dynamic-contrast-enhanced-magnetic-resonance-imaging-an-orthotopic

Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been limitedly used for orthotopic pancreatic tumor xenografts due to severe ...

University of Alabama at Birmingham

The selectins, along with very late antigen-4 and CD44, have been implicated in mediating leukocyte rolling interactions that lead to joint recruitment and inflammation during the pathogenesis of rheumatoid arthritis. Previously, we showed that P-selectin deficiency in mice resulted in accelerated onset of joint inflammation in the murine collagen-immunized arthritis model. Here, we report that mice deficient either in E-selectin or in E-selectin and P-selectin (E/P-selectin mutant) also exhibit accelerated development of arthritis compared with wild type mice in the CIA model, suggesting that these adhesion molecules perform overlapping functions in regulating joint disease. Analyses of cytokine and chemokine expression in joint tissue from E/P-selectin mutant mice before the onset of joint swelling revealed significantly higher joint levels of macrophage inflammatory protein-1alpha and IL-1beta compared to wild-type mice. IL-1beta remained significantly increased in E/P-selectin mutant joint tissue during the early and chronic phases of arthritis. Overall, these data illustrate the novel finding that E-selectin and P-selectin expression can significantly influence cytokine and chemokine production in joint tissue, and suggest that these adhesion molecules play important regulatory roles in the development of arthritis in E/P-selectin mutant mice.

Accelerated development of arthritis in mice lacking endothelial selectins.

Previous studies have described in vitro serial passage of a Deltagamma(1)34.5 herpes simplex virus type 1 (HSV-1) strain in SK-N-SH neuroblastoma cells and selection of mutants that have acquired the ability to infect and replicate in this previously nonpermissive cell line. Here we describe the selection of a mutant HSV-1 strain by in vivo serial passage, which prolongs survival in two separate experimental murine brain tumor models. Two conditionally replication-competent Deltagamma(1)34.5 viruses, M002, which expresses murine interleukin-12, and its parent virus, R3659, were serially passaged within human malignant glioma D54-MG cell lines in vitro or flank tumor xenografts in vivo. The major findings are (i) viruses passaged in vivo demonstrate decreased neurovirulence, whereas those passaged in vitro demonstrate a partial recovery of the neurovirulence associated with HSV-1; and (ii) vvD54-M002, the virus selected after in vivo serial passage of M002 in D54-MG tumors, improves survival in two independent murine brain tumor models compared to the parent (unpassaged) M002. Additionally, in vitro-passaged, but not in vivo-passaged, M002 displayed changes in the protein synthesis profile in previously nonpermissive cell lines, as well as early U(S)11 transcription. Thus, a mutant HSV-1 strain expressing a foreign gene can be selected for enhanced antitumor efficacy via in vivo serial passage within flank D54-MG tumor xenografts. The enhanced antitumor efficacy of vvD54-M002 is not due to restoration of protein synthesis or early U(S)11 expression. This finding emphasizes the contribution of the in vivo tumor environment for selecting novel oncolytic HSV specifically adapted for tumor cell destruction in vivo.

Serial passage through human glioma xenografts selects for a Deltagamma134.5 herpes simplex virus type 1 mutant that exhibits decreased neurotoxicity and prolongs survival of mice with experimental brain tumors.

&#x7D20;&#x548C;&#x5176;&#x914D;&#x4F53;&#x8C03;&#x89E3;&#x767D;&#x7EC6;&#x80DE;&#x8F67;&#x4E0A;&#x76AE;&#x7EC6;&#x80DE;&#xFF0C;&#x5BFC;&#x81F4;&#x767D;&#x7EC6;&#x80DE;&#x6D78;&#x6DA6;&#x7684;&#x7EC4;&#x7EC7;&#x79FB;&#x6C11;&#x68AF;&#x7EA7;&#x4E2D;&#x7684;&#x7B2C;&#x4E00;&#x6B65;&#x3002;&#x8FD9;&#x4E9B;&#x7C98;&#x9644;&#x5206;&#x5B50;&#x8868;&#x660E;&#x5173;&#x952E;&#x8005;&#x7684;&#x6025;&#x6027;&#x767D;&#x7EC6;&#x80DE;&#x79FB;&#x6C11;&#x4E8B;&#x4EF6; &#xFF1B;&#x4F46;&#x662F;&#xFF0C;&#x5B83;&#x4EEC;&#x5728;&#x53D1;&#x5C55;&#x957F;&#x671F;&#x7684;&#x708E;&#x75C7;&#x53CD;&#x5E94;&#xFF0C;&#x5305;&#x62EC;&#x90A3;&#x4E9B;&#x5728;&#x6162;&#x6027;&#x708E;&#x75C7;&#x75BE;&#x75C5;&#x5982;&#x7CFB;&#x7EDF;&#x6027;&#x7EA2;&#x6591;&#x72FC;&#x75AE;&#xFF0C;&#x671F;&#x95F4;&#x53D1;&#x751F;&#x7684;&#x4F5C;&#x7528;&#x5C1A;&#x4E0D;&#x6E05;&#x695A;&#x3002;&#x4E3A;&#x4E86;&#x8BC4;&#x4F30; P-&#x9009;&#x62E9;&#x7D20;&#x5728;&#x8FD9;&#x4E9B;&#x75BE;&#x75C5;&#x4E2D;&#x7684;&#x53C2;&#x4E0E;&#xFF0C;&#x6211;&#x4EEC;&#x7814;&#x7A76;&#x8FDB;&#x5C55;&#x7684;&#x7CFB;&#x7EDF;&#x6027;&#x7EA2;&#x6591;&#x72FC;&#x75AE;&#x6837;&#x75C5;&#x7F3A;&#x78F7;&#x7D20;&#x53CA;&#x63A7;&#x5236; MRL/MpJ-Fas(lpr) (Fas(lpr)) &#x5C0F;&#x9F20;&#x3002;&#x5947;&#x602A;&#x7684;&#x662F;&#xFF0C;&#x6211;&#x4EEC;&#x53D1;&#x73B0; P-&#x9009;&#x62E9;&#x7D20;&#x865A;&#x5BFC;&#x81F4;&#x5927;&#x5927;&#x65E9;&#x671F;&#x6B7B;&#x4EA1;&#x7387;&#xFF0C;&#x7279;&#x70B9;&#x662F;&#x80BE;&#x5C0F;&#x7403;&#x80BE;&#x708E;&#x548C;&#x76AE;&#x708E;&#x66F4;&#x8FC5;&#x901F;&#x7684;&#x53D1;&#x5C55;&#x3002;CCL2 &#x7684;&#x8868;&#x8FBE; (MCP 1&#xFF09; &#x589E;&#x52A0;&#x4E86; P-&#x9009;&#x62E9;&#x7D20;&#x57FA;&#x56E0;&#x7A81;&#x53D8;&#x5C0F;&#x9F20;&#x80BE;&#x7EC4;&#x7EC7;&#x4E2D;&#xFF0C;&#x5E76;&#x4ECE;&#x8FD9;&#x4E9B;&#x5C0F;&#x9F20;&#x8102;&#x591A;&#x7CD6;&#x523A;&#x6FC0;&#x80BE;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x7EC6;&#x80DE;&#x6587;&#x5316;&#x57F9;&#x517B;&#x4E0A;&#x6E05;&#x6DB2;&#x4E2D;&#x3002;&#x5927;&#x81F4;&#x76F8;&#x540C;&#x7684;&#x8868;&#x578B;&#xFF0C;&#x5305;&#x62EC; CCL2&#xFF0C;&#x63D0;&#x5347;&#x80BE;&#x810F;&#x7684;&#x8868;&#x8FBE;&#x4E5F;&#x6709;&#x4EBA;&#x6709;&#x4E0D;&#x8DB3;&#x4E4B;&#x5904;&#x4E3B;&#x8981; P-&#x9009;&#x62E9;&#x7D20;&#x914D; P-&#x9009;&#x62E9;&#x7D20;&#x7CD6;&#x86CB;&#x767D;&#x914D;&#x4F53;-1 Fas(lpr) &#x5C0F;&#x9F20;&#x3002;&#x8FD9;&#x4E9B;&#x7ED3;&#x679C;&#x8868;&#x660E; P-&#x9009;&#x62E9;&#x7D20;&#x548C; P-&#x9009;&#x62E9;&#x7D20;&#x7CD6;&#x86CB;&#x767D;&#x914D;&#x4F53;-1 &#x4E0D;&#x662F;&#x767D;&#x7EC6;&#x80DE;&#x6D78;&#x6DA6;&#x548C; Fas(lpr) &#x5C0F;&#x9F20;&#x81EA;&#x8EAB;&#x514D;&#x75AB;&#x6027;&#x75BE;&#x75C5;&#x7684;&#x53D1;&#x5C55;&#x6240;&#x5FC5;&#x9700;&#x7684;&#x800C;&#x8FD9;&#x4E9B;&#x7C98;&#x9644;&#x5206;&#x5B50;&#x8868;&#x8FBE;&#x7684;&#x5F71;&#x54CD;&#x662F;&#x91CD;&#x8981;&#x7684;&#x8C03;&#x8282;&#x7684;&#x80BE;&#x5C0F;&#x7403;&#x80BE;&#x708E;&#xFF0C;&#x53EF;&#x80FD;&#x901A;&#x8FC7;&#x4E0B;&#x8C03;&#x8840;&#x7BA1;&#x5185;&#x76AE; CCL2 &#x8868;&#x8FBE;&#x7684;&#x7814;&#x7A76;&#x8FDB;&#x5C55;&#x3002;

P-&#x9009;&#x62E9;&#x7D20;&#x6216; P-&#x9009;&#x62E9;&#x7D20;&#x7CD6;&#x86CB;&#x767D;&#x914D;&#x4F53;-1 &#x7684;&#x7F3A;&#x5931;&#x4F1A;&#x5BFC;&#x81F4;&#x80BE;&#x5C0F;&#x7403;&#x80BE;&#x708E;&#x7684;&#x52A0;&#x901F;&#x7684;&#x53D1;&#x5C55;&#x548C; CC &#x8D8B;&#x5316;&#x56E0;&#x5B50;&#x914D;&#x4F53; 2 &#x6613;&#x53D1;&#x751F;&#x72FC;&#x75AE;&#x5C0F;&#x9F20;&#x8868;&#x8FBE;&#x589E;&#x52A0;&#x3002;

The selectins and their ligands mediate leukocyte rolling on endothelial cells, the initial step in the emigration cascade leading to leukocyte infiltration of tissue. These adhesion molecules have been shown to be key promoters of acute leukocyte emigration events; however, their roles in the development of long-term inflammatory responses, including those that occur during chronic inflammatory diseases such as systemic lupus erythematosus, are unclear. To assess participation of P-selectin in such disorders, we studied the progression of systemic lupus erythematosus-like disease in P-selectin-deficient and control MRL/MpJ-Fas(lpr) (Fas(lpr)) mice. Surprisingly, we found that P-selectin deficiency resulted in significantly earlier mortality, characterized by a more rapid development of glomerulonephritis and dermatitis. Expression of CCL2 (MCP-1) was increased in the kidneys of P-selectin mutant mice and in supernatants of LPS-stimulated primary renal endothelial cell cultures from these mice. A closely similar phenotype, including elevated renal expression of CCL2, was also observed in Fas(lpr) mice deficient in the major P-selectin ligand, P-selectin glycoprotein ligand-1. These results indicate that P-selectin and P-selectin glycoprotein ligand-1 are not required for leukocyte infiltration and the development of autoimmune disease in Fas(lpr) mice, but rather expression of these adhesion molecules is important for modulating the progression of glomerulonephritis, possibly through down-regulation of endothelial CCL2 expression.

Deficiency of P-selectin or P-selectin glycoprotein ligand-1 leads to accelerated development of glomerulonephritis and increased expression of CC chemokine ligand 2 in lupus-prone mice.

Les s&eacute;lectines et leurs ligands m&eacute;dient les leucocytes de roulement sur les cellules endoth&eacute;liales, l&#39;&eacute;tape initiale dans la cascade d&#39;&eacute;migration conduisant &agrave; l&#39;infiltration leucocytaire du tissu. Ces mol&eacute;cules d&#39;adh&eacute;sion ont d&eacute;montr&eacute; d&#39;&ecirc;tre les principaux promoteurs d&#39;&eacute;v&eacute;nements d&#39;&eacute;migration leucocytaire aigu&euml; ; Cependant, leur r&ocirc;le dans le d&eacute;veloppement de r&eacute;actions inflammatoires &agrave; long terme, y compris ceux qui surviennent au cours des maladies inflammatoires chroniques telles que le lupus &eacute;ryth&eacute;mateux diss&eacute;min&eacute;, n&#39;est pas claires. Pour &eacute;valuer la participation de la P-s&eacute;lectine dans ces troubles, nous avons &eacute;tudi&eacute; la progression de la maladie comme le lupus &eacute;ryth&eacute;mateux diss&eacute;min&eacute; dans la P-s&eacute;lectine-deficient et contr&ocirc;le MRL/MpJ-Fas(lpr) (souris Fas(lpr)). &Eacute;tonnamment, nous avons constat&eacute; que d&eacute;ficience en P-s&eacute;lectine a entra&icirc;n&eacute; des taux de mortalit&eacute; beaucoup plus ancienne, caract&eacute;ris&eacute;e par un d&eacute;veloppement plus rapide de glom&eacute;rulon&eacute;phrite et de dermatite. Expression de CCL2 (MCP-1) a &eacute;t&eacute; augment&eacute; dans les reins des souris mutantes P-s&eacute;lectine et dans les surnageants de cultures de cellules endoth&eacute;liales r&eacute;nales primaires stimul&eacute;es par LPS de ces souris. Un ph&eacute;notype tr&egrave;s semblable, y compris expression r&eacute;nale &eacute;lev&eacute;e de CCL2, a &eacute;galement &eacute;t&eacute; observ&eacute; chez les Fas(lpr) souris d&eacute;ficientes du ligand de P-selectin majeur, la glycoprot&eacute;ine P-s&eacute;lectine ligand-1. Ces r&eacute;sultats indiquent que la P-s&eacute;lectine et la glycoprot&eacute;ine P-s&eacute;lectine ligand-1 ne sont pas requis pour l&#39;infiltration leucocytaire et le d&eacute;veloppement de maladies auto-immunes chez des souris Fas(lpr), mais plut&ocirc;t l&#39;expression de ces mol&eacute;cules d&#39;adh&eacute;sion est importante pour moduler la progression de la glom&eacute;rulon&eacute;phrite, &eacute;ventuellement par le biais de r&eacute;gulation n&eacute;gative de l&#39;expression de CCL2 endoth&eacute;liale.

