intraductal-delivery-to-the-rabbit-mammary-gland

Intraductal Delivery to the Rabbit Mammary Gland

Localized intraductal treatments for breast cancer offer potential advantages, including efficient delivery to the tumor and reduced systemic toxicity and ...

The University of Texas at Austin

Complement signaling has been implicated as important for normal hepatic regeneration. However, the specific mechanism by which complement is activated during liver regeneration remains undefined. To address this question, we investigated the hepatic regenerative response to partial hepatectomy in wildtype mice, C3-, C4-, and factor B-null mice, and C4-null mice treated with a factor B neutralizing antibody (mAb 1379). The results showed that following partial hepatectomy, C3-null mice exhibit reduced hepatic regeneration compared to wildtype mice as assessed by quantification of hepatic cyclin D1 expression and hepatocellular DNA synthesis and mitosis. In contrast, C4-null mice and factor B-null mice demonstrated normal liver regeneration. Moreover, animals in which all of the traditional upstream C3 activation pathways were disrupted, i.e. C4-null mice treated with mAb 1379, exhibited normal C3 activation and hepatocellular proliferation following partial hepatectomy. In order to define candidate non-traditional mechanisms of C3 activation during liver regeneration, plasmin and thrombin were investigated for their abilities to activate C3 in mouse plasma in vitro. The results showed that both proteases are capable of initiating C3 activation, and that plasmin can do so independent of the classical and alternative pathways.

Evidence for non-traditional activation of complement factor C3 during murine liver regeneration.

