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result sql = Extracellular zinc and zinc-citrate, acting through a putative zinc-sensing receptor, regulate growth and survival of prostate cancer cells.
Extracellular zinc and zinc-citrate, acting through a putative zinc-sensing receptor, regulate growth and survival of prostate cancer cells.
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char = n;code = 110
char = s;code = 115
char = e;code = 101
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 = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = G;code = 71
char = a;code = 97
char = l;code = 108
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = q;code = 113
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = o;code = 111
char = s;code = 115
char = p;code = 112
char = h;code = 104
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = p;code = 112
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = C;code = 67
char = ;code = 32
char = (;code = 40
char = P;code = 80
char = L;code = 76
char = C;code = 67
char = );code = 41
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = s;code = 115
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 = b;code = 98
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = r;code = 114
char = ;code = 32
char = C;code = 67
char = a;code = 97
char = (;code = 40
char = 2;code = 50
char = +;code = 43
char = );code = 41
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = p;code = 112
char = l;code = 108
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ,;code = 44
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = i;code = 105
char = t;code = 116
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
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 = b;code = 98
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = G;code = 71
char = q;code = 113
char = -;code = 45
char = c;code = 99
char = o;code = 111
char = u;code = 117
char = p;code = 112
char = l;code = 108
char = e;code = 101
char = d;code = 100
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 = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = t;code = 116
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = o;code = 111
char = s;code = 115
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = I;code = 73
char = P;code = 80
char = (;code = 40
char = 3;code = 51
char = );code = 41
char = );code = 41
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = h;code = 104
char = w;code = 119
char = a;code = 97
char = y;code = 121
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = v;code = 118
char = i;code = 105
char = o;code = 111
char = u;code = 117
char = s;code = 115
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = i;code = 105
char = f;code = 102
char = i;code = 105
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = z;code = 122
char = i;code = 105
char = n;code = 110
char = c;code = 99
char = -;code = 45
char = s;code = 115
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
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 = Z;code = 90
char = n;code = 110
char = R;code = 82
char = );code = 41
char = .;code = 46
char = ;code = 32
char = Z;code = 90
char = n;code = 110
char = (;code = 40
char = 2;code = 50
char = +;code = 43
char = );code = 41
char = -;code = 45
char = d;code = 100
char = e;code = 101
char = p;code = 112
char = e;code = 101
char = n;code = 110
char = d;code = 100
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = r;code = 114
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = g;code = 103
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = -;code = 45
char = r;code = 114
char = e;code = 101
char = g;code = 103
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = A;code = 65
char = K;code = 75
char = T;code = 84
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
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 = 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 = e;code = 101
char = n;code = 110
char = h;code = 104
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = Z;code = 90
char = n;code = 110
char = (;code = 40
char = 2;code = 50
char = +;code = 43
char = );code = 41
char = -;code = 45
char = d;code = 100
char = e;code = 101
char = p;code = 112
char = e;code = 101
char = n;code = 110
char = d;code = 100
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
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 = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = v;code = 118
char = i;code = 105
char = v;code = 118
char = a;code = 97
char = l;code = 108
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
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 = i;code = 105
char = n;code = 110
char = ;code = 32
char = P;code = 80
char = C;code = 67
char = -;code = 45
char = 3;code = 51
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 = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = ;code = 32
char = Z;code = 90
char = n;code = 110
char = R;code = 82
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 = b;code = 98
char = u;code = 117
char = t;code = 116
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = t;code = 116
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = Z;code = 90
char = n;code = 110
char = R;code = 82
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 = 45
char = d;code = 100
char = e;code = 101
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = i;code = 105
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = P;code = 80
char = C;code = 67
char = -;code = 45
char = 3;code = 51
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = b;code = 98
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = .;code = 46
char = ;code = 32
char = I;code = 73
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = l;code = 108
char = y;code = 121
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = p;code = 112
char = p;code = 112
char = l;code = 108
char = i;code = 105
char = c;code = 99
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 = Z;code = 90
char = n;code = 110
char = (;code = 40
char = 2;code = 50
char = +;code = 43
char = );code = 41
char = -;code = 45
char = c;code = 99
char = i;code = 105
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = Z;code = 90
char = n;code = 110
char = (;code = 40
char = 2;code = 50
char = +;code = 43
char = );code = 41
char = C;code = 67
char = i;code = 105
char = t;code = 116
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = y;code = 121
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = l;code = 108
char = o;code = 111
char = g;code = 103
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
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 = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = f;code = 102