Carence en P-s&eacute;lectine ou de la glycoprot&eacute;ine P-s&eacute;lectine ligand-1 conduit &agrave; un d&eacute;veloppement acc&eacute;l&eacute;r&eacute; de glom&eacute;rulon&eacute;phrite et une expression accrue de CC chemokine ligand 2 souris sujettes &agrave; lupus.

Die Selectins und ihrer Liganden vermitteln Leukozyten Rollen auf Endothelzellen, der erste Schritt in der Auswanderung-Kaskade, die Leukozyten-Infiltration des Gewebes f&uuml;hrt. Diese Adh&auml;sionsmolek&uuml;le nachweislich wichtige F&ouml;rderer der akuten Leukozyten Auswanderung Ereignisse werden; Ihre Rolle bei der Entwicklung von langfristigen entz&uuml;ndliche Reaktionen, einschlie&szlig;lich derjenigen, die bei chronisch entz&uuml;ndlichen Erkrankungen wie Lupus erythematodes, auftreten sind jedoch unklar. Um die Beteiligung von P-selectin in solche St&ouml;rungen zu bewerten, studierte wir das Fortschreiten des systemischen Lupus erythematodes-&auml;hnliche Krankheit in P-selectin-Mangel und MRL/MpJ-Fas(lpr) (Fas(lpr)) M&auml;use. &Uuml;berraschenderweise fanden wir, dass P-selectin-Mangel deutlich fr&uuml;here Sterblichkeit, zeichnet sich durch eine raschere Entwicklung der Glomerulonephritis und Dermatitis gef&uuml;hrt. Ausdruck der CCL2 (MCP-1) wurde erh&ouml;ht, in den Nieren P-selectin Mutante M&auml;use und Supernatants LPS stimuliert prim&auml;re renale endothelial Zellen Kulturen von diesen M&auml;usen. Auch wurde ein eng &auml;hnlicher Ph&auml;notyp, einschlie&szlig;lich erh&ouml;hte renale Ausdruck des CCL2, bei Fas(lpr) M&auml;usen einen Mangel an der gro&szlig;en P-selectin Ligand, P-selectin Glykoprotein Ligand-1 beobachtet. Diese Ergebnisse zeigen, dass P-selectin und P-selectin Glykoprotein Ligand-1 nicht erforderlich f&uuml;r die Leukozyten-Infiltration und die Entwicklung von Autoimmun-Krankheit bei Fas(lpr) M&auml;usen sind, sondern Ausdruck dieser Adh&auml;sion Molek&uuml;le wichtig ist f&uuml;r die Modulierung der Progression der Glomerulonephritis, m&ouml;glicherweise durch Herunterregulation endothelial CCL2 Ausdruck.

P-selectin oder P-selectin Glykoprotein Ligand-1-Mangel f&uuml;hrt zu beschleunigten Entwicklung der Glomerulonephritis und erh&ouml;hte Expression von CC-Chemokine Ligand 2 Lupus-anf&auml;lligen M&auml;usen.

Le selectine e loro ligandi mediano leucocita rotolamento sulle cellule endoteliali, il passo iniziale per la cascata di emigrazione che porta all&#39;infiltrazione del leucocita del tessuto. Queste molecole di adesione hanno dimostrate di essere i principali promotori di eventi di emigrazione del leucocita acuta; Tuttavia, il loro ruolo nello sviluppo delle risposte infiammatorie a lungo termine, compresi quelli che si verificano durante le malattie infiammatorie croniche come il lupus eritematoso sistemico, &egrave; chiare. Per valutare la partecipazione della P-Selectina in tali disturbi, abbiamo studiato la progressione della malattia lupus eritematoso sistemico-come nel P-Selectina-carenti e controllo MRL/MpJ-Fas(lpr) (topi Fas(lpr)). Sorprendentemente, abbiamo trovato che il deficit di P-Selectina ha portato a mortalit&agrave; significativamente precedenti, caratterizzata da un pi&ugrave; rapido sviluppo di glomerulonefrite e dermatite. Espressione di CCL2 (MCP-1) &egrave; stato aumentato nei reni dei topi mutanti P-Selectina e in supernatanti di colture LPS-stimolato primario renale cellule endoteliali da questi topi. Un fenotipo simile, tra cui elevata espressione renale di CCL2, inoltre &egrave; stato osservato in Fas(lpr) topi carenti di ligando principale P-Selectina, ligando-1 glicoproteina P-Selectina. Questi risultati indicano che la P-Selectina e P-Selectina glicoproteina legante-1 non sono richiesti per l&#39;infiltrazione del leucocita e lo sviluppo della malattia autoimmune nel topo Fas(lpr), ma piuttosto espressione di queste molecole di adesione &egrave; importante per modulare la progressione della glomerulonefrite, possibilmente attraverso la down-regulation dell&#39;espressione CCL2 endoteliale.

Deficit di P-Selectina o ligando-1 glicoproteina P-Selectina conduce a sviluppo accelerato di glomerulonefrite e aumentata espressione del ligand di chemokine CC 2 nei topi lupus-inclini.

Selectins &#x3068; ligands &#x5185;&#x76AE;&#x7D30;&#x80DE;&#x4E0A;&#x3092;&#x30ED;&#x30FC;&#x30EA;&#x30F3;&#x30B0;&#x767D;&#x8840;&#x7403;&#x767D;&#x8840;&#x7403;&#x6D78;&#x6F64;&#x306E;&#x7D44;&#x7E54;&#x3092;&#x30EA;&#x30FC;&#x30C9;&#x79FB;&#x6C11;&#x30AB;&#x30B9;&#x30B1;&#x30FC;&#x30C9;&#x306E;&#x6700;&#x521D;&#x306E;&#x30B9;&#x30C6;&#x30C3;&#x30D7;&#x3092;&#x4EF2;&#x4ECB;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x63A5;&#x7740;&#x5206;&#x5B50;&#x304C;&#x6025;&#x6027;&#x767D;&#x8840;&#x7403;&#x79FB;&#x4F4F;&#x30A4;&#x30D9;&#x30F3;&#x30C8;&#x306E;&#x30AD;&#x30FC;&#x306E;&#x30D7;&#x30ED;&#x30E2;&#x30FC;&#x30BF;&#x30FC;&#x306B;&#x793A;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;;&#x3057;&#x304B;&#x3057;&#x3001;&#x305D;&#x306E;&#x767A;&#x751F;&#x3059;&#x308B;&#x6162;&#x6027;&#x306E;&#x708E;&#x75C7;&#x6027;&#x75BE;&#x60A3;&#x3001;&#x5168;&#x8EAB;&#x6027;&#x30A8;&#x30EA;&#x30C6;&#x30DE;&#x30C8;&#x30FC;&#x30C7;&#x30B9;&#x306A;&#x3069;&#x3082;&#x542B;&#x3081;&#x3066;&#x3001;&#x9577;&#x671F;&#x7684;&#x306A;&#x708E;&#x75C7;&#x53CD;&#x5FDC;&#x306E;&#x958B;&#x767A;&#x306B;&#x304A;&#x3051;&#x308B;&#x5F79;&#x5272;&#x306F;&#x4E0D;&#x660E;&#x3067;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;P-&#x30BB;&#x30EC;&#x30AF;&#x30C1;&#x30F3;&#x3053;&#x3046;&#x3057;&#x305F;&#x75BE;&#x60A3;&#x3067;&#x306E;&#x53C2;&#x52A0;&#x3092;&#x8A55;&#x4FA1;&#x3059;&#x308B;&#x306B;&#x306F;&#x3001;&#x79C1;&#x305F;&#x3061;&#x306E; P-&#x30BB;&#x30EC;&#x30AF;&#x30C1;&#x30F3;&#x6B20;&#x4E4F;&#x3068;&#x5236;&#x5FA1; MRL/MpJ-Fas(lpr) &#xFF08;Fas(lpr)) &#x30DE;&#x30A6;&#x30B9;&#x3002; &#x5168;&#x8EAB;&#x6027;&#x30A8;&#x30EA;&#x30C6;&#x30DE;&#x30C8;&#x30FC;&#x30C7;&#x30B9;&#x306E;&#x3088;&#x3046;&#x306A;&#x75C5;&#x6C17;&#x306E;&#x9032;&#x884C;&#x3092;&#x52C9;&#x5F37;&#x9A5A;&#x3044;&#x305F;&#x3053;&#x3068;&#x306B;&#x3001;&#x6211;&#x3005; &#x306F; P-&#x30BB;&#x30EC;&#x30AF;&#x30C1;&#x30F3;&#x6B20;&#x4E4F;&#x6027;&#x7CF8;&#x7403;&#x4F53;&#x814E;&#x708E;&#x3068;&#x76AE;&#x819A;&#x708E;&#x306E;&#x3088;&#x308A;&#x6025;&#x901F;&#x306A;&#x958B;&#x767A;&#x306B;&#x3088;&#x3063;&#x3066;&#x7279;&#x5FB4;&#x3065;&#x3051;&#x3089;&#x308C;&#x308B;&#x5927;&#x5E45;&#x306B;&#x4EE5;&#x524D;&#x306E;&#x6B7B;&#x4EA1;&#x7387;&#x306E;&#x7D50;&#x679C;&#x304C;&#x898B;&#x3064;&#x304B;&#x308A;&#x307E;&#x3057;&#x305F;&#x3002;CCL2 &#x306E;&#x767A;&#x73FE; (MCP-1&#xFF09; &#x306F;&#x3001;P-&#x30BB;&#x30EC;&#x30AF;&#x30C1;&#x30F3;&#x5909;&#x7570;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x814E;&#x81D3;&#x3068;&#x6E05; LPS &#x523A;&#x6FC0;&#x814E;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x7D30;&#x80DE;&#x304B;&#x3089;&#x306E;&#x6587;&#x5316;&#x3053;&#x308C;&#x3089;&#x306E;&#x30DE;&#x30A6;&#x30B9;&#x3092;&#x5897;&#x52A0;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x814E;&#x767A;&#x73FE;&#x3092; CCL2 &#x3092;&#x542B;&#x3080;&#x3001;&#x5BC6;&#x63A5;&#x306B;&#x4F3C;&#x3066;&#x3044;&#x308B;&#x8868;&#x73FE;&#x578B;&#x306F;&#x3001;&#x4E3B;&#x8981;&#x306A; P-&#x30BB;&#x30EC;&#x30AF;&#x30C1;&#x30F3; &#x30EA;&#x30AC;&#x30F3;&#x30C9;&#x3067;&#x3001;&#x30BB;&#x30EC;&#x30AF;&#x30C1;&#x30F3; P &#x7CD6;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x30EA;&#x30AC;&#x30F3;&#x30C9; 1 &#x6B20;&#x640D; Fas(lpr) &#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;&#x3082;&#x89B3;&#x5BDF;&#x3055;&#x308C;&#x305F;.P-&#x30BB;&#x30EC;&#x30AF;&#x30C1;&#x30F3;&#x3068;&#x30BB;&#x30EC;&#x30AF;&#x30C1;&#x30F3; P &#x7CD6;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x30EA;&#x30AC;&#x30F3;&#x30C9; 1 &#x767D;&#x8840;&#x7403;&#x6D78;&#x6F64;&#x3068; Fas(lpr) &#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;&#x81EA;&#x5DF1;&#x514D;&#x75AB;&#x75BE;&#x60A3;&#x306E;&#x958B;&#x767A;&#x306E;&#x305F;&#x3081;&#x5FC5;&#x8981;&#x306F;&#x3042;&#x308A;&#x307E;&#x305B;&#x3093;&#x304C;&#x3001;&#x3080;&#x3057;&#x308D;&#x3053;&#x308C;&#x3089;&#x306E;&#x63A5;&#x7740;&#x5206;&#x5B50;&#x306E;&#x767A;&#x73FE;&#x306F;&#x5185;&#x76AE; CCL2 &#x767A;&#x73FE;&#x306E;&#x30C0;&#x30A6;&#x30F3;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x3092;&#x901A;&#x3057;&#x3066;&#x304A;&#x305D;&#x3089;&#x304F;&#x6027;&#x7CF8;&#x7403;&#x4F53;&#x814E;&#x708E;&#x306E;&#x9032;&#x884C;&#x3092;&#x8ABF;&#x7BC0;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x91CD;&#x8981;&#x3067;&#x3059;&#x793A;&#x5506;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;

P-&#x30BB;&#x30EC;&#x30AF;&#x30C1;&#x30F3;&#x3084;&#x30BB;&#x30EC;&#x30AF;&#x30C1;&#x30F3; P &#x7CD6;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x30EA;&#x30AC;&#x30F3;&#x30C9;-1 &#x306E;&#x6B20;&#x4E4F;&#x7CF8;&#x7403;&#x4F53;&#x814E;&#x708E;&#x306E;&#x52A0;&#x901F;&#x958B;&#x767A;&#x3084;&#x30EB;&#x30FC;&#x30D7;&#x30B9;&#x304C;&#x767A;&#x751F;&#x3057;&#x3084;&#x3059;&#x3044;&#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B; CC &#x30B1;&#x30E2;&#x30AB;&#x30A4;&#x30F3; &#x30EA;&#x30AC;&#x30F3;&#x30C9; 2 &#x306E;&#x767A;&#x73FE;&#x5897;&#x52A0;&#x306B; &#x3057;&#x307E;&#x3059;&#x3002;