&#x8F6C;&#x5F55;&#x8C03;&#x8282; CITED2 (CBP/p300-Interacting-Transactivator-with-ED-rich-tail-2) &#x5DF2;&#x77E5;&#x6291;&#x5236;&#x57FA;&#x56E0;&#x4ECB;&#x5BFC;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x548C;&#x7EC6;&#x80DE;&#x5916;&#x57FA;&#x8D28; (ECM) &#x91CD;&#x5851;&#x3002;&#x7136;&#x800C;&#xFF0C;CITED2 &#x662F;&#x5426;&#x6709;&#x63A7;&#x5236;&#x9AA8;&#x9ABC;&#x808C;&#x4FEE;&#x590D;&#x6216;&#x91CD;&#x6784;&#x4E2D;&#x7684;&#x4F5C;&#x7528;&#x5C1A;&#x4E0D;&#x6E05;&#x695A;&#x3002;&#x6211;&#x4EEC;&#x6D4B;&#x8BD5;&#x5047;&#x8BBE;&#x7684; CITED2 &#x51FD;&#x6570;&#x4E2D;&#x9AA8;&#x9AA8;&#x6298;&#x6108;&#x5408;&#x7684;&#x6291;&#x5236; ECM &#x91CD;&#x5851;&#xFF0C;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x4E0E;&#x9AA8;&#xFF0C;&#x91CD;&#x8981;&#x7684;&#x662F;&#x57FA;&#x8D28;&#x91D1;&#x5C5E;&#x86CB;&#x767D;&#x9176; (&#x57FA;&#x8D28;&#x91D1;&#x5C5E;&#x86CB;&#x767D;&#x9176;) &#x7684;&#x5173;&#x952E;&#x57FA;&#x56E0;&#x7684;&#x8868;&#x8FBE;&#x3002;&#x4E0B;&#x988C;&#x89D2;&#x622A;&#x9AA8;&#x6216;&#x6DF1;&#x6C34;&#x7684;&#x6210;&#x5E74;&#x5927;&#x9F20;&#x624B;&#x672F;&#x540E;&#x4E09;&#x4E2A;&#x5C0F;&#x65F6;&#x6536;&#x83B7;&#x4E86;&#x622A;&#x9AA8;&#x6218;&#x7EBF;&#x548C; CITED2 &#x548C;&#x4E0E;&#x9AA8;&#x6298;&#x6108;&#x5408;&#x76F8;&#x5173;&#x57FA;&#x56E0;&#x8868;&#x8FBE;&#x7684;&#x786E;&#x5B9A;&#x5B9A;&#x91CF; pcr&#x3002;&#x540C;&#x65F6;&#xFF0C;&#x589E;&#x76CA;&#x7684;&#x51FD;&#x6570;&#x7814;&#x7A76;&#x5BA1;&#x67E5;&#x4E86;&#x8D85;&#x91CF; CITED2 &#x8868;&#x8FBE;&#x5BF9;&#x8868;&#x8FBE;&#x548C;&#x6D3B;&#x6027;&#x7684;&#x51E0;&#x79CD;&#x57FA;&#x8D28;&#x91D1;&#x5C5E;&#x86CB;&#x767D;&#x9176;&#x7684;&#x5F71;&#x54CD;&#x3002;&#x88C2;&#x9699;&#x4E0B;&#x988C;&#x9AA8;&#xFF0C;CITED2 &#x8868;&#x8FBE;&#x6210;&#x53CD;&#x6BD4;&#x76F8;&#x5173;&#x8868;&#x8FBE;&#x57FA;&#x8D28;&#x91D1;&#x5C5E;&#x86CB;&#x767D;&#x9176;-2&#x3001;-3&#x3001;-9&#x3001;-13 VEGF&#x3001; HIF-1alpha M-CSF&#xFF0C;&#x79E9;-L &#x548C;&#x9AA8;&#x3002;&#x4E0E;&#x6B64;&#x76F8;&#x4E00;&#x81F4;&#xFF0C;CITED2 &#x6210;&#x9AA8;&#x7EC6;&#x80DE;&#x8FC7;&#x8868;&#x8FBE;&#x6291;&#x5236;&#x8868;&#x8FBE;&#x53CA;&#x6D3B;&#x6027;&#x7684;&#x57FA;&#x8D28;&#x91D1;&#x5C5E;&#x86CB;&#x767D;&#x9176;-2-3&#x3001;-9 &#x548C;-13&#x3002;&#x4E24;&#x8005;&#x5408;&#x8BA1;&#xFF0C;&#x8FD9;&#x4E9B;&#x7814;&#x7A76;&#x8868;&#x660E; CITED2 &#x662F;&#x9AA8;&#x6298;&#x6108;&#x5408;&#x7684;&#x5173;&#x952E;&#x4E0A;&#x6E38;&#x8C03;&#x8282;&#x5668;&#x3002;CITED2 &#x5236;&#x6B62;&#x540E;&#x9AA8;&#x6298;&#x65E9;&#x671F;&#x53EF;&#x80FD;&#x5141;&#x8BB8;&#x7684;&#x6108;&#x5408;&#x53CD;&#x5E94;&#x6700;&#x4F73;&#x8D77;&#x7206;&#x3002;

&#x4F5C;&#x4E3A;&#x4E00;&#x4E2A;&#x8D1F;&#x76D1;&#x7BA1;&#x7684;&#x9AA8;&#x6298;&#x6108;&#x5408;&#x7684; CITED2 &#x6807;&#x8BC6;&#x3002;

The transcription regulator CITED2 (CBP/p300-Interacting-Transactivator-with-ED-rich-tail-2) is known to suppress genes mediating angiogenesis and extracellular matrix (ECM) remodeling. However, it is unclear whether CITED2 has a role in controlling skeletal repair or remodeling. We tested the hypothesis that CITED2 functions in bone fracture healing by suppressing the expression of genes critical to ECM remodeling, angiogenesis and osteogenesis, importantly the matrix metalloproteinases (MMPs). Three hours following mandibular osteotomy or sham surgery of adult rats, osteotomy fronts were harvested and the expression of CITED2 and genes associated with fracture healing was ascertained by quantitative PCR. In parallel, gain-of-function studies examined the effect of overexpressing CITED2 on the expression and activity of several MMPs. In the fractured mandible, CITED2 expression was inversely related to the expression of MMP-2, -3, -9, -13, VEGF, HIF-1alpha, M-CSF, RANK-L, and OPG. Consistent with this, the over-expression of CITED2 in osteoblasts inhibited the expression and activity of MMP-2, -3, -9, and -13. Taken together, the studies suggest that CITED2 is a critical upstream regulator of fracture healing. The suppression of CITED2 early after fracture may allow an optimal initiation of the healing response.