char = o;code = 111
char = u;code = 117
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = f;code = 102
char = u;code = 117
char = n;code = 110
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = s;code = 115
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = z;code = 122
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = r;code = 114
char = ;code = 32
char = Z;code = 90
char = n;code = 110
char = (;code = 40
char = 2;code = 50
char = +;code = 43
char = );code = 41
char = -;code = 45
char = d;code = 100
char = e;code = 101
char = p;code = 112
char = e;code = 101
char = n;code = 110
char = d;code = 100
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = g;code = 103
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = u;code = 117
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 = Z;code = 90
char = n;code = 110
char = (;code = 40
char = 2;code = 50
char = +;code = 43
char = );code = 41
char = -;code = 45
char = d;code = 100
char = e;code = 101
char = p;code = 112
char = e;code = 101
char = n;code = 110
char = d;code = 100
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
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 = 46
char = ;code = 32
char = O;code = 79
char = u;code = 117
char = r;code = 114
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = u;code = 117
char = l;code = 108
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = r;code = 114
char = ;code = 32
char = Z;code = 90
char = n;code = 110
char = (;code = 40
char = 2;code = 50
char = +;code = 43
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = Z;code = 90
char = n;code = 110
char = (;code = 40
char = 2;code = 50
char = +;code = 43
char = );code = 41
char = C;code = 67
char = i;code = 105
char = t;code = 116
char = ,;code = 44
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = i;code = 105
char = g;code = 103
char = g;code = 103
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = s;code = 115
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = z;code = 122
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = Z;code = 90
char = n;code = 110
char = R;code = 82
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 = d;code = 100
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = c;code = 99
char = t;code = 116
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = g;code = 103
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = t;code = 116
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
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result sql = Prostate Zn(2+) concentrations are among the highest in the body, and a marked decrease in the level of this ion is observed in prostate cancer. Extracellular Zn(2+) is known to regulate cell survival and proliferation in numerous tissues. In spite of this, a signaling role for extracellular Zn(2+) in prostate cancer has not been established. In the present study, we demonstrate that prostate metastatic cells are impermeable to Zn(2+), but extracellular Zn(2+) triggers a metabotropic Ca(2+) rise that is also apparent in the presence of citrate. Employing fluorescent imaging, we measured this activity in androgen-insensitive metastatic human cell lines, PC-3 and DU-145, and in mouse prostate tumor TRAMP-1 cells but not in androgen-sensitive LNCaP cells. The Ca(2+) response was inhibited by Galphaq and phospholipase C (PLC) inhibitors as well as by intracellular Ca(2+) store depletion, indicating that it is mediated by a Gq-coupled receptor that activates the inositol phosphate (IP(3)) pathway consistent with the previously identified zinc-sensing receptor (ZnR). Zn(2+)-dependent extracellular signal-regulated kinase and AKT activation, as well as enhanced Zn(2+)-dependent cell growth and survival, were observed in PC-3 cells that exhibit ZnR activity, but not in a ZnR activity-deficient PC-3 subline. Interestingly, application of Zn(2+)-citrate (Zn(2+)Cit), at physiological concentrations, was followed by a profound functional desensitization of extracellular Zn(2+)-dependent signaling and attenuation of Zn(2+)-dependent cell growth. Our results indicate that extracellular Zn(2+) and Zn(2+)Cit, by triggering or desensitizing ZnR activity, distinctly regulate prostate cancer cell growth. Thus, therapeutic strategies based either on Zn(2+) chelation or administration of Zn(2+)Cit may be effective in attenuating prostate tumor growth.

Publication: Carcinogenesis 2008 Sep ;29(9)::1692-700. :doi: 10.1093/carcin/bgn027.
Publication Date: 2008 Sep
Study Author(s): Dubi, Noga;Gheber, Larisa;Fishman, Daniel;Sekler, Israel;Hershfinkel, Michal;
Institution: Department of Morphology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University, PO Box 653, Beer Sheva 84105, Israel.
Shortcut link to this study:
Prostate Zn(2+) concentrations are among the highest in the body, and a marked decrease in the level of this ion is observed in prostate cancer. Extracellular Zn(2+) is known to regulate cell survival and proliferation in numerous tissues. In spite of this, a signaling role for extracellular Zn(2+) in prostate cancer has not been established. In the present study, we demonstrate that prostate metastatic cells are impermeable to Zn(2+), but extracellular Zn(2+) triggers a metabotropic Ca(2+) rise that is also apparent in the presence of citrate. Employing fluorescent imaging, we measured this activity in androgen-insensitive metastatic human cell lines, PC-3 and DU-145, and in mouse prostate tumor TRAMP-1 cells but not in androgen-sensitive LNCaP cells. The Ca(2+) response was inhibited by Galphaq and phospholipase C (PLC) inhibitors as well as by intracellular Ca(2+) store depletion, indicating that it is mediated by a Gq-coupled receptor that activates the inositol phosphate (IP(3)) pathway consistent with the previously identified zinc-sensing receptor (ZnR). Zn(2+)-dependent extracellular signal-regulated kinase and AKT activation, as well as enhanced Zn(2+)-dependent cell growth and survival, were observed in PC-3 cells that exhibit ZnR activity, but not in a ZnR activity-deficient PC-3 subline. Interestingly, application of Zn(2+)-citrate (Zn(2+)Cit), at physiological concentrations, was followed by a profound functional desensitization of extracellular Zn(2+)-dependent signaling and attenuation of Zn(2+)-dependent cell growth. Our results indicate that extracellular Zn(2+) and Zn(2+)Cit, by triggering or desensitizing ZnR activity, distinctly regulate prostate cancer cell growth. Thus, therapeutic strategies based either on Zn(2+) chelation or administration of Zn(2+)Cit may be effective in attenuating prostate tumor growth.
PMID: 18310092

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