Selectins &#xBC0F; &#xADF8;&#xB4E4;&#xC758; ligands &#xBC31;&#xD608;&#xAD6C; &#xB0B4; &#xD53C; &#xC138;&#xD3EC;&#xC5D0; &#xC555; &#xC5F0; &#xC870;&#xC9C1;&#xC758; &#xCE68;&#xD22C; &#xBC31;&#xD608;&#xAD6C;&#xB85C; &#xC774;&#xC5B4;&#xC9C0;&#xB294; &#xD574;&#xC678; &#xC774;&#xC8FC; &#xCE90;&#xC2A4;&#xCF00;&#xC774;&#xB4DC;&#xC758; &#xCD08;&#xAE30; &#xB2E8;&#xACC4;&#xC5D0;&#xC11C; &#xC911;&#xC7AC;. &#xC774;&#xB7EC;&#xD55C; &#xC811;&#xCC29; &#xBD84;&#xC790; &#xAE09;&#xC131; &#xBC31;&#xD608;&#xAD6C; &#xC774;&#xC8FC; &#xC774;&#xBCA4;&#xD2B8;;&#xC758; &#xC8FC;&#xC694; &#xBC1C;&#xAE30;&#xC778; &#xB420; &#xD45C;&#xC2DC; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, &#xC7A5;&#xAE30; &#xC5FC;&#xC99D; &#xC131; &#xBC18;&#xC751;, &#xC804;&#xC2E0; &#xB8E8; &#xD478; &#xC2A4; &#xB4F1; &#xB9CC;&#xC131; &#xC5FC;&#xC99D; &#xC131; &#xC9C8;&#xD658; &#xC911; &#xBC1C;&#xC0DD; &#xD558;&#xB294; &#xB4F1;&#xC758; &#xAC1C;&#xBC1C;&#xC5D0; &#xC790;&#xC2E0;&#xC758; &#xC5ED;&#xD560; &#xBA85;&#xD655; &#xD558;&#xC9C0; &#xC54A;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xC7A5;&#xC560;&#xC5D0; P selectin&#xC758; &#xCC38;&#xC5EC; &#xD3C9;&#xAC00;, &#xC6B0;&#xB9AC; &#xACF5;&#xBD80; P selectin &#xACB0;&#xD54D; &#xBC0F; &#xCEE8;&#xD2B8;&#xB864; MRL/MpJ-Fas(lpr) (Fas(lpr)) &#xC950; &#xC804;&#xC2E0; &#xB8E8; &#xD478; &#xC2A4; &#xAC19;&#xC740; &#xBCD1;&#xC758; &#xC9C4;&#xD589;. &#xB180;&#xB78D;&#xAC8C;&#xB3C4;, P selectin &#xACB0;&#xD54D; &#xD2B9;&#xC9D5; &#xC0AC; &#xAD6C; &#xCCB4;&#xC2E0; &#xC5FC; &#xBC0F; &#xD53C;&#xBD80;&#xC5FC;&#xC758; &#xB354; &#xAE09;&#xC18D; &#xD55C; &#xBC1C;&#xC804;&#xC73C;&#xB85C; &#xD06C;&#xAC8C; &#xC774;&#xC804; &#xC0AC;&#xB9DD;&#xB960;&#xC5D0;&#xC11C; &#xACB0;&#xACFC; &#xCC3E;&#xC558;&#xC2B5;&#xB2C8;&#xB2E4;. &#xD45C;&#xD604;&#xC758; CCL2 P selectin &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xC950;&#xC758; &#xC2E0;&#xC7A5; &#xBC0F; &#xC774;&#xB7EC;&#xD55C; &#xC950;&#xC5D0;&#xC11C; LPS &#xC790;&#xADF9; &#xC8FC; &#xC2E0;&#xC7A5; &#xB0B4; &#xD53C; &#xC138;&#xD3EC; &#xBC30;&#xC591;&#xC758; supernatants (MCP-1) &#xC99D;&#xAC00; &#xD588;&#xB2E4;. &#xBC00;&#xC811; &#xD558; &#xAC8C; &#xC720;&#xC0AC;&#xD55C; &#xD45C;&#xD604; &#xD615; CCL2&#xC758; &#xB192;&#xC740; &#xC2E0;&#xC7A5; &#xC2DD; &#xB4F1; &#xB610;&#xD55C; Fas(lpr) &#xB9C8;&#xC6B0;&#xC2A4; &#xC8FC;&#xC694; P selectin &#xB9AC;&#xAC04;&#xB4DC;, &#xB2F9;&#xB2E8;&#xBC31;&#xC9C8; &#xB9AC;&#xAC04;&#xB4DC; 1 P selectin &#xACB0;&#xD54D;&#xC5D0;&#xC11C; &#xAD00;&#xCC30; &#xB418;&#xC5C8;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xACB0;&#xACFC; &#xD45C;&#xC2DC; P selectin &#xBC0F; &#xB2F9;&#xB2E8;&#xBC31;&#xC9C8; &#xB9AC;&#xAC04;&#xB4DC; 1 P selectin&#xC740; &#xBC31;&#xD608;&#xAD6C; &#xCE68;&#xD22C; &#xBC0F; Fas(lpr) &#xB9C8;&#xC6B0;&#xC2A4;, &#xC790;&#xAC00; &#xBA74;&#xC5ED; &#xC9C8;&#xD658;&#xC758; &#xAC1C;&#xBC1C;&#xC744; &#xC704;&#xD574; &#xD544;&#xC694; &#xD558;&#xC9C0;&#xB9CC; &#xC624;&#xD788;&#xB824; &#xC774;&#xB7EC;&#xD55C; &#xC811;&#xCC29; &#xBD84;&#xC790;&#xC758; &#xD45C;&#xD604;&#xC744; &#xBCC0;&#xC870; &#xAC00;&#xB2A5;&#xC131;&#xC774; &#xB0B4; &#xD53C; CCL2 &#xC2DD;&#xC758; &#xB2E4;&#xC6B4; &#xB808; &#xADE4; &#xB808;&#xC774; &#xC158;&#xC744; &#xD1B5;&#xD574; &#xC0AC; &#xAD6C; &#xCCB4;&#xC2E0; &#xC5FC;&#xC758; &#xC9C4;&#xD589;&#xC744; &#xC704;&#xD574; &#xC911;&#xC694; &#xD558;&#xB2E4;.

P selectin &#xB610;&#xB294; P selectin &#xB2F9;&#xB2E8;&#xBC31;&#xC9C8; &#xB9AC;&#xAC04;&#xB4DC;-1&#xC758; &#xACB0;&#xD54D;&#xC73C;&#xB85C; &#xC0AC; &#xAD6C; &#xCCB4;&#xC2E0; &#xC5FC;&#xC758; &#xAC00;&#xC18D; &#xBC1C;&#xC804;&#xACFC; CC chemokine &#xB9AC;&#xAC04;&#xB4DC; 2 &#xB8E8; &#xD478; &#xC2A4; &#xBC1C;&#xC0DD; &#xD558;&#xAE30; &#xC26C;&#xC6B4; &#xC950;&#xC5D0; &#xC788;&#xB294; &#xC99D;&#xAC00; &#xD45C;&#xD604;&#xC758; &#xC774;&#xC5B4;&#xC9D1;&#xB2C8;&#xB2E4;.

Las selectinas y sus ligandos median del leucocito rodando en las c&eacute;lulas endoteliales, el paso inicial en la cascada de emigraci&oacute;n hacia la infiltraci&oacute;n de leucocitos del tejido. Estas mol&eacute;culas de adhesi&oacute;n han demostrado ser los principales promotores de eventos de emigraci&oacute;n del leucocito aguda; sin embargo, su papel en el desarrollo de las respuestas inflamatorias a largo plazo, los que se producen durante las enfermedades inflamatorias cr&oacute;nicas como lupus eritematoso sist&eacute;mico, incluidos es claros. Evaluar la participaci&oacute;n de P-selectina en dichos trastornos, estudiamos la progresi&oacute;n de la enfermedad de lupus eritematoso sist&eacute;mico-como en P-selectina-deficientes y control MRL/MpJ-Fas(lpr) (ratones Fas(lpr)). Sorprendentemente, encontramos que la deficiencia de P-selectina dio lugar a mortalidad significativamente m&aacute;s temprano, caracterizada por un desarrollo m&aacute;s r&aacute;pido de la glomerulonefritis y dermatitis. Expresi&oacute;n de CCL2 (MCP-1) se increment&oacute; en los ri&ntilde;ones de ratones mutantes P-selectina y en los sobrenadantes de los cultivos celulares endoteliales renal primaria LPS-estimulado de estos ratones. Tambi&eacute;n se observ&oacute; un fenotipo muy similar, incluyendo la elevada expresi&oacute;n renal de CCL2, en Fas(lpr) ratones deficientes en el ligando principal de P-selectina, P-selectina glicoprote&iacute;na ligand-1. Estos resultados indican que no son necesarios para la infiltraci&oacute;n de leucocitos y el desarrollo de enfermedades autoinmunes en ratones Fas(lpr) P-selectina y P-selectina glicoprote&iacute;na ligand-1, sino expresi&oacute;n de estas mol&eacute;culas de adhesi&oacute;n es importante para la modulaci&oacute;n de la progresi&oacute;n de la glomerulonefritis, posiblemente a trav&eacute;s de la regulaci&oacute;n de la expresi&oacute;n endotelial de CCL2.

Deficiencia de P-selectina o P-selectina glicoprote&iacute;na ligand-1 conduce a un desarrollo acelerado de la glomerulonefritis y la expresi&oacute;n creciente de CC chemokine ligando 2 en ratones propensos a lupus.

In contrast to antigen-specific alphabeta-T cells (adaptive immune system), gammadelta-T cells can recognize and lyse malignantly transformed cells almost immediately upon encounter in a manner that does not require the recognition of tumor-specific antigens (innate immune system). Given the well-documented capacity of gammadelta-T cells to innately kill a variety of malignant cells, efforts are now actively underway to exploit the antitumor properties of gammadelta-T cells for clinical purposes. Here, we present for the first time preclinical in vivo mouse models of gammadelta-T cell-based immunotherapy directed against breast cancer. These studies were explicitly designed to approximate clinical situations in which adoptively transferred gammadelta-T cells would be employed therapeutically against breast cancer. Using radioisotope-labeled gammadelta-T cells, we first show that adoptively transferred gammadelta-T cells localize to breast tumors in a mouse model (4T1 mammary adenocarcinoma) of human breast cancer. Moreover, by using an antibody directed against the gammadelta-T cell receptor (TCR), we determined that localization of adoptively transferred gammadelta-T cells to tumor is a TCR-dependant process. Additionally, biodistribution studies revealed that adoptively transferred gammadelta-T cells traffic differently in tumor-bearing mice compared to healthy mice with fewer gammadelta-T cells localizing into the spleens of tumor-bearing mice. Finally, in both syngeneic (4T1) and xenogeneic (2Lmp) models of breast cancer, we demonstrate that adoptively transferred gammadelta-T cells are both effective against breast cancer and are otherwise well-tolerated by treated animals. These findings provide a strong preclinical rationale for using ex vivo expanded adoptively transferred gammadelta-T cells as a form of cell-based immunotherapy for the treatment of breast cancer. Additionally, these studies establish that clinically applicable methods for radiolabeling gammadelta-T cells allows for the tracking of adoptively transferred gammadelta-T cells in tumor-bearing hosts.

Adoptively transferred ex vivo expanded gammadelta-T cells mediate in vivo antitumor activity in preclinical mouse models of breast cancer.

&#x8FD9;&#x9879;&#x7814;&#x7A76;&#x7684;&#x76EE;&#x7684;&#x662F;&#x8BC4;&#x4F30;&#x7EC6;&#x80DE;&#x5916;&#x57FA;&#x8D28;&#x91D1;&#x5C5E;&#x86CB;&#x767D;&#x9176; &#xFF08;EMMPRIN&#xFF09; &#x4F5C;&#x4E3A;&#x4E00;&#x79CD;&#x65B0;&#x578B;&#x76EE;&#x6807;&#x539F;&#x4F4D;&#x80F0;&#x817A;&#x764C;&#x5C0F;&#x9F20;&#x6A21;&#x578B;&#x4E2D;&#x3002;MIA PaCa 2 &#x80F0;&#x817A;&#x80BF;&#x7624;&#x7EC6;&#x80DE;&#x88AB;&#x690D;&#x5165;&#x7EC4; 1 &#x548C; 3-7&#xFF0C;&#x800C; MIA PaCa 2 EMMPRIN &#x7EC4;&#x5408;&#x5F0F;&#x7EC6;&#x80DE;&#x88AB;&#x690D;&#x5165;&#x7B2C;&#x4E8C;&#x7EC4;&#x3002;&#x5177;&#x6709;&#x6297; EMMPRIN &#x6297;&#x4F53;&#x52A0;&#x836F;&#x690D;&#x5165;&#x7EC4; 1-3 &#xFF08;&#x6B8B;&#x4F59;&#x80BF;&#x7624;&#x6A21;&#x578B;&#xFF09; &#x548C; &#xFF08;&#x65E2;&#x5B9A;&#x7684;&#x80BF;&#x7624;&#x6A21;&#x578B;&#xFF09; 4-7 &#x7EC4;&#x7EC6;&#x80DE;&#x690D;&#x5165;&#x540E;&#x7684; 21 &#x5929;&#x540E;&#x7ACB;&#x5373;&#x5F00;&#x59CB;&#x3002;3&#x3001; 5 &#x548C; 7 &#x7EC4;&#x6CBB;&#x7597;&#x6297; EMMRPIN &#x6297;&#x4F53; &#xFF08;0.2-1.0 &#x6BEB;&#x514B;&#xFF09; &#x6BCF;&#x5468;&#x4E24;&#x6B21;&#x4E3A; 2-3 &#x5468;&#xFF0C;&#x800C;&#x5176;&#x4ED6;&#x7EC4;&#x62C5;&#x4EFB;&#x8BE5;&#x63A7;&#x4EF6;&#x3002;&#x5728;&#x6B8B;&#x4F59;&#x80BF;&#x7624;&#x6A21;&#x578B;&#x4E2D;&#xFF0C;&#x6297; EMMPRIN &#x6CBB;&#x7597;&#x7EC4;&#x7684;&#x80BF;&#x7624;&#x751F;&#x957F;&#x88AB;&#x6210;&#x529F;&#x902E;&#x6355; 21 &#x5929; (15 &plusmn; 4 mm(3))&#xFF0C;&#x8FD9;&#x662F;&#x5927;&#x5927;&#x4F4E;&#x4E8E; EMMPRIN &#x7EC4;&#x5408;&#x5F0F;&#x7EC4; (80 &plusmn; 15 mm(3) &#xFF1B;P = 0.001) &#x6216;&#x63A7;&#x5236;&#x7EC4; &#xFF08;240 &plusmn; 41 mm(3) &#xFF1B;P &lt; 0.001&#xFF09;&#x3002;&#x5728;&#x65E2;&#x5B9A;&#x7684;&#x80BF;&#x7624;&#x6A21;&#x578B;&#x4E2D;&#xFF0C;&#x6297; EMMPRIN &#x7597;&#x6CD5;&#x964D;&#x4F4E;&#x80BF;&#x7624;&#x4F53;&#x79EF;&#x589E;&#x52A0;&#x5927;&#x7EA6; 40%&#xFF0C;&#x800C;&#x8BE5;&#x63A7;&#x4EF6;&#xFF0C;&#x65E0;&#x8BBA;&#x5242;&#x91CF;&#x591A;&#x5C11;&#x3002;Ki67 &#x8868;&#x8FBE;&#x7EC6;&#x80DE;&#x5BC6;&#x5EA6;&#x7684;&#x7B2C;&#x4E94;&#x7EC4;&#x662F; 939 &plusmn; 150 mm(-2)&#xFF0C;&#x8FD9;&#x662F;&#x5927;&#x5927;&#x4F4E;&#x4E8E;&#x7EC4; 4 (1709&#x5E74; &plusmn; 145 mm(-2) &#xFF1B;P = 0.006)&#x3002;&#x7B2C;&#x4E94;&#x7EC4;&#x7684;&#x5FAE;&#x8840;&#x7BA1;&#x5BC6;&#x5EA6; (30 &plusmn; 6 mm(-2)) &#x4E5F;&#x662F;&#x5927;&#x5927;&#x4F4E;&#x4E8E;&#x7EC4; 4 &#xFF08;53 &plusmn; 5 mm(-2) &#xFF1B;P = 0.014&#xFF09;&#xFF0C;&#x800C;&#x7B2C;&#x4E94;&#x7EC4;&#x7684;&#x5FAE;&#x8840;&#x7BA1;&#x5927;&#x5C0F; (191 &plusmn; 22 &mu;m(2)) &#x662F;&#x660E;&#x663E;&#x5927;&#x4E8E;&#x7EC4; 4 (113 &plusmn; 26 &mu;m(2) &#xFF1B;P = 0.049)&#x3002;&#x8FD9;&#x4E9B;&#x6570;&#x636E;&#x663E;&#x793A;&#x9AD8;&#x6F5C;&#x5728;&#x7684;&#x53CD; EMMPRIN &#x6CBB;&#x7597;&#x80F0;&#x817A;&#x764C;&#x548C;&#x652F;&#x6301;&#x5176;&#x4E34;&#x5E8A;&#x7684;&#x7FFB;&#x8BD1;&#x3002;