Identification of CITED2 as a negative regulator of fracture healing.

Le r&eacute;gulateur de la transcription CITED2 (CBP/p300-Interacting-Transactivator-with-ED-rich-tail-2) est connu pour supprimer les g&egrave;nes m&eacute;diant l&#39;angiogen&egrave;se et le remodelage de la matrice extracellulaire (ECM). Toutefois, on ignore si CITED2 a un r&ocirc;le dans le contr&ocirc;le squelettique r&eacute;paration ou r&eacute;novation. Nous avons test&eacute; l&#39;hypoth&egrave;se que les fonctions CITED2 fracture osseuse gu&eacute;rison en supprimant l&#39;expression des g&egrave;nes essentiels &agrave; l&#39;ECM, remodelage, angiogen&egrave;se et ost&eacute;ogen&egrave;se, surtout les m&eacute;talloprot&eacute;inases matricielles (MMP). Trois heures apr&egrave;s ost&eacute;otomie mandibulaire ou chirurgie de simulacre de rats adultes, fa&ccedil;ades ost&eacute;otomie ont &eacute;t&eacute; r&eacute;colt&eacute;s et l&#39;expression des g&egrave;nes associ&eacute;s &agrave; la gu&eacute;rison des fractures et des CITED2 a &eacute;t&eacute; confirm&eacute;e par PCR quantitative. En parall&egrave;le, des &eacute;tudes de gain de fonction a examin&eacute; l&#39;effet de surexprimant CITED2 sur l&#39;expression et l&#39;activit&eacute; des MMP plusieurs. &Agrave; la mandibule fractur&eacute;e, CITED2 expression &eacute;tait inversement reli&eacute;e &agrave; l&#39;expression de MMP-2, -3, -9, -13, VEGF, HIF-1alpha, M-CSF, RANK-L et l&#39;OPG. Conform&eacute;ment &agrave; cela, la sur-expression de CITED2 en ost&eacute;oblastes inhibe l&#39;expression et l&#39;activit&eacute; des MMP-2, -3 et -9 -13. Pris ensemble, les &eacute;tudes sugg&egrave;rent que le CITED2 est un r&eacute;gulateur essentiel en amont de la gu&eacute;rison des fractures. La r&eacute;pression des CITED2 t&ocirc;t apr&egrave;s fracture peut permettre une ouverture optimale de la r&eacute;ponse de gu&eacute;rison.

Identification de CITED2 comme un r&eacute;gulateur n&eacute;gatif de la gu&eacute;rison des fractures.

Der Regulator der Transkription CITED2 (CBP/p300-Interacting-Transactivator-with-ED-rich-tail-2) ist bekannt, dass Gene, die Vermittlung von Angiogenese und Umbau der extrazellul&auml;ren Matrix (ECM) zu unterdr&uuml;cken. Es ist jedoch unklar, ob CITED2 eine Rolle bei der Steuerung der Skelettmuskulatur Reparatur oder Umbau hat. Wir testeten der Hypothese, CITED2-Funktionen in Knochenbr&uuml;chen, die Heilung durch die Unterdr&uuml;ckung der Expression von Genen, die entscheidend f&uuml;r die ECM-Umbau, Angiogenese und Osteogenese, wichtiger ist die Matrix-Metalloproteinasen (MMPs). Drei Stunden nach der Mandibula Osteotomie oder vorget&auml;uschte Operation der Erwachsenen Ratten, Osteotomie Fronten geerntet wurden und der Ausdruck von CITED2 und Gene, die Heilung der Fraktur zugeordnet wurde durch quantitative PCR festgestellt. Gleichzeitig untersuchten Gain of Function Studien den Effekt einer CITED2 &uuml;ber den Ausdruck und die T&auml;tigkeit von mehreren MMPs &uuml;berexprimierenden. In der gebrochenen Unterkiefer, CITED2 Ausdruck umgekehrt betraf den Ausdruck von MMP-2,-3, 9,-13, VEGF, HIF-1alpha, M-CSF, RANK-L und OPG. Folgerichtig die &Uuml;berexpression des CITED2 in Osteoblasten gehemmt, den Ausdruck und die Aktivit&auml;t der MMP-2,-3 und -9 -13. Zusammen genommen die Studien geht hervor, dass CITED2 einen kritischen upstream Regulator der Bruch zu heilen ist. Die Unterdr&uuml;ckung der CITED2 fr&uuml;h nach Fraktur kann eine optimale Initiation der heilenden Antwort.

