
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = p;code = 112
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 = c;code = 99
char = u;code = 117
char = r;code = 114
char = c;code = 99
char = u;code = 117
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = 2;code = 50
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
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 = o;code = 111
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = i;code = 105
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = r;code = 114
char = e;code = 101
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = h;code = 104
char = i;code = 105
char = e;code = 101
char = v;code = 118
char = e;code = 101
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 = t;code = 116
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
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 = 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 = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = c;code = 99
char = o;code = 111
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result sql = BACKGROUND : Curcumin is a food chemical present in tumeric (Curcuma longa) that has pharmacological activity to suppress carcinogenesis and inhibits multiple signaling pathways such as nuclear factor kappaB (NF-kappaB), cyclooxygenase-2 (Cox-2) and interleukin-8 (IL-8). Oral curcumin has poor oral bioavailability limiting its clinical activity; however, a patent pending liposomal formulation of curcumin was developed to improve drug delivery and has demonstrated activity in multiple cancers. This study was designed to determine the minimum effective dose (MED) as well as the optimal dosing schedule of liposomal curcumin in a xenograft mouse model of human pancreatic cancer.
MATERIALS AND METHODS : The MED determination and optimal schedule was evaluated in female athymic nude mice injected subcutaneously with MiaPaCa-2 cells. Dosing was initiated at an average tumor size of 5mm. For the MED, mice were treated with the following dose levels of liposomal curcumin: no treatment, liposome only, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg given by tail vein injection three times weekly for 28 days. For the optimum dosing schedule, three additional schedules were evaluated and compared to the control of three times weekly; daily (five days per week), every four days, and weekly for 28 days. All mice were weighed and tumor measurements taken three times weekly to evaluate toxicity and efficacy.
RESULTS : The 20 mg/kg dose had the greatest decrease in tumor growth at 52% decrease in tumor growth when compared to no treatment control mice. MED was determined to be 20 mg/kg and was used for the optimal dosing schedule determination. Daily dosing and three times per week dosing had greater inhibition of tumor growth with no discernable difference than once weekly or every 4 day dosing. No toxicity was observed at any dose or schedule.
CONCLUSION : The MED for liposomal curcumin is 20 mg/kg given once daily three times per week to achieve optimal tumor growth inhibition. This was dose recommended for additional preclinical studies to define safety and tolerability of liposomal curcumin in rat and dog models.
Publication: Anticancer Res. 2009 Jun ;29(6)::1895-9.
Publication Date: 2009 Jun
Study Author(s): Mach, Claire M;Mathew, Lata;Mosley, Scott A;Kurzrock, Razelle;Smith, Judith A;
Institution: Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1439, U.S.A.
Shortcut link to this study:
Publication Date: 2009 Jun
Study Author(s): Mach, Claire M;Mathew, Lata;Mosley, Scott A;Kurzrock, Razelle;Smith, Judith A;
Institution: Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1439, U.S.A.
Shortcut link to this study:
BACKGROUND : Curcumin is a food chemical present in tumeric (Curcuma longa) that has pharmacological activity to suppress carcinogenesis and inhibits multiple signaling pathways such as nuclear factor kappaB (NF-kappaB), cyclooxygenase-2 (Cox-2) and interleukin-8 (IL-8). Oral curcumin has poor oral bioavailability limiting its clinical activity; however, a patent pending liposomal formulation of curcumin was developed to improve drug delivery and has demonstrated activity in multiple cancers. This study was designed to determine the minimum effective dose (MED) as well as the optimal dosing schedule of liposomal curcumin in a xenograft mouse model of human pancreatic cancer.
MATERIALS AND METHODS : The MED determination and optimal schedule was evaluated in female athymic nude mice injected subcutaneously with MiaPaCa-2 cells. Dosing was initiated at an average tumor size of 5mm. For the MED, mice were treated with the following dose levels of liposomal curcumin: no treatment, liposome only, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg given by tail vein injection three times weekly for 28 days. For the optimum dosing schedule, three additional schedules were evaluated and compared to the control of three times weekly; daily (five days per week), every four days, and weekly for 28 days. All mice were weighed and tumor measurements taken three times weekly to evaluate toxicity and efficacy.
RESULTS : The 20 mg/kg dose had the greatest decrease in tumor growth at 52% decrease in tumor growth when compared to no treatment control mice. MED was determined to be 20 mg/kg and was used for the optimal dosing schedule determination. Daily dosing and three times per week dosing had greater inhibition of tumor growth with no discernable difference than once weekly or every 4 day dosing. No toxicity was observed at any dose or schedule.
CONCLUSION : The MED for liposomal curcumin is 20 mg/kg given once daily three times per week to achieve optimal tumor growth inhibition. This was dose recommended for additional preclinical studies to define safety and tolerability of liposomal curcumin in rat and dog models.
MATERIALS AND METHODS : The MED determination and optimal schedule was evaluated in female athymic nude mice injected subcutaneously with MiaPaCa-2 cells. Dosing was initiated at an average tumor size of 5mm. For the MED, mice were treated with the following dose levels of liposomal curcumin: no treatment, liposome only, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg given by tail vein injection three times weekly for 28 days. For the optimum dosing schedule, three additional schedules were evaluated and compared to the control of three times weekly; daily (five days per week), every four days, and weekly for 28 days. All mice were weighed and tumor measurements taken three times weekly to evaluate toxicity and efficacy.
RESULTS : The 20 mg/kg dose had the greatest decrease in tumor growth at 52% decrease in tumor growth when compared to no treatment control mice. MED was determined to be 20 mg/kg and was used for the optimal dosing schedule determination. Daily dosing and three times per week dosing had greater inhibition of tumor growth with no discernable difference than once weekly or every 4 day dosing. No toxicity was observed at any dose or schedule.
CONCLUSION : The MED for liposomal curcumin is 20 mg/kg given once daily three times per week to achieve optimal tumor growth inhibition. This was dose recommended for additional preclinical studies to define safety and tolerability of liposomal curcumin in rat and dog models.
PMID: 19528445
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