&#x80DE;&#x5916;&#x57FA;&#x8D28;&#x91D1;&#x5C5E;&#x86CB;&#x767D;&#x9176;&#x4F5C;&#x4E3A;&#x80F0;&#x817A;&#x764C;&#x6CBB;&#x7597;&#x7684;&#x65B0;&#x9776;&#x70B9;&#x3002;

The objective of this study was to evaluate extracellular matrix metalloproteinase (EMMPRIN) as a novel target in orthotopic pancreatic cancer murine models. MIA PaCa-2 human pancreatic tumor cells were implanted in groups 1 and 3-7, whereas MIA PaCa-2 EMMPRIN knockdown cells were implanted in group 2. Dosing with anti-EMMPRIN antibody started immediately after implantation for groups 1-3 (residual tumor model) and at 21 days after cell implantation for groups 4-7 (established tumor model). Groups 3, 5, and 7 were treated with anti-EMMRPIN antibody (0.2-1.0 mg) twice weekly for 2-3 weeks, whereas the other groups served as the control. In the residual tumor model, tumor growth of anti-EMMPRIN-treated group was successfully arrested for 21 days (15 Â± 4 mm(3)), which was significantly lower than that of the EMMPRIN knockdown group (80 Â± 15 mm(3); P=0.001) or the control group (240 Â± 41 mm(3); P<0.001). In the established tumor model, anti-EMMPRIN therapy lowered tumor volume increase by approximately 40% compared with the control, regardless of the dose amount. Ki67-expressed cell density of group 5 was 939 Â± 150 mm(-2), which was significantly lower than that of group 4 (1709 Â± 145 mm(-2); P=0.006). Microvessel density of group 5 (30 Â± 6 mm(-2)) was also significantly lower than that of group 4 (53 Â± 5 mm(-2); P=0.014), whereas the microvessel size of group 5 (191 Â± 22 Î¼m(2)) was significantly larger than that of group 4 (113 Â± 26 Î¼m(2); P=0.049). These data show the high potential of anti-EMMPRIN therapy for pancreatic cancer and support its clinical translation.

Extracelluar matrix metalloproteinase as a novel target for pancreatic cancer therapy.

L&#39;objectif de cette &eacute;tude &eacute;tait d&#39;&eacute;valuer m&eacute;talloprot&eacute;inases de la matrice extracellulaire (EMMPRIN) comme une nouvelle cible dans les mod&egrave;les murins orthotopique du cancer du pancr&eacute;as. Cellules tumorales pancr&eacute;atiques humaines MIA PaCa-2 ont &eacute;t&eacute; implant&eacute;s dans les groupes 1 et 3-7, alors que les cellules knockdown EMMPRIN MIA PaCa-2 ont &eacute;t&eacute; implant&eacute;s dans le groupe 2. Dosage avec l&#39;anticorps anti-EMMPRIN a commenc&eacute; imm&eacute;diatement apr&egrave;s l&#39;implantation des groupes 1 &agrave; 3 (mod&egrave;le de tumeur r&eacute;siduelle) et &agrave; 21 jours apr&egrave;s l&#39;implantation de cellules pour les groupes 4-7 (mod&egrave;le de tumeur &eacute;tablie). Groupes de 3, 5 et 7 ont &eacute;t&eacute; trait&eacute;es avec des anticorps anti-EMMRPIN (0,2 &agrave; 1,0 mg) deux fois par semaine pendant 2 ou 3 semaines, alors que les autres groupes a servi le contr&ocirc;le. Le mod&egrave;le de tumeur r&eacute;siduelle, la croissance tumorale du groupe trait&eacute; anti-EMMPRIN a &eacute;t&eacute; arr&ecirc;t&eacute;e avec succ&egrave;s pendant 21 jours (15 &plusmn; 4 mm(3)), qui est nettement inf&eacute;rieur &agrave; celui du groupe knockdown EMMPRIN (80 &plusmn; 15 mm(3) ; P = 0,001) ou le groupe de contr&ocirc;le (240 &plusmn; 41 mm(3) ; P &lt; 0,001). Dans le mod&egrave;le de tumeur &eacute;tablie, la th&eacute;rapie anti-EMMPRIN abaiss&eacute; augmentation de volume de tumeur d&#39;environ 40 %, compar&eacute;e au t&eacute;moin, ind&eacute;pendamment de la quantit&eacute; de la dose. Densit&eacute; cellulaire KI67-exprim&eacute;e de groupe 5 a 939 &plusmn; 150 mm(-2), qui est nettement inf&eacute;rieur &agrave; celui du groupe 4 (1709 &plusmn; 145 mm(-2) ; P = 0,006). Densit&eacute; des microvaisseaux de groupe 5 (30 &plusmn; 6 mm(-2)) &eacute;tait &eacute;galement significativement plus faible que celle du groupe 4 (53 &plusmn; 5 mm(-2) ; P = 0, 014), tandis que la taille des microvaisseaux de groupe 5 (191 &plusmn; 22 &mu;m(2)) &eacute;tait significativement sup&eacute;rieure &agrave; celle du groupe 4 (113 &plusmn; 26 &mu;m(2) ; P = 0,049). Ces donn&eacute;es montrent le haut potentiel de la th&eacute;rapie anti-EMMPRIN cancer du pancr&eacute;as et soutiennent sa traduction clinique.

M&eacute;talloprot&eacute;inase de matrice extracellulaire comme une nouvelle cible pour le traitement du cancer du pancr&eacute;as.

Das Ziel dieser Studie war als neues Ziel in Orthotopic Bauchspeicheldr&uuml;senkrebs murinen Modelle extrazellul&auml;ren Matrix-Metalloproteasen (EMMPRIN) zu bewerten. MIA PaCa-2 menschlichen pankreatischen Tumor-Zellen wurden in den Gruppen 1 und 3-7, implantiert, w&auml;hrend in Gruppe 2 MIA PaCa-2 EMMPRIN Niederschlag Zellen implantiert wurden. Dosierung mit Anti-EMMPRIN Antik&ouml;rper begann unmittelbar nach der Implantation f&uuml;r Gruppen 1-3 (residual Tumor-Modell) und 21 Tage nach der Implantation der Zelle f&uuml;r Gruppen von 4-7 (etablierten Tumor-Modell). Gruppen 3, 5 und 7 wurden mit Anti-EMMRPIN Antik&ouml;rper behandelt (0.2-1.0 mg) zweimal w&ouml;chentlich f&uuml;r 2-3 Wochen, w&auml;hrend die anderen Gruppen wie das Steuerelement serviert. Im Modell residual Tumor wurde Tumorwachstum Anti-EMMPRIN-behandelte Gruppe erfolgreich verhaftet f&uuml;r 21 Tage (15 &plusmn; 4 mm(3)), die war signifikant niedriger als der EMMPRIN-Niederschlag-Gruppe (80 &plusmn; 15 mm(3); P = 0,001) oder der Kontrollgruppe (240 &plusmn; 41 mm(3); P &lt; 0,001). Im etablierten Tumor-Modell gesenkt Anti-EMMPRIN Therapie Tumor Volume Anstieg um ca. 40 % verglichen mit dem Steuerelement, unabh&auml;ngig von der Dosis. Ki67-ausgedr&uuml;ckt Zelldichte Gruppe 5 wurde 939 &plusmn; 150 mm(-2), die war wesentlich niedriger als die der Gruppe 4 (1709 &plusmn; 145 mm(-2); P = 0,006). Microvessel Dichte der Gruppe 5 (30 &plusmn; 6 mm(-2)) war auch deutlich niedriger als die der Gruppe 4 (53 &plusmn; 5 mm(-2); P = 0,014), w&auml;hrend die Microvessel Gr&ouml;&szlig;e der Gruppe 5 (191 &plusmn; 22 &mu;m(2)) war deutlich gr&ouml;&szlig;er als die der Gruppe 4 (113 &plusmn; 26 &mu;m(2); P = 0.035). Diese Daten zeigen das hohe potential der Anti-EMMPRIN-Therapie f&uuml;r Bauchspeicheldr&uuml;senkrebs und seine klinische &Uuml;bersetzung zu unterst&uuml;tzen.

Extracelluar Matrix-Metalloprotease als neues Ziel f&uuml;r Bauchspeicheldr&uuml;senkrebs-Therapie.

L&#39;obiettivo di questo studio era di valutare extracellular matrix metalloproteinase (EMMPRIN) come destinazione romanzo in modelli murini di cancro al pancreas ortotopico. Cellule del tumore pancreatico umano MIA PaCa-2 sono state impiantate nei gruppi 1 e 3-7, mentre celle di colpo EMMPRIN MIA PaCa-2 sono state impiantate nel gruppo 2. Dosaggio con anticorpo anti-EMMPRIN iniziato immediatamente dopo l&#39;impianto per gruppi di 1-3 (modello di tumore residuo) e a 21 giorni dopo l&#39;impianto di cellule per gruppi di 4-7 (modello stabilito tumore). Gruppi di 3, 5 e 7 sono stati trattati con l&#39;anticorpo anti-EMMRPIN (0.2-1.0 mg) due volte settimanali per 2-3 settimane, mentre altri gruppi servito come controllo. Nel modello di tumore residuo, crescita tumorale del gruppo anti-EMMPRIN-trattato con successo &egrave; stato arrestato per 21 giorni (15 &plusmn; 4 mm(3)), che era notevolmente inferiore a quello del gruppo EMMPRIN di atterramento (80 &plusmn; 15 mm(3); P = 0,001) o il gruppo di controllo (240 &plusmn; 41 mm(3); P &lt; 0.001). Nel modello stabilito tumore, terapia anti-EMMPRIN abbassato aumento del volume di tumore di circa il 40% rispetto al controllo, indipendentemente dalla quantit&agrave; di dose. La densit&agrave; delle cellule Ki67-espresso del gruppo 5 &egrave; stata 939 mm(-2) &plusmn; 150, che era notevolmente inferiore a quello del gruppo 4 (1709 &plusmn; mm(-2) 145; P = 0.006). Densit&agrave; del Microvessel del gruppo 5 (30 &plusmn; 6 mm(-2)) era anche significativamente inferiore a quello del gruppo 4 (53 &plusmn; 5 mm(-2); P = 0.014), mentre la dimensione microvessel di gruppo 5 (191 &plusmn; 22 &mu;m(2)) era significativamente pi&ugrave; grande di quello del gruppo 4 (113 &mu;m(2) &plusmn; 26; P = 0.049). Questi dati mostrano l&#39;alto potenziale della terapia anti-EMMPRIN per il cancro del pancreas e sostengono la sua traduzione clinica.

Extracelluar matrix metalloproteinase come un romanzo bersaglio per la terapia del cancro del pancreas.