Identifizierung der CITED2 als einen negativen Regulator der Bruch zu heilen.

Il regolatore della trascrizione CITED2 (CBP/p300-Interacting-Transactivator-with-ED-rich-tail-2) &egrave; conosciuto per sopprimere i geni di mediazione angiogenesi e rimodellamento della matrice extracellulare (ECM). Tuttavia, non &egrave; chiaro se CITED2 ha un ruolo nel controllo riparazione scheletrica o di rimodellamento. Abbiamo testato l&#39;ipotesi che le funzioni CITED2 in frattura ossea guarigione sopprimendo l&#39;espressione dei geni critici per ECM rimodellamento, angiogenesi e osteogenesi, soprattutto le metalloproteinasi della matrice (MMP). Tre ore dopo osteotomia mandibola o sham chirurgia dei ratti adulti, sono state raccolte fronti l&#39;osteotomia e l&#39;espressione dei geni associati a guarigione della frattura e CITED2 &egrave; stata accertata mediante PCR quantitativa. In parallelo, guadagno di funzione studi ha esaminato l&#39;effetto di con sovraesprimono relativa CITED2 sull&#39;espressione e l&#39;attivit&agrave; di MMP diversi. Nella mandibola fratturata, CITED2 espressione era inversamente proporzionale alla espressione di MMP-2, -3, -9, -13, VEGF, HIF-1alpha, M-CSF, RANK-L e OPG. Coerente con questa, la sovraespressione di CITED2 in osteoblasti inibita l&#39;espressione e l&#39;attivit&agrave; di MMP-2, -3, -9 e -13. Presi insieme, gli studi suggeriscono che il CITED2 &egrave; un regolatore critico a monte della guarigione della frattura. La soppressione del CITED2 presto dopo frattura pu&ograve; consentire un&#39;iniziazione della risposta guarigione ottima.

Identificazione di CITED2 come un regolatore negativo della guarigione della frattura.