&#x672C;&#x7814;&#x7A76;&#x306E;&#x76EE;&#x7684;&#x306F;&#x65B0;&#x3057;&#x3044;&#x6A19;&#x7684;&#x3068;&#x3057;&#x3066;&#x306E;&#x540C;&#x6240;&#x6027;&#x540C;&#x7A2E;&#x81B5;&#x764C;&#x30DE;&#x30A6;&#x30B9;&#x30E2;&#x30C7;&#x30EB;&#x3067;&#x7D30;&#x80DE;&#x5916;&#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9; &#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9;&#x30E1;&#x30BF;&#x30ED;&#x30D7;&#x30ED;&#x30C6;&#x30A2;&#x30FC;&#x30BC; (EMMPRIN) &#x3092;&#x8A55;&#x4FA1;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x3060;&#x3063;&#x305F;&#x3002;MIA &#x30D1;&#x30AB; 2 EMMPRIN &#x30CE;&#x30C3;&#x30AF;&#x30C0;&#x30A6;&#x30F3;&#x7D30;&#x80DE;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 2 &#x306B;&#x79FB;&#x690D;&#x3055;&#x308C;&#x305F;&#x306B;&#x5BFE;&#x3057; MIA &#x30D1;&#x30AB; 2 &#x30D2;&#x30C8;&#x81B5;&#x816B;&#x760D;&#x7D30;&#x80DE;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 1 &#x304A;&#x3088;&#x3073; 3-7&#x3001;&#x79FB;&#x690D;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x6297; EMMPRIN &#x6297;&#x4F53;&#x3092;&#x6295;&#x4E0E;&#x76F4;&#x5F8C;&#x306E;&#x6CE8;&#x5165;&#x306E;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 1-3 (&#x6B8B;&#x5B58;&#x816B;&#x760D;&#x30E2;&#x30C7;&#x30EB;) &#x3068; 21 &#x65E5; &#xFF08;&#x8A2D;&#x7ACB;&#x816B;&#x760D;&#x30E2;&#x30C7;&#x30EB;) &#x7D30;&#x80DE;&#x306E;&#x79FB;&#x690D;&#x306B;&#x3088;&#x308B;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 4-7 &#x5F8C;&#x59CB;&#x3081;&#x305F;&#x3002;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 3&#x3001;5&#x3001;&#x304A;&#x3088;&#x3073; 7 &#x306F;&#x3001;&#x6297; EMMRPIN &#x6297;&#x4F53;&#x3092;&#x6CBB;&#x7642;&#x3057;&#x305F; (0.2 &#x301C; 1.0 mg) 2 &#x56DE;&#x9031;&#x9593; 2-3 &#x9031;&#x9593;&#x306F;&#x3001;&#x4ED6;&#x306E;&#x30B0;&#x30EB;&#x30FC;&#x30D7;&#x3092;&#x30B3;&#x30F3;&#x30C8;&#x30ED;&#x30FC;&#x30EB;&#x3068;&#x3057;&#x3066;&#x63D0;&#x4F9B;&#x3057;&#x3066;&#x306B;&#x5BFE;&#x3057;&#x3002;&#x6B8B;&#x5B58;&#x816B;&#x760D;&#x30E2;&#x30C7;&#x30EB;&#x3067;&#x306F;&#x3001;&#x53CD; EMMPRIN &#x6295;&#x4E0E;&#x7FA4;&#x306E;&#x816B;&#x760D;&#x306E;&#x6210;&#x9577;&#x306F;&#x6B63;&#x5E38;&#x306B; 21 &#x65E5;&#x9593; &#xFF08;EMMPRIN &#x30CE;&#x30C3;&#x30AF;&#x30C0;&#x30A6;&#x30F3; &#x30B0;&#x30EB;&#x30FC;&#x30D7; &#xFF08;80 &plusmn; 15 mm(3); &#x3088;&#x308A;&#x3082;&#x5927;&#x5E45;&#x306B;&#x4F4E;&#x3044;&#x3044;&#x305F; 15 &plusmn; 4 mm(3))&#x3001;&#x902E;&#x6355;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;P = 0.001) &#x307E;&#x305F;&#x306F;&#x30B3;&#x30F3;&#x30C8;&#x30ED;&#x30FC;&#x30EB;&#x306E;&#x30B0;&#x30EB;&#x30FC;&#x30D7; (240 &plusmn; 41 mm(3);P &lt; 0.001&#xFF09;&#x3002;&#x78BA;&#x7ACB;&#x3055;&#x308C;&#x305F;&#x816B;&#x760D;&#x30E2;&#x30C7;&#x30EB;&#x3067;&#x306F;&#x3001;&#x53CD; EMMPRIN &#x7642;&#x6CD5;&#x306F;&#x6295;&#x4E0E;&#x91CF;&#x306B;&#x304B;&#x304B;&#x308F;&#x3089;&#x305A;&#x3001;&#x30B3;&#x30F3;&#x30C8;&#x30ED;&#x30FC;&#x30EB;&#x3068;&#x6BD4;&#x8F03;&#x3057;&#x3066;&#x7D04; 40 &#xFF05; &#x3067;&#x816B;&#x760D;&#x306E;&#x30DC;&#x30EA;&#x30E5;&#x30FC;&#x30E0;&#x5897;&#x52A0;&#x3092;&#x4E0B;&#x3052;&#x305F;&#x3002;&#x30AD;67 &#x8868;&#x3055;&#x30BB;&#x30EB;&#x5BC6;&#x5EA6;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 5 &#x306E;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 4 &#xFF08;1709&#x5E74; &plusmn; 145 mm(-2); &#x3088;&#x308A;&#x3082;&#x5927;&#x5E45;&#x306B;&#x4F4E;&#x3044;&#x306A;&#x3089;&#x3070;&#x3001;939 &#x306E; &plusmn; 150 mm(-2) &#x3060;&#x3063;&#x305F;P = 0.006 &#x3060;&#xFF09;&#x3002;&#x5FAE;&#x5C0F;&#x8840;&#x7BA1;&#x5BC6;&#x5EA6;&#x306E;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 5 (30 &plusmn; 6 mm(-2)) &#x3082;&#x3042;&#x3063;&#x305F;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 4 &#xFF08;53 &plusmn; 5 mm(-2); &#x3088;&#x308A;&#x3082;&#x5927;&#x5E45;&#x306B;&#x4F4E;&#x3044;P = 0.014) &#x306B;&#x5BFE;&#x3057;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 5 &#x306E;&#x5FAE;&#x5C0F;&#x8840;&#x7BA1;&#x30B5;&#x30A4;&#x30BA; (191 &plusmn; 22 &mu;m(2)) &#x3060;&#x3063;&#x305F;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 4 &#xFF08;113 &plusmn; 26 &mu;m(2); &#x3088;&#x308A;&#x3082;&#x5927;&#x5E45;&#x306B;&#x5927;&#x304D;&#x3044;P P=0.049)&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x30C7;&#x30FC;&#x30BF;&#x9AD8;&#x3044;&#x81B5;&#x304C;&#x3093;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x6297; EMMPRIN &#x7642;&#x6CD5;&#x306E;&#x6F5C;&#x5728;&#x7684;&#x306A;&#x8868;&#x793A;&#x3057;&#x3001;&#x305D;&#x306E;&#x81E8;&#x5E8A;&#x306E;&#x7FFB;&#x8A33;&#x3092;&#x30B5;&#x30DD;&#x30FC;&#x30C8;&#x3057;&#x307E;&#x3059;&#x3002;

Extracelluar &#x30E1;&#x30BF;&#x30ED;&#x30D7;&#x30ED;&#x30C6;&#x30A2;&#x30FC;&#x30BC;&#x81B5;&#x81D3;&#x764C;&#x6CBB;&#x7642;&#x306E;&#x65B0;&#x3057;&#x3044;&#x6A19;&#x7684;&#x3068;&#x3057;&#x3066;&#x3002;

&#xC774; &#xC5F0;&#xAD6C;&#xC758; &#xBAA9;&#xC801;&#xC740; orthotopic &#xCDCC;&#xC7A5;&#xC554; murine &#xBAA8;&#xB378;&#xC5D0;&#xC11C; &#xC18C;&#xC124;&#xC744; &#xB300;&#xC0C1;&#xC73C;&#xB85C; &#xC138;&#xD3EC; &#xC678; &#xAE30;&#xC9C8; metalloproteinase (EMMPRIN)&#xB97C; &#xD3C9;&#xAC00; &#xD558;&#xB294;. &#xBBF8;&#xC544; PaCa 2 EMMPRIN &#xCD5C;&#xC800;&#xC758; &#xC140; &#xADF8;&#xB8F9; 2&#xC5D0;&#xC5D0;&#xC11C; &#xC774;&#xC2DD; &#xB41C; &#xBC18;&#xBA74; &#xADF8;&#xB8F9; 1 &#xBC0F; 3-7 &#xBBF8;&#xC544; PaCa 2 &#xC778;&#xAC04;&#xC758; &#xCDCC; &#xC7A5; &#xC885;&#xC591; &#xC138;&#xD3EC; &#xC774;&#xC2DD; &#xD588;&#xB2E4;. &#xC548;&#xD2F0;-EMMPRIN &#xD56D; &#xCCB4;&#xC640; &#xC8FC;&#xC785; &#xADF8;&#xB8F9; 1-3 (&#xC794;&#xC5EC; &#xC885;&#xC591; &#xBAA8;&#xB378;) &#xBC0F; (&#xC124;&#xB9BD;&#xB41C; &#xC885;&#xC591; &#xBAA8;&#xB378;) &#xADF8;&#xB8F9; 4-7&#xC5D0; &#xB300; &#xD55C; &#xC138;&#xD3EC; &#xC774;&#xC2DD; &#xD6C4; 21 &#xC77C; &#xB0B4;&#xC5D0; &#xC8FC;&#xC785; &#xD6C4; &#xC989;&#xC2DC; &#xC2DC;&#xC791; &#xD588;&#xB2E4;. 3, 5, &#xBC0F; 7 &#xADF8;&#xB8F9; &#xC548;&#xD2F0;-EMMRPIN &#xD56D; &#xCCB4;&#xB85C; &#xCDE8;&#xAE09; &#xD588;&#xB2E4; (0.2-1.0 mg) &#xBC18;&#xBA74;&#xC5D0; &#xB2E4;&#xB978; &#xADF8;&#xB8F9; &#xCEE8;&#xD2B8;&#xB864; &#xC5ED;&#xC784; 2-3 &#xC8FC; &#xB3D9;&#xC548; &#xB450; &#xBC88; &#xC8FC;&#xAC04;. &#xC794;&#xC5EC; &#xC885;&#xC591; &#xBAA8;&#xB378;&#xC5D0;&#xC11C; &#xC548;&#xD2F0; EMMPRIN &#xB300;&#xC6B0; &#xADF8;&#xB8F9;&#xC758; &#xC885;&#xC591; &#xC131;&#xC7A5;&#xC740; &#xC131;&#xACF5;&#xC801;&#xC73C;&#xB85C; 21 &#xC77C; (15 &plusmn; 4 mm(3)), EMMPRIN &#xCD5C;&#xC800;&#xC758; &#xADF8;&#xB8F9; (80 &plusmn; 15 mm(3); &#xBCF4;&#xB2E4; &#xD604;&#xC800; &#xD558; &#xAC8C; &#xB0AE;&#xC740; &#xC774;&#xC5C8;&#xB358;&#xC5D0; &#xB300; &#xD55C; &#xCCB4;&#xD3EC; &#xB410;&#xB2E4; P = 0.001) &#xB610;&#xB294; &#xCEE8;&#xD2B8;&#xB864; &#xADF8;&#xB8F9; (240 &plusmn; 41 mm(3); P &lt; 0.001). &#xC124;&#xB9BD;&#xB41C; &#xC885;&#xC591; &#xBAA8;&#xB378;&#xC5D0;&#xC11C; &#xC548;&#xD2F0; EMMPRIN &#xCE58;&#xB8CC; &#xC885;&#xC591; &#xBCFC;&#xB968; &#xC99D;&#xAC00; &#xBCF5;&#xC6A9;&#xB7C9; &#xAE08;&#xC561;&#xACFC; &#xAD00;&#xACC4; &#xC5C6;&#xC774; &#xCEE8;&#xD2B8;&#xB864;&#xC5D0; &#xBE44;&#xD574; &#xC57D; 40% &#xC778;&#xD558;. &#xADF8;&#xB8F9; 5&#xC758; Ki67 &#xD45C;&#xD604; &#xC140; &#xBC00;&#xB3C4; &#xADF8;&#xB8F9; 4 (1709 &plusmn; 145 mm(-2); &#xBCF4;&#xB2E4; &#xD604;&#xC800; &#xD558; &#xAC8C; &#xB0AE;&#xC740; 939 &plusmn; 150 mm(-2) P = 0.006). &#xADF8;&#xB8F9; 5&#xC758; Microvessel &#xBC00;&#xB3C4; (30 &plusmn; 6 mm(-2))&#xB294; &#xB610;&#xD55C; &#xADF8;&#xB8F9; 4 (53 &plusmn; 5 mm(-2);&#xC758; &#xADF8;&#xAC83; &#xBCF4;&#xB2E4; &#xD6E8;&#xC52C; &#xB0AE;&#xC740; P = 0.014), &#xBC18;&#xBA74; &#xADF8;&#xB8F9; 5&#xC758; microvessel &#xD06C;&#xAE30; (191 &plusmn; 22 &mu;m(2)) &#xD06C;&#xAC8C; &#xCD08;&#xACFC; &#xD558;&#xB294; &#xADF8;&#xB8F9; 4 (113 &plusmn; 26 &mu;m(2); P = 0049). &#xC774;&#xB7EC;&#xD55C; &#xB370;&#xC774;&#xD130;&#xB294; &#xB192;&#xC740; &#xCDCC;&#xC7A5;&#xC554;&#xC5D0; &#xB300; &#xD55C; &#xC548;&#xD2F0;-EMMPRIN &#xCE58;&#xB8CC;&#xC758; &#xC7A0;&#xC7AC;&#xC801;&#xC778; &#xD45C;&#xC2DC; &#xD558; &#xACE0; &#xC784;&#xC0C1;&#xC758; &#xBC88;&#xC5ED; &#xC9C0;&#xC6D0;.

&#xCDCC;&#xC7A5;&#xC554; &#xCE58;&#xB8CC;&#xC5D0; &#xB300; &#xD55C; &#xC18C;&#xC124;&#xC744; &#xB300;&#xC0C1;&#xC73C;&#xB85C; Extracelluar &#xB9E4;&#xD2B8;&#xB9AD;&#xC2A4; metalloproteinase.

El objetivo de este estudio fue evaluar la metaloproteinasa de la matriz extracelular (EMMPRIN) como una nueva Diana en modelos murinos de c&aacute;ncer pancre&aacute;tico ortot&oacute;pico. Las c&eacute;lulas del tumor pancre&aacute;tico humano MIA PaCa-2 fueron implantadas en los grupos 1 y 3-7, mientras que las c&eacute;lulas precipitaci&oacute;n MIA PaCa-2 EMMPRIN fueron implantadas en el grupo 2. Dosificaci&oacute;n con anticuerpos anti-EMMPRIN iniciado inmediatamente despu&eacute;s de la implantaci&oacute;n para grupos de 1-3 (modelo de tumor residual) y a los 21 d&iacute;as despu&eacute;s de la implantaci&oacute;n de la c&eacute;lula para grupos de 4-7 (modelo de tumor establecido). Grupos de 3, 5 y 7 fueron tratados con el anticuerpo anti-EMMRPIN (0.2-1.0 mg) dos veces por semana durante 2-3 semanas, mientras que los otros grupos sirven como control. En el modelo de tumor residual, el crecimiento del tumor de grupo anti-EMMPRIN-tratado con &eacute;xito fue detenido durante 21 d&iacute;as (15 &plusmn; 4 mm(3)), que fue significativamente menor que la del grupo precipitaci&oacute;n EMMPRIN (80 &plusmn; 15 mm(3); P = 0.001) o el grupo de control (240 &plusmn; 41 mm(3); P &lt; 0.001). En el modelo establecido del tumor, terapia anti-EMMPRIN reducido aumento del volumen del tumor por aproximadamente 40% en comparaci&oacute;n con el control, sin importar la cantidad de dosis. Densidad de c&eacute;lulas Ki67 expresados del grupo 5 fue 939 &plusmn; 150 mm(-2), que fue significativamente menor que la del grupo 4 (1709 &plusmn; 145 mm(-2); P = 0.006). Densidad de microvasos del grupo 5 (30 &plusmn; 6 mm(-2)) fue tambi&eacute;n significativamente menor que la del grupo 4 (53 &plusmn; 5 mm(-2); P = 0.014), mientras que el tama&ntilde;o de los microvasos del grupo 5 (191 &plusmn; 22 &mu;m(2)) fue significativamente mayor que el del grupo 4 (113 &plusmn; 26 &mu;m(2); P = 0.049). Estos datos demuestran el alto potencial de la terapia anti-EMMPRIN para el c&aacute;ncer pancre&aacute;tico y apoyan su traducci&oacute;n cl&iacute;nica.

Metaloproteinasa de la matriz de extracelluar como una nueva diana para el tratamiento de c&aacute;ncer de p&aacute;ncreas.

&#x8FD9;&#x9879;&#x7814;&#x7A76;&#x7684;&#x76EE;&#x6807;&#x662F;&#x8BC4;&#x4F30;&#x8054;&#x5408;&#x7EC6;&#x80DE;&#x5916;&#x57FA;&#x8D28;&#x7684;&#x7597;&#x6548;&#x91D1;&#x5C5E;&#x86CB;&#x767D;&#x9176;&#x8BF1;&#x5BFC;&#x56E0;&#x5B50; (EMMPRIN) &#x548C; 5 (DR5) &#x6B7B;&#x4EA1;&#x53D7;&#x4F53;&#x9776;&#x5411;&#x6CBB;&#x7597;&#x7684;&#x80F0;&#x817A;&#x764C;&#x5728;&#x539F;&#x4F4D;&#x5C0F;&#x9F20;&#x6A21;&#x578B;&#x4E0E;&#x591A;&#x5F0F;&#x8054;&#x8FD0;&#x7684;&#x6210;&#x50CF;&#x3002;&#x6297; EMMPRIN &#x6297;&#x4F53;&#x548C;&#x6297; DR5 &#x6297;&#x4F53; (TRA-8&#xFF09; MIA PaCa 2 &#x548C;&#x6F58;&#x8328;-1 &#x7684;&#x7EC6;&#x80DE;&#x682A;&#x7684;&#x7EC6;&#x80DE;&#x6BD2;&#x4F5C;&#x7528;&#x662F; ATPlite &#x4F53;&#x5916;&#x7528;&#x6765;&#x8861;&#x91CF;&#x7684;&#x3002;&#x5206;&#x5E03;&#x7684; Cy5.5 &#x6807;&#x8BB0; TRA 8 &#x548C; Cy3 &#x6807;&#x8BB0;&#x6297;-EMMPRIN &#x6297;&#x4F53; 2 &#x7EC6;&#x80DE;&#x7CFB;&#x4F53;&#x5916;&#x8367;&#x5149;&#x6210;&#x50CF;&#x6280;&#x672F;&#x8FDB;&#x884C;&#x5206;&#x6790;&#x3002;&#x7EC4; 1 &#x5230; 12 &#x7684;&#x8F74;&#x627F;&#x539F;&#x4F4D; MIA PaCa-2 &#xFF08;&#x7EC4; 1-8&#xFF09; &#x6216;&#x6F58;&#x8328;-1 (9-12 &#x7EC4;&#xFF09; &#x7684;&#x4E25;&#x91CD;&#x8054;&#x5408;&#x514D;&#x75AB;&#x7F3A;&#x9677;&#x5C0F;&#x9F20;&#x80BF;&#x7624;&#x7528;&#x4E8E;&#x4F53;&#x5185;&#x7814;&#x7A76;&#x3002;&#x52A8;&#x6001;&#x5BF9;&#x6BD4;&#x5EA6;-&#x589E;&#x5F3A;&#x78C1;&#x5171;&#x632F;&#x6210;&#x50CF;&#x9002;&#x7528;&#x4E8E;&#x7B2C; 1 &#x7EC4; &#xFF08;&#x6CBB;&#x7597;&#xFF09; &#x6216;&#x7EC4; 2 (&#x6297; EMMPRIN &#x6297;&#x4F53;)&#x3002;Tc 99 m &#x6807;&#x8BB0; TRA 8 &#x80BF;&#x7624;&#x5438;&#x6536;&#x8BA1;&#x91CF;&#x5355;&#x4F4D;&#x7EC4; 3 (&#x672A;&#x7ECF;&#x5904;&#x7406;&#xFF09; &#x548C;&#x7EC4; 4 (&#x6297; EMMPRIN &#x6297;&#x4F53;)&#x3002;&#x6B63;&#x7535;&#x5B50;&#x53D1;&#x5C04;&#x65AD;&#x5C42;&#x626B;&#x63CF;/&#x8BA1;&#x7B97;&#x65AD;&#x5C42;&#x663E;&#x50CF;&#x5BF9; 18F-FDG (18) &#x88AB;&#x5E94;&#x7528;&#x4E8E;&#x7EC4; 11:55 &#x4E0A;&#x5348;&#x3002;5 &#x5230; 8 &#x7EC4; &#xFF08;&#x6216;&#x7EC4; 9 &#x5230; 12&#xFF09; &#x672A;&#x7ECF;&#x5904;&#x7406;&#x6216;&#x6297; EMMPRIN &#x6297;&#x4F53;&#x3001; TRA-8&#x3001; &#x7EC4;&#x5408;&#xFF0C;&#x5206;&#x522B;&#x6CBB;&#x7597;&#x3002;TRA 8 &#x663E;&#x793A; MIA PaCa 2 &#x548C;&#x6F58;&#x8328;-1 &#x5355;&#x5143;&#x683C;&#x9AD8;&#x6740;&#x706D;&#x4F53;&#x5916;&#xFF0C;&#x4F46;&#x989D;&#x5916;&#x7684;&#x6297; EMMPRIN &#x6CBB;&#x7597;&#x6CA1;&#x6709;&#x6539;&#x5584;&#x7EC6;&#x80DE;&#x6BD2;&#x6027;&#x4F5C;&#x7528;&#x3002;Cy5.5-TRA-8 &#x5F62;&#x6210;&#x8702;&#x7A9D;&#x5E3D;&#x5728;&#x8FD9;&#x4E24;&#x4E2A;&#x5355;&#x5143;&#x683C;&#x884C;&#x4E2D;&#xFF0C;&#x800C;&#x4E0E;&#x94C1;&#x8DEF;&#x5C40; 8 &#x7EC6;&#x80DE;&#x6BD2;&#x6027;&#x76F8;&#x5173;&#x7684;&#x6700;&#x5927;&#x4FE1;&#x53F7;&#x5F3A;&#x5EA6;&#x3002;&#x6297; EMMPRIN &#x7597;&#x6CD5;&#x5927;&#x5927;&#x589E;&#x5F3A;&#x4E86;&#x80BF;&#x7624; MR &#x5BF9;&#x6BD4;&#x5242;&#xFF0C;&#x4F46;&#x4E0D;&#x662F; Tc-99 m-TRA-8&#x3002;&#x7EC4;&#x5408;&#x7597;&#x6CD5;&#xFF0C;&#x5927;&#x5927;&#x6291;&#x5236;&#x4E86;&#x80BF;&#x7624;&#x7684;&#x751F;&#x957F;&#x548C;&#x6DFB;&#x52A0;&#x5242;&#x6548;&#x679C;&#x7684;&#x7EC4;&#x5408; MIA PaCa 2 &#x548C;&#x6F58;&#x8328;-1 &#x80BF;&#x7624;&#x6A21;&#x578B;&#x4E2D;&#x6240;&#x793A;&#x3002;Mol &#x764C;&#x75C7;&#x90A3;&#x91CC; &#xFF1B;11 (2) &#xFF1B;405 15.&copy; 2011 AACR&#x3002;

&#x9488;&#x5BF9; DR5 &#x548C; EMMPRIN &#x5728;&#x80F0;&#x817A;&#x764C;&#x7EC4;&#x7EC7;&#x4E2D;&#x7684;&#x53CC;&#x91CD;&#x7EC4;&#x5408;&#x7597;&#x6CD5;&#x3002;

The goal of the study was to assess the efficacy of combined extracellular matrix metalloprotease inducer (EMMPRIN)- and death receptor 5 (DR5)-targeted therapy for pancreatic adenocarcinoma in orthotopic mouse models with multimodal imaging. Cytotoxicity of anti-EMMPRIN antibody and anti-DR5 antibody (TRA-8) in MIA PaCa-2 and PANC-1 cell lines was measured by ATPlite assay in vitro. The distributions of Cy5.5-labeled TRA-8 and Cy3-labeled anti-EMMPRIN antibody in the 2 cell lines were analyzed by fluorescence imaging in vitro. Groups 1 to 12 of severe combined immunodeficient mice bearing orthotopic MIA PaCa-2 (groups 1-8) or PANC-1 (groups 9-12) tumors were used for in vivo studies. Dynamic contrast-enhanced-MRI was applied in group 1 (untreated) or group 2 (anti-EMMPRIN antibody). The tumor uptake of Tc-99m-labeled TRA-8 was measured in group 3 (untreated) and group 4 (anti-EMMPRIN antibody). Positron emission tomography/computed tomography imaging with (18)F-FDG was applied in groups 5 to 12. Groups 5 to 8 (or groups 9 to 12) were untreated or treated with anti-EMMPRIN antibody, TRA-8, and combination, respectively. TRA-8 showed high killing efficacy for both MIA PaCa-2 and PANC-1 cells in vitro, but additional anti-EMMPRIN treatment did not improve the cytotoxicity. Cy5.5-TRA-8 formed cellular caps in both the cell lines, whereas the maximum signal intensity was correlated with TRA-8 cytotoxicity. Anti-EMMPRIN therapy significantly enhanced the tumor delivery of the MR contrast agent, but not Tc-99m-TRA-8. Tumor growth was significantly suppressed by the combination therapy, and the additive effect of the combination was shown in both MIA PaCa-2 and PANC-1 tumor models. Mol Cancer Ther; 11(2); 405-15. Â©2011 AACR.

Dual Combination Therapy Targeting DR5 and EMMPRIN in Pancreatic Adenocarcinoma.

L&#39;objectif de l&#39;&eacute;tude &eacute;tait d&#39;&eacute;valuer l&#39;efficacit&eacute; de la matrice extracellulaire combin&eacute;e m&eacute;talloprot&eacute;ase inducteur (EMMPRIN) - et les r&eacute;cepteurs de mort 5 (DR5) - traitement cibl&eacute; contre un ad&eacute;nocarcinome pancr&eacute;atique dans des mod&egrave;les murins orthotopique avec imagerie multimodale. Cytotoxicit&eacute; des anticorps anti-EMMPRIN et anticorps d&#39;anti-DR5 (TRA-8) dans les lign&eacute;es cellulaires MIA PaCa-2 et PANC-1 a &eacute;t&eacute; mesur&eacute;e par dosage ATPlite in vitro. Les distributions des anticorps marqu&eacute;s Cy5. 5 TRA-8 et marqu&eacute;s au Cy3 anti-EMMPRIN dans les lign&eacute;es 2 cellulaires ont &eacute;t&eacute; analys&eacute;es par imagerie de fluorescence in vitro. Tumeurs des groupes 1 &agrave; 12 de graves souris immunod&eacute;ficientes combin&eacute;s portant orthotopique MIA PaCa-2 (groupes 1-8) ou PANC-1 (9-12 groupes) ont &eacute;t&eacute; utilis&eacute;s pour des &eacute;tudes in vivo. Dynamic contrast-am&eacute;lior&eacute;e-MRI a &eacute;t&eacute; appliqu&eacute; dans le groupe 1 (non trait&eacute;) ou groupe 2 (anticorps anti-EMMPRIN). Le pr&eacute;l&egrave;vement de tumeur de Tc-99 m-&eacute;tiquet&eacute; TRA-8 a &eacute;t&eacute; mesur&eacute;e dans le groupe 3 (non trait&eacute;) et le groupe 4 (anticorps anti-EMMPRIN). Tomographie par &eacute;mission de positons/calcul&eacute;e d&#39;imagerie par tomographie avec F-FDG (18) a &eacute;t&eacute; appliqu&eacute; dans les groupes 11:55. Groupes de 5 &agrave; 8 (ou 9 &agrave; 12) &eacute;taient non trait&eacute;es ou trait&eacute;es avec des anticorps anti-EMMPRIN, TRA-8 et combinaison, respectivement. TRA-8 a montr&eacute; meurtre haute efficacit&eacute; pour les cellules de la MIA PaCa-2 et PANC-1 in vitro, mais traitement anti-EMMPRIN suppl&eacute;mentaires n&#39;am&eacute;liorait pas la cytotoxicit&eacute;. TRA-Cy5. 5-8 form&eacute; casquettes cellulaires dans les deux lign&eacute;es cellulaires, tandis que l&#39;intensit&eacute; maximale du signal a &eacute;t&eacute; corr&eacute;l&eacute;e avec la cytotoxicit&eacute; de la TRA-8. La th&eacute;rapie anti-EMMPRIN a consid&eacute;rablement accru la livraison de tumeur de l&#39;agent de contraste de Monsieur, mais pas Tc-99 m-TRA-8. La croissance tumorale a &eacute;t&eacute; significativement supprim&eacute;e par la trith&eacute;rapie, et l&#39;effet additif de la combinaison a &eacute;t&eacute; montr&eacute; dans la MIA PaCa-2 et PANC-1 mod&egrave;les de tumeur. Mol Ther de Cancer ; 11 (2) ; 405-15. &copy; 2011 AACR.

Polyth&eacute;rapie double ciblage DR5 et EMMPRIN dans l&#39;ad&eacute;nocarcinome pancr&eacute;atique.

Ziel der Studie war es, bewerten die Wirksamkeit der kombinierten extrazellul&auml;ren Matrix Metalloproteinase Induktor (EMMPRIN)- und Tod-Rezeptor 5 (DR5) - gezielte Therapie f&uuml;r Pankreas Adenokarzinom in Orthotopic Mausmodelle mit multimodale Bildgebung. Zytotoxizit&auml;t der Anti-EMMPRIN-Antik&ouml;rper und Anti-DR5 Antik&ouml;rper (TRA-8) in MIA PaCa-2 und PANC-1 Zelllinien wurde durch in-vitro-ATPlite-Assay gemessen. Die Verteilungen von beschrifteten Cy5.5 TRA-8 und Cy3-markierten Anti-EMMPRIN-Antik&ouml;rper bei der 2 Zelllinien wurden durch in-vitro-Fluoreszenz-Bildgebung analysiert. Gruppen 1 bis 12 von schweren kombinierten immungeschw&auml;chte M&auml;use mit Orthotopic MIA PaCa-2 (1-8 Gruppen) oder PANC-1 (9-12 Gruppen) Tumoren dienten f&uuml;r in-vivo-Studien. Dynamische Kontrast-verst&auml;rkte-MRI Gruppe 2 (Anti-EMMPRIN Antik&ouml;rper) oder war in Gruppe 1 (unbehandelt) angewendet. Die Tumor-Aufnahme von Tc-99 m-markierten TRA-8 wurde in Gruppe 3 (unbehandelt) gemessen und Gruppe 4 (Anti-EMMPRIN-Antik&ouml;rper). Positronen-Emissions-Tomographie/berechnet Tomographie-Bildgebung mit (18) F-FDG wurde in Gruppen 11:55 angewendet. Gruppen 5 bis 8 (oder Gruppen 9 bis 12) wurden unbehandelt oder Anti-EMMPRIN Antik&ouml;rper, TRA-8 und Kombination, behandelt. TRA-8 zeigte hohe T&ouml;tung Wirksamkeit f&uuml;r MIA PaCa-2 und PANC-1 Zellen in vitro, aber zus&auml;tzliche Anti-EMMPRIN Behandlung nicht verbessern, die Zytotoxizit&auml;t. Cy5.5-TRA-8 gebildet zellul&auml;re Kappen in den Zelllinien, w&auml;hrend der maximale Signalintensit&auml;t mit TRA-8 Zytotoxizit&auml;t korrelierte. Anti-EMMPRIN Therapie verbessert signifikant die Tumor-Lieferung der MR-Kontrastmittel, aber nicht Tc-99 m-TRA-8. Tumorwachstum wurde wesentlich durch die Kombinationstherapie unterdr&uuml;ckt, und die additive Wirkung der Kombination wurde in MIA PaCa-2 und PANC-1 Tumor-Modelle gezeigt. Mol Cancer Ther; 11 Absatz 2; 405-15. &copy; 2011 AACR.