&#x8EE2;&#x5199;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30BF; CITED2 (CBP/p300-Interacting-Transactivator-with-ED-rich-tail-2) &#x7D30;&#x80DE;&#x5916;&#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9; (ECM) &#x306E;&#x6539;&#x9020;&#x3068;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x3092;&#x4EF2;&#x4ECB;&#x3059;&#x308B;&#x907A;&#x4F1D;&#x5B50;&#x3092;&#x6291;&#x5236;&#x3059;&#x308B;&#x305F;&#x3081;&#x77E5;&#x3089;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;&#x305D;&#x308C; CITED2 &#x9AA8;&#x683C;&#x4FEE;&#x5FA9;&#x3092;&#x5236;&#x5FA1;&#x3059;&#x308B;&#x304B;&#x3001;&#x307E;&#x305F;&#x306F;&#x6539;&#x9020;&#x3059;&#x308B;&#x5F79;&#x5272;&#x3092;&#x3057;&#x3066;&#x3044;&#x308B;&#x304B;&#x3069;&#x3046;&#x304B;&#x660E;&#x78BA;&#x3067;&#x306F;&#x306A;&#x3044;&#x3067;&#x3059;&#x3002;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x304A;&#x3088;&#x3073;&#x9AA8;&#x5F62;&#x6210;&#x3001;&#x91CD;&#x8981;&#x306A;&#x306E;&#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9;&#x30E1;&#x30BF;&#x30ED;&#x30D7;&#x30ED;&#x30C6;&#x30A2;&#x30FC;&#x30BC; &#xFF08;Mmp&#xFF09; &#x6539;&#x9020;&#x3001;ECM &#x306B;&#x91CD;&#x5927;&#x306A;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x767A;&#x73FE;&#x3092;&#x6291;&#x5236;&#x3059;&#x308B;&#x3053;&#x3068;&#x306B;&#x3088;&#x3063;&#x3066;&#x6CBB;&#x7652;&#x9AA8;&#x6298;&#x3067; CITED2 &#x95A2;&#x6570;&#x304C;&#x4EEE;&#x8AAC;&#x3092;&#x691C;&#x8A3C;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;3 &#x6B21;&#x306E;&#x4E0B;&#x984E;&#x9AA8;&#x5207;&#x308A;&#x8853;&#x307E;&#x305F;&#x306F;&#x507D;&#x624B;&#x8853;&#x30E9;&#x30C3;&#x30C8;, &#x306E;&#x6642;&#x9593;&#x306F;&#x3001;&#x9AA8;&#x5207;&#x308A;&#x8853;&#x306E;&#x524D;&#x7DDA;&#x53CE;&#x7A6B;&#x3057;&#x3001;&#x5B9A;&#x91CF;&#x7684; PCR &#x306B;&#x3088;&#x3063;&#x3066; CITED2 &#x304A;&#x3088;&#x3073;&#x9AA8;&#x6298;&#x306E;&#x6CBB;&#x7652;&#x3068;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x305F;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x767A;&#x73FE;&#x304C;&#x78BA;&#x8A8D;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x4E26;&#x884C;&#x3057;&#x3066;&#x3001;&#x5229;&#x5F97;&#x95A2;&#x6570;&#x7814;&#x7A76;&#x306F; CITED2 &#x5F0F;&#x3068;&#x3044;&#x304F;&#x3064;&#x304B;&#x306E; MMPs &#x6D3B;&#x6027;&#x306B;&#x95A2;&#x3059;&#x308B;&#x904E;&#x5270;&#x306E;&#x52B9;&#x679C;&#x3092;&#x691C;&#x8A0E;&#x3057;&#x305F;.&#x4E0B;&#x984E;&#x9AA8;&#x9AA8;&#x6298;&#x3067;&#x306F;&#x3001;CITED2 &#x5F0F;&#x53CD;&#x6BD4;&#x4F8B;-13, VEGF&#x3001;hif-1&#x3001;-9-3 MMP-2 &#x306E;&#x767A;&#x73FE;&#x306B;&#x95A2;&#x9023;&#x3057;&#x3066;&#x3044;&#x305F; M CSF &#x30E9;&#x30F3;&#x30AF; L &#x3068; OPG&#x3002;&#x3053;&#x306E;&#x4E00;&#x8CAB;&#x6027;&#x306E;&#x3042;&#x308B;&#x3001;CITED2 &#x306E;&#x904E;&#x5270;&#x767A;&#x73FE;&#x306E;&#x9AA8;&#x82BD;&#x7D30;&#x80DE;&#x3067;&#x306E;&#x767A;&#x73FE;&#x3084;&#x6D3B;&#x6027; MMP 2 &#x306E;&#x6291;&#x5236;-3&#x3001;-9&#x3001;&#x304A;&#x3088;&#x3073;-13&#x3002;&#x4E00;&#x7DD2;&#x306B;&#x53D6;&#x3089;&#x308C;&#x3066;&#x3001;&#x7814;&#x7A76;&#x306F;&#x3001;CITED2 &#x9AA8;&#x6298;&#x6CBB;&#x7652;&#x3059;&#x308B;&#x91CD;&#x8981;&#x306A;&#x4E0A;&#x6D41;&#x306E;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30BF;&#x304C;&#x793A;&#x5506;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;CITED2 &#x306E;&#x6291;&#x5727;&#x7834;&#x58CA;&#x5F8C;&#x65E9;&#x671F;&#x306B;&#x6CBB;&#x7642;&#x306E;&#x5FDC;&#x7B54;&#x306E;&#x6700;&#x9069;&#x306A;&#x958B;&#x59CB;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;