Dual-Kombinationstherapie Targeting DR5 und EMMPRIN im Pankreas Adenokarzinom.

L&#39;obiettivo dello studio &egrave; stato quello di valutare l&#39;efficacia della matrice extracellulare combinato metalloprotease induttore (EMMPRIN) - e il recettore di morte 5 (DR5) - mirata terapia per adenocarcinoma pancreatico in modelli murini ortotopico con imaging multimodale. Citotossicit&agrave; anticorpo anti-EMMPRIN e anticorpo anti-DR5 (TRA-8) in linee cellulari MIA PaCa-2 e PANC-1 &egrave; stata misurata mediante ATPlite saggio in vitro. Le distribuzioni di anticorpo marcato con incubiamo TRA-8 e Cy3-etichetta anti-EMMPRIN nelle linee 2 cellulari sono state analizzate da imaging di fluorescenza in vitro. I tumori gruppi da 1 a 12 di gravi combinati topi immunodeficienti cuscinetto ortotopico MIA PaCa-2 (gruppi 1-8) o PANC-1 (gruppi di 9-12) sono stati utilizzati per studi in vivo. Dinamico contrasto-enhanced-MRI &egrave; stato applicato nel gruppo 1 (non trattata) o gruppo 2 (anticorpo anti-EMMPRIN). La captazione tumorale di Tc-99 m-etichettato TRA-8 &egrave; stata misurata nel gruppo 3 (non trattata) e 4 (anticorpo anti-EMMPRIN). Immagini di tomografia tomografia ad emissione di positroni/calcolata con (18) F-FDG &egrave; stata applicata in gruppi 11:55. Gruppi di 5-8 (o gruppi di 9-12) erano non trattati o trattati con anticorpo anti-EMMPRIN, TRA-8 e combinazione, rispettivamente. TRA-8 ha dimostrato uccisione ad alta efficacia per la MIA PaCa-2 sia PANC-1 cellule in vitro, ma trattamento supplementare anti-EMMPRIN non migliorare la citotossicit&agrave;. Incubiamo-TRA-8 formato cellulare tappi in entrambe le linee cellulari, considerando che l&#39;intensit&agrave; massima del segnale &egrave; stata correlata con citotossicit&agrave; TRA-8. La terapia anti-EMMPRIN notevolmente migliorato la consegna di tumore del signor agente di contrasto, ma non Tc-99 m-TRA-8. Crescita tumorale era significativamente soppressa per la terapia di combinazione, e l&#39;effetto additivo della combinazione &egrave; stato dimostrato in modelli di tumore sia MIA PaCa-2 e PANC-1. Mol Cancer Ther; 11, paragrafo 2; 405-15. &copy; 2011 AACR.

Doppia terapia di combinazione di Targeting DR5 ed EMMPRIN in Adenocarcinoma pancreatico.

&#x7D30;&#x80DE;&#x5916;&#x57FA;&#x8CEA;&#x7D50;&#x5408;&#x306E;&#x6709;&#x52B9;&#x6027;&#x3092;&#x8A55;&#x4FA1;&#x3059;&#x308B;&#x7814;&#x7A76;&#x306E;&#x76EE;&#x6A19;&#x3060;&#x3063;&#x305F;&#x30E1;&#x30BF;&#x30ED;&#x30D7;&#x30ED;&#x30C6;&#x30A2;&#x30FC;&#x30BC; &#x30A4;&#x30F3;&#x30C7;&#x30E5;&#x30FC;&#x30B5; &#xFF08;EMMPRIN&#xFF09; - &#x3068;&#x6B7B;&#x53D7;&#x5BB9;&#x4F53; 5 (DR5) - &#x6A19;&#x7684;&#x7642;&#x6CD5;&#x81B5;&#x817A;&#x764C;&#x306B;&#x304A;&#x3051;&#x308B;&#x540C;&#x6240;&#x6027;&#x540C;&#x7A2E;&#x30DE;&#x30A6;&#x30B9; &#x30E2;&#x30C7;&#x30EB;&#x3092;&#x30DE;&#x30EB;&#x30C1; &#x30E2;&#x30FC;&#x30C0;&#x30EB; &#x30A4;&#x30E1;&#x30FC;&#x30B8;&#x30F3;&#x30B0;&#x3002;&#x6297; EMMPRIN &#x6297;&#x4F53;&#x3068;&#x6297; DR5 &#x6297;&#x4F53; (TRA-8) MIA &#x30D1;&#x30AB; 2 &#x3068; PANC 1 &#x7D30;&#x80DE;&#x682A;&#x306E;&#x7D30;&#x80DE;&#x6BD2;&#x6027; ATPlite &#x3092; in vitro &#x3067;&#x6E2C;&#x5B9A;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;2 &#x7D30;&#x80DE;&#x682A; Cy5.5 &#x30E9;&#x30D9;&#x30EB; TRA 8 &#x3068; Cy3 &#x6A19;&#x8B58;&#x6297;-EMMPRIN &#x6297;&#x4F53;&#x306E;&#x5206;&#x5E03;&#x8A66;&#x9A13;&#x7BA1;&#x5185;&#x306E;&#x86CD;&#x5149;&#x30A4;&#x30E1;&#x30FC;&#x30B8;&#x30F3;&#x30B0;&#x306B;&#x3088;&#x308B;&#x5206;&#x6790;&#x3092;&#x884C;&#x3044;&#x307E;&#x3057;&#x305F;&#x3002;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 1 &#x306B; 12 &#x306E;&#x540C;&#x6240;&#x6027;&#x540C;&#x7A2E; MIA &#x30D1;&#x30AB;-2 (&#x30B0;&#x30EB;&#x30FC;&#x30D7; 1-8) &#x307E;&#x305F;&#x306F; PANC-1 &#xFF08;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 9-12&#xFF09; &#x8EF8;&#x53D7;&#x91CD;&#x75C7;&#x8907;&#x5408;&#x514D;&#x75AB;&#x4E0D;&#x5168;&#x30DE;&#x30A6;&#x30B9;&#x816B;&#x760D;&#x306F; in vivo &#x3067;&#x306E;&#x7814;&#x7A76;&#x306E;&#x305F;&#x3081;&#x306B;&#x4F7F;&#x7528;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x30C0;&#x30A4;&#x30CA;&#x30DF;&#x30C3;&#x30AF; &#x30B3;&#x30F3;&#x30C8;&#x30E9;&#x30B9;&#x30C8;-&#x5F37;&#x5316;-MRI (&#x672A;&#x51E6;&#x7406;) &#x30B0;&#x30EB;&#x30FC;&#x30D7; 1 &#x304C;&#x9069;&#x7528;&#x3055;&#x308C;&#x305F;&#x307E;&#x305F;&#x306F;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 2 &#xFF08;&#x6297; EMMPRIN &#x6297;&#x4F53;&#xFF09;&#x3002;Tc 99 TRA 8 m &#x3068;&#x30E9;&#x30D9;&#x30EB;&#x8868;&#x793A;&#x306E;&#x816B;&#x760D;&#x53D6;&#x308A;&#x8FBC;&#x307F;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 3 (&#x672A;&#x51E6;&#x7406;) &#x3068;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 4 &#xFF08;&#x6297; EMMPRIN &#x6297;&#x4F53;) &#x306B;&#x6E2C;&#x5B9A;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x967D;&#x96FB;&#x5B50;&#x653E;&#x5C04;&#x65AD;&#x5C64;&#x64AE;&#x5F71;/&#x8A08;&#x7B97;&#x65AD;&#x5C64;&#x30A4;&#x30E1;&#x30FC;&#x30B8;&#x30F3;&#x30B0; (18) F-FDG &#x3068;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 11:55 &#x3067;&#x9069;&#x7528;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;5 &#x306B; 8 &#x306E;&#x30B0;&#x30EB;&#x30FC;&#x30D7; (&#x307E;&#x305F;&#x306F;&#x30B0;&#x30EB;&#x30FC;&#x30D7; 9 &#x306B; 12) &#x3055;&#x308C;&#x305F;&#x672A;&#x6CBB;&#x7642;&#x307E;&#x305F;&#x306F;&#x6297; EMMPRIN &#x6297;&#x4F53;&#x3001;TRA 8 &#x3068;&#x7D44;&#x307F;&#x5408;&#x308F;&#x305B;&#x3001;&#x305D;&#x308C;&#x305E;&#x308C;&#x306E;&#x51E6;&#x7406;&#x3057;&#x307E;&#x3059;&#x3002;TRA 8 &#x9AD8;&#x6BBA;&#x5BB3;&#x52B9;&#x529B; MIA &#x30D1;&#x30AB; 2 &#x3068; PANC 1 &#x7D30;&#x80DE;&#x3092; in vitro &#x3067;&#x793A;&#x3057;&#x305F;&#x304C;&#x3001;&#x8FFD;&#x52A0;&#x306E;&#x53CD; EMMPRIN &#x6CBB;&#x7642;&#x7D30;&#x80DE;&#x6BD2;&#x6027;&#x3092;&#x6539;&#x5584;&#x3057;&#x306A;&#x304B;&#x3063;&#x305F;&#x3002;&#x6700;&#x5927;&#x4FE1;&#x53F7;&#x5F37;&#x5EA6; TRA 8 &#x7D30;&#x80DE;&#x6BD2;&#x6027;&#x3068;&#x76F8;&#x95A2;&#x3057;&#x3066;&#x3044;&#x305F;&#x306B;&#x5BFE;&#x3057; Cy5.5 TRA 8 &#x4E21;&#x7D30;&#x80DE;&#x682A;&#x306B;&#x304A;&#x3051;&#x308B;&#x7D30;&#x80DE;&#x30AD;&#x30E3;&#x30C3;&#x30D7;&#x3092;&#x5F62;&#x6210;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x30A2;&#x30F3;&#x30C1; EMMPRIN &#x7642;&#x6CD5;&#x306F;&#x816B;&#x760D;&#x914D;&#x4FE1; MR &#x9020;&#x5F71;&#x5264;&#x304C;&#x306A;&#x3044; Tc 99 m-TRA-8 &#x306E;&#x8457;&#x3057;&#x304F;&#x9AD8;&#x3081;&#x3089;&#x308C;&#x307E;&#x3059;&#x3002;&#x4F75;&#x7528;&#x7642;&#x6CD5;&#x306B;&#x3088;&#x3063;&#x3066;&#x816B;&#x760D;&#x306E;&#x6210;&#x9577;&#x3092;&#x6709;&#x610F;&#x306B;&#x6291;&#x5236;&#x3055;&#x308C;&#x3001;&#x7D44;&#x307F;&#x5408;&#x308F;&#x305B;&#x306E;&#x6DFB;&#x52A0;&#x52B9;&#x679C;&#x306F; MIA &#x30D1;&#x30AB; 2 &#x3068; PANC 1 &#x306E;&#x816B;&#x760D;&#x30E2;&#x30C7;&#x30EB;&#x3067;&#x793A;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;Mol &#x304C;&#x3093; Ther;11 (2);405 15. &copy; 2011 AACR&#x3002;

&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8; DR5 &#x3068;&#x81B5;&#x81D3;&#x817A;&#x764C;&#x306B;&#x304A;&#x3051;&#x308B; EMMPRIN &#x30C7;&#x30E5;&#x30A2;&#x30EB;&#x306E;&#x7D44;&#x307F;&#x5408;&#x308F;&#x305B;&#x7642;&#x6CD5;&#x3002;