&#x9AA8;&#x6298;&#x6CBB;&#x7652;&#x306E;&#x8CA0;&#x306E;&#x8ABF;&#x7BC0;&#x56E0;&#x5B50;&#x3068;&#x3057;&#x3066;&#x306E; CITED2 &#x306E;&#x540C;&#x5B9A;

&#xC804;&#xC0AC; &#xB808; &#xADE4; &#xB808;&#xC774; &#xD130; CITED2 (CBP/p300-Interacting-Transactivator-with-ED-rich-tail-2) &#xC2E0;&#xC0DD; &#xBC0F; &#xC138;&#xD3EC; &#xC678; &#xAE30;&#xC9C8; (ECM) &#xB9AC; &#xBAA8;&#xB378;&#xB9C1;&#xC744; &#xC911;&#xC7AC; &#xD558;&#xB294; &#xC720;&#xC804;&#xC790;&#xB97C; &#xC5B5;&#xC81C; &#xD558;&#xB294; &#xAC83;&#xC73C;&#xB85C; &#xC54C;&#xB824;&#xC838; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, &#xADF8;&#xAC83; &#xC5EC;&#xBD80; CITED2 &#xC81C;&#xC5B4; &#xACE8;&#xACA9; &#xC218;&#xB9AC; &#xB610;&#xB294; &#xAC1C;&#xC870;&#xC5D0; &#xC5ED;&#xD560;&#xC774; &#xBA85;&#xD655; &#xD558;&#xC9C0;&#xB294;. CITED2 &#xAE30;&#xB2A5;&#xC744; &#xD558; &#xC5B5;&#xC81C; &#xC720;&#xC804;&#xC790; ECM &#xAC1C;&#xC7A5;, &#xC2E0;&#xC0DD; &#xBC0F; &#xACE8;, &#xB9E4;&#xD2B8;&#xB9AD;&#xC2A4; metalloproteinases (MMPs) &#xC911;&#xC694; &#xD55C; &#xAC83;&#xC740; &#xC911;&#xC694; &#xD55C;&#xC758; &#xC2DD;&#xC744; &#xD558; &#xC5EC; &#xCE58;&#xC720; &#xD558;&#xB294; &#xBF08; &#xACE8;&#xC808;&#xC5D0; &#xAC00;&#xC124; &#xD14C;&#xC2A4;&#xD2B8;. Mandibular &#xBF08; &#xB610;&#xB294; &#xC131;&#xC778; &#xC950;&#xC758; &#xAC00;&#xC9DC; &#xC218;&#xC220; 3 &#xC2DC;&#xAC04; &#xBF08; &#xC804;&#xC120;&#xC740;&#xAC00; &#xAC77;&#xC774; &#xD558; &#xACE0; CITED2 &#xBC0F; &#xACE8;&#xC808; &#xCE58;&#xC720;&#xC640; &#xAD00;&#xB828; &#xB41C; &#xC720;&#xC804;&#xC790;&#xC758; &#xC2DD; &#xC591;&#xC774; &#xB9CE;&#xC740; PCR&#xC5D0; &#xC758;&#xD574; ascertained&#xB294;. &#xB3D9;&#xC2DC;&#xC5D0; &#xD568;&#xC218; &#xC774;&#xB4DD; &#xC5F0;&#xAD6C; &#xD45C;&#xD604;&#xACFC; &#xC5EC;&#xB7EC; Mmps&#xC758; &#xD65C;&#xB3D9;&#xC5D0; CITED2 overexpressing&#xC758; &#xD6A8;&#xACFC;&#xB97C; &#xC870;&#xC0AC; &#xD588;&#xB2E4;. MMP-2,-3,-9,-13, VEGF, HIF 1alpha &#xC2DD;&#xC73C;&#xB85C; &#xACE8;&#xC808;&#xB41C; mandible CITED2 &#xC2DD; &#xAD00;&#xB828; &#xBC18;&#xBE44;&#xB840;&#xB294; M-CSF &#xC21C;&#xC704;-L, &#xBC0F; OPG. &#xC774; &#xC77C;&#xCE58;, osteoblasts&#xC5D0;&#xC11C; cited2&#xC758; over-expression &#xC800;&#xD574; &#xD45C;&#xD604;&#xACFC; &#xD65C;&#xB3D9; MMP-2,-3,-9 &#xBC0F;-13. &#xD568;&#xAED8; &#xCC0D;&#xC740;, &#xC5F0;&#xAD6C; CITED2 &#xACE8;&#xC808; &#xCE58;&#xB8CC;&#xC758; &#xC911;&#xC694; &#xD55C; &#xC5C5;&#xC2A4;&#xD2B8;&#xB9BC; &#xB808; &#xADE4; &#xB808;&#xC774; &#xD130;&#xB294; &#xAC83;&#xC774; &#xC88B;&#xC2B5;&#xB2C8;&#xB2E4;. &#xACE8;&#xC808; &#xD6C4; &#xCD08;&#xAE30; cited2&#xC758; &#xC5B5;&#xC81C; &#xCE58;&#xB8CC; &#xC751;&#xB2F5;&#xC758; &#xCD5C;&#xC801;&#xC758; &#xAC1C;&#xC2DC;&#xB97C; &#xD5C8;&#xC6A9;&#xD560; &#xC218;&#xB3C4; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xACE8;&#xC808; &#xCE58;&#xC720;&#xC758; &#xBD80;&#xC815;&#xC801;&#xC778; &#xB808; &#xADE4; &#xB808;&#xC774; &#xD130;&#xB85C; cited2&#xC758; id.