&#xC5F0;&#xAD6C;&#xC758; &#xBAA9;&#xD45C;&#xB294; &#xACB0;&#xD569; &#xD558; &#xC5EC; &#xC138;&#xD3EC; &#xC678; &#xB9E4;&#xD2B8;&#xB9AD;&#xC2A4;&#xC758; &#xD6A8;&#xB2A5;&#xC744; &#xD3C9;&#xAC00; &#xD558;&#xAE30; &#xC704;&#xD574; metalloprotease &#xC720;&#xB3C4; (EMMPRIN)-&#xC640; &#xC8FD;&#xC74C; &#xC218;&#xC6A9; &#xCCB4; 5 (DR5)-&#xB300;&#xC0C1; &#xBCF5;&#xD569; &#xC601;&#xC0C1;&#xC73C;&#xB85C; orthotopic &#xB9C8;&#xC6B0;&#xC2A4; &#xBAA8;&#xB378;&#xC5D0;&#xC11C; &#xCDCC; &#xC7A5; &#xC120; &#xC554;&#xC5D0; &#xB300; &#xD55C; &#xCE58;&#xB8CC;. &#xC548;&#xD2F0;-EMMPRIN &#xD56D; &#xCCB4;&#xC640; &#xC548;&#xD2F0;-DR5 &#xD56D; &#xCCB4; (TRA-8) &#xBBF8;&#xC544; PaCa 2 &#xBC0F; PANC-1 &#xC140; &#xB77C;&#xC778;&#xC5D0;&#xC11C;&#xC758; &#xC138;&#xD3EC; &#xB3C5;&#xC131; ATPlite &#xBD84;&#xC11D; &#xACB0;&#xACFC; &#xCCB4; &#xC678;&#xC5D0;&#xC11C; &#xCE21;&#xC815; &#xB418;&#xC5C8;&#xB2E4;. 2 &#xC140; &#xB77C;&#xC778;&#xC5D0; &#xC788;&#xB294; Cy5.5 &#xD45C;&#xC2DC; &#xB41C; TRA-8, Cy3 &#xB77C;&#xB294; &#xC548;&#xD2F0;-EMMPRIN &#xD56D; &#xCCB4;&#xC758; &#xBC30;&#xD3EC;&#xD310; &#xCCB4; &#xC678; &#xD615;&#xAD11; &#xC774;&#xBBF8;&#xC9D5;&#xC73C;&#xB85C; &#xBD84;&#xC11D; &#xD588;&#xB2E4;. &#xADF8;&#xB8F9; 1 ~ 12 &#xBCA0;&#xC5B4;&#xB9C1; &#xBBF8;&#xC544; PaCa-2 (&#xADF8;&#xB8F9; 1-8) orthotopic &#xB610;&#xB294; PANC-1 (&#xADF8;&#xB8F9; 9-12) &#xC2EC;&#xD55C; &#xACB0;&#xD569;&#xB41C; immunodeficient &#xC950;&#xC758; &#xC885;&#xC591;&#xC740; in vivo &#xC5F0;&#xAD6C;&#xC5D0; &#xC0AC;&#xC6A9; &#xB418;&#xC5C8;&#xB2E4;. &#xB3D9;&#xC801; &#xB300;&#xBE44;-&#xAC15;&#xD654;-MRI &#xADF8;&#xB8F9; 1 (&#xCE58;&#xB8CC;)&#xC5D0; &#xC801;&#xC6A9; &#xD558;&#xAC70;&#xB098; &#xADF8;&#xB8F9; 2 (&#xC548;&#xD2F0;-EMMPRIN &#xD56D; &#xCCB4;). 99 M t c &#xD45C;&#xC2DC; &#xB41C; TRA 8 &#xC885;&#xC591; &#xD1B5;&#xD48D; &#xAD00; &#xADF8;&#xB8F9; 3 (&#xCE58;&#xB8CC;)&#xC5D0;&#xC11C; &#xCE21;&#xC815; &#xD588;&#xB2E4; &#xBC0F; 4 (&#xC548;&#xD2F0;-EMMPRIN &#xD56D; &#xCCB4;)&#xB97C; &#xADF8;&#xB8F9;&#xD654; &#xD569;&#xB2C8;&#xB2E4;. (18) F FDG&#xC640; &#xC591;&#xC804;&#xC790; &#xBC29;&#xCD9C; &#xB2E8;&#xCE35; &#xCD2C;&#xC601;/&#xACC4;&#xC0B0; &#xB41C; &#xB2E8;&#xCE35; &#xCD2C;&#xC601; &#xC774;&#xBBF8;&#xC9D5; &#xADF8;&#xB8F9; 5 ~ 12&#xC5D0; &#xC801;&#xC6A9; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xADF8;&#xB8F9; 5-8 (&#xB610;&#xB294; 9 ~ 12 &#xADF8;&#xB8F9;) &#xCE58;&#xB8CC; &#xB610;&#xB294; &#xCE58;&#xB8CC; &#xC548;&#xD2F0;-EMMPRIN &#xD56D; &#xCCB4;, TRA-8&#xC640; &#xC870;&#xD569;, &#xAC01;&#xAC01;. TRA-8 &#xCCB4; &#xC678;, &#xBBF8;&#xC544; PaCa 2 &#xBC0F; PANC-1 &#xC140; &#xC8FD;&#xC774; &#xB192;&#xC740; &#xD6A8;&#xB2A5;&#xC744; &#xBCF4;&#xC600;&#xB2E4; &#xD558;&#xC9C0;&#xB9CC; &#xCD94;&#xAC00; &#xC548;&#xD2F0;-EMMPRIN &#xCE58;&#xB8CC;&#xB294; &#xC138;&#xD3EC; &#xB3C5;&#xC131; &#xAC1C;&#xC120; &#xB418;&#xC9C0; &#xC54A;&#xC558;&#xB2E4;. &#xBC18;&#xBA74; &#xCD5C;&#xB300; &#xC2E0;&#xD638; &#xAC15;&#xB3C4; TRA-8 &#xC138;&#xD3EC; &#xB3C5;&#xC131; &#xC5F0;&#xAD00; Cy5.5 TRA 8 &#xBAA8;&#xB450; &#xC140; &#xB77C;&#xC778;, &#xC140;&#xB8F0;&#xB7EC; &#xBAA8;&#xC790; &#xD615;&#xC131;. &#xC548;&#xD2F0;-EMMPRIN &#xCE58;&#xB8CC;&#xB294; &#xD06C;&#xAC8C; &#xC885;&#xC591; &#xBC30;&#xB2EC; &#xBBF8;&#xC2A4;&#xD130; &#xB300;&#xBE44; &#xC5D0;&#xC774;&#xC804;&#xD2B8;, &#xD558;&#xC9C0;&#xB9CC; &#xD558;&#xC9C0; Tc-99 m-TRA-8&#xC758; &#xD5A5;&#xC0C1;. &#xCF64;&#xBE44;&#xB124;&#xC774;&#xC158; &#xCE58;&#xB8CC; &#xD558; &#xC5EC; &#xC885;&#xC591;&#xC758; &#xC131;&#xC7A5;&#xC744; &#xD06C;&#xAC8C; &#xC5B5;&#xC81C; &#xD558; &#xACE0; &#xC870;&#xD569;&#xC758; &#xCCA8;&#xAC00;&#xC81C; &#xD6A8;&#xACFC; &#xBBF8;&#xC544; PaCa 2 &#xBC0F; PANC-1 &#xC885;&#xC591; &#xBAA8;&#xB378;&#xC5D0;&#xC11C; &#xBCF4;&#xC5EC; &#xC92C;&#xB358;. Mol &#xC554; &#xAC70;&#xAE30;; 11(2); 405-15. &copy; 2011 AACR.

&#xB4C0;&#xC5BC; &#xCF64;&#xBE44;&#xB124;&#xC774;&#xC158; &#xCE58;&#xB8CC; DR5 &#xBC0F; &#xCDCC; &#xC7A5; &#xC120; &#xC554;&#xC5D0; EMMPRIN&#xB97C; &#xB300;&#xC0C1;&#xC73C;&#xB85C; &#xD569;&#xB2C8;&#xB2E4;.

El objetivo del estudio fue evaluar la eficacia de la matriz extracelular conjunta metalloprotease inductor (EMMPRIN) - y receptor de muerte 5 (DR5) - objeto de terapia para el adenocarcinoma pancre&aacute;tica en modelos de rat&oacute;n orthotopic con im&aacute;genes multimodales. Citotoxicidad de anti-EMMPRIN y el anticuerpo anti-DR5 (TRA-8) en las l&iacute;neas celulares MIA PaCa-2 y PANC-1 se midi&oacute; por ATPlite ensayo in vitro. Las distribuciones de anticuerpo marcado con Cy5.5 TRA-8 y marcado Cy3 anti-EMMPRIN en las l&iacute;neas 2 celulares se analizaron mediante im&aacute;genes de fluorescencia in vitro. Tumores de los grupos 1 a 12 de severas ratones inmunodeficientes combinados teniendo ortot&oacute;pico MIA PaCa-2 (grupos 1-8) o PANC-1 (grupos 9-12) fueron utilizados para estudios in vivo. Contraste din&aacute;mico-mejorada-MRI se aplic&oacute; en el grupo 1 (sin tratamiento) o grupo 2 (anticuerpos anti-EMMPRIN). La captaci&oacute;n de tumor de Tc-99 m-labeled TRA-8 se midi&oacute; en el grupo 3 (sin tratamiento) y grupo 4 (anticuerpos anti-EMMPRIN). Im&aacute;genes de tomograf&iacute;a computada de emisi&oacute;n de positrones/con (18) F-FDG se aplican en grupos 11:55. Grupos de 5 a 8 (o grupos de 9 a 12) fueron sin tratar o tratados con anticuerpos anti-EMMPRIN, TRA-8 y combinaci&oacute;n, respectivamente. TRA-8 mostraron una eficacia alta matar c&eacute;lulas MIA PaCa-2 tanto PANC-1 in vitro, pero tratamiento anti-EMMPRIN adicional no mejor&oacute; la citotoxicidad. Cy5.5-TRA-8 hab&iacute;a formado celulares tapones en las l&iacute;neas de la c&eacute;lula, mientras que la intensidad m&aacute;xima se correlacion&oacute; con la citotoxicidad de TRA-8. Terapia anti-EMMPRIN hab&iacute;a mejorado significativamente la entrega del tumor del Sr. agente de contraste, pero no de Tc-99 m-TRA-8. El crecimiento del tumor fue suprimido significativamente por la terapia de combinaci&oacute;n, y el efecto aditivo de la combinaci&oacute;n fue demostrado en modelos de tumores tanto MIA PaCa-2 y PANC-1. Mol c&aacute;ncer all&iacute;; 11 (2); 405-15. &copy; 2011 AACR.

Terapia de combinaci&oacute;n doble DR5 y EMMPRIN en Adenocarcinoma de p&aacute;ncreas.

To examine the antagonistic effects of anti-extracellular matrix metalloprotease inducer (anti-EMMPRIN) antibody when combined with chemotherapy using a hypovascular pancreatic tumor model.

Antagonistic effects of anti-EMMPRIN antibody when combined with chemotherapy against hypovascular pancreatic cancers.

To assess the early response of triple-negative breast-cancer (TNBC) following TRA-8 and carboplatin therapy using DWI and MRS in 2LMP and SUM159 mouse models.

Early therapy assessment of combined anti-DR5 antibody and carboplatin in triple-negative breast cancer xenografts in mice using diffusion-weighted imaging and (1)H MR spectroscopy.

To evaluate binding of P-selectin targeted microbubbles (MB) in tumor vasculature; a whole-body imaging and biodistribution study was performed in a tumor bearing mouse model.

Biodistribution of P-selectin targeted microbubbles.

To determine whether volumetric contrast-enhanced ultrasound (US) imaging has the potential to monitor changes in renal perfusion after vascular injury.

Volumetric contrast-enhanced ultrasound imaging of renal perfusion.

The use of receptor-targeted antibodies conjugated to fluorophores is actively being explored for real-time imaging of disease states; however, the toxicity of the bioconjugate has not been assessed in non-human primates.

IND-directed safety and biodistribution study of intravenously injected cetuximab-IRDye800 in cynomolgus macaques.

TRA-8, a monoclonal antibody targeting death receptor, has demonstrated high therapeutic effect for triple negative breast cancer (TNBC) in preclinical models. Tamoxifen, the standard of care for ERα-positive breast cancer, induces apoptosis via ERβ, which commonly presents in TNBC cells. The current study investigates the combination effects of TRA-8 and tamoxifen for TNBC. In vitro assays were implemented with two ERβ-positive TNBC cell lines, SUM159 and 2LMP, and in vivo therapy studies were followed using orthotopic breast tumor mouse models. IC50 of tamoxifen for SUM159 and 2LMP were 29 μM and 38 μM, respectively. Synergy between TRA-8 (0-1000 ng/mL) and tamoxifen (20 μM) was observed for both the cell lines. Tamoxifen (400 mg/kg diet) markedly suppressed the growth of SUM159 tumors for 6 weeks after therapy initiation, but it did not induce antitumor effect for 2LMP tumors. TRA-8 (0.1 mg, weekly, i.p.) successfully arrested the growth of both SUM159 and 2LMP tumors during therapy, but an antagonistic effect was observed when tamoxifen was combined. TRA-8 uptake into tumors was not changed by tamoxifen treatment. Histological analysis confirmed that caspase-3 activation induced by TRA-8 was significantly decreased when tamoxifen was used in combination. In conclusion, our findings suggest that the combined use of TRA-8 and tamoxifen may cause antagonistic effects for TNBC patients.

Combination therapy with anti-DR5 antibody and tamoxifen for triple negative breast cancer.

Much of modern agriculture is based on immense populations of genetically identical or near-identical varieties, called cultivars. However, advancement of knowledge, and thus experimental utility, is found through biodiversity, whether naturally-found or induced by the experimenter. Globally we are confronted by ever-growing food and energy challenges. Here we demonstrate how such biodiversity from the food legume crop soybean (Glycine max L. Merr) and the bioenergy legume tree Pongamia (Millettia) pinnata is a great value. Legume plants are diverse and are represented by over 18,000 species on this planet. Some, such as soybean, pea and medics are used as food and animal feed crops. Others serve as ornamental (e.g., wisteria), timber (e.g., acacia/wattle) or biofuel (e.g., Pongamia pinnata) resources. Most legumes develop root organs (nodules) after microsymbiont induction that serve as their habitat for biological nitrogen fixation. Through this, nitrogen fertiliser demand is reduced by the efficient symbiosis between soil Rhizobium-type bacteria and the appropriate legume partner. Mechanistic research into the genetics, biochemistry and physiology of legumes is thus strategically essential for future global agriculture. Here we demonstrate how molecular plant science analysis of the genetics of an established food crop (soybean) and an emerging biofuel P. pinnata feedstock contributes to their utility by sustainable production aided by symbiotic nitrogen fixation.

Article	Year
Accelerated development of arthritis in mice lacking endothelial selectins. Arthritis research & therapy\| PubMed ID: 16207337	2005
Serial passage through human glioma xenografts selects for a Deltagamma134.5 herpes simplex virus type 1 mutant that exhibits decreased neurotoxicity and prolongs survival of mice with exper... Journal of virology\| PubMed ID: 16840311	2006
Deficiency of P-selectin or P-selectin glycoprotein ligand-1 leads to accelerated development of glomerulonephritis and increased expression of CC chemokine ligand 2 in lupus-prone mice. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 17142777	2006
Adoptively transferred ex vivo expanded gammadelta-T cells mediate in vivo antitumor activity in preclinical mouse models of breast cancer. Breast cancer research and treatment\| PubMed ID: 19763820	2010
Extracelluar matrix metalloproteinase as a novel target for pancreatic cancer therapy. Anti-cancer drugs\| PubMed ID: 21730821	2011
Dual Combination Therapy Targeting DR5 and EMMPRIN in Pancreatic Adenocarcinoma. Molecular cancer therapeutics\| PubMed ID: 22203731	2012
Antagonistic effects of anti-EMMPRIN antibody when combined with chemotherapy against hypovascular pancreatic cancers. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging\| PubMed ID: 23836505	2014
Early therapy assessment of combined anti-DR5 antibody and carboplatin in triple-negative breast cancer xenografts in mice using diffusion-weighted imaging and (1)H MR spectroscopy. Journal of magnetic resonance imaging : JMRI\| PubMed ID: 24151215	2014
Biodistribution of P-selectin targeted microbubbles. Journal of drug targeting\| PubMed ID: 24731055	2014
Volumetric contrast-enhanced ultrasound imaging of renal perfusion. Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine\| PubMed ID: 25063408	2014
IND-directed safety and biodistribution study of intravenously injected cetuximab-IRDye800 in cynomolgus macaques. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging\| PubMed ID: 25080323	2015
Combination therapy with anti-DR5 antibody and tamoxifen for triple negative breast cancer. Cancer biology & therapy\| PubMed ID: 25084100	2014
The value of biodiversity in legume symbiotic nitrogen fixation and nodulation for biofuel and food production. Journal of plant physiology\| PubMed ID: 25240795	2015

Sharon Samuel

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