El regulador de la transcripci&oacute;n CITED2 (CBP/p300-Interacting-Transactivator-with-ED-rich-tail-2) se conoce para suprimir genes mediando la angiog&eacute;nesis y remodelaci&oacute;n de matriz extracelular (MEC). Sin embargo, no est&aacute; claro si el CITED2 tiene un papel en controlar esquel&eacute;tico reparaci&oacute;n o remodelaci&oacute;n. Probamos la hip&oacute;tesis que funciona CITED2 en curaci&oacute;n suprimiendo la expresi&oacute;n de genes cr&iacute;ticos para ECM remodelaci&oacute;n, angiog&eacute;nesis y osteog&eacute;nesis, lo importante es que las metaloproteinasas de la matriz (MMP) de la fractura del hueso. Tres horas despu&eacute;s de la osteotom&iacute;a mandibular o cirug&iacute;a ficticia de ratas adultas, se cosecharon los frentes de la osteotom&iacute;a y la expresi&oacute;n de CITED2 y genes asociados con la curaci&oacute;n de la fractura fue comprobada por PCR cuantitativa. En paralelo, ganancia de funci&oacute;n estudios examinaron el efecto de overexpressing CITED2 en la expresi&oacute;n y actividad de MMP varios. En la mand&iacute;bula fracturada, CITED2 expresi&oacute;n fue inversamente proporcional a la expresi&oacute;n de MMP-2, -3, -9 -13, VEGF, HIF-1alfa, M-CSF, RANK-L y OPG. De acuerdo con esto, la sobreexpresi&oacute;n de CITED2 en osteoblastos inhibi&oacute; la expresi&oacute;n y actividad de MMP-2, -3 y -9 -13. Tomados en conjunto, los estudios sugieren que CITED2 es un regulador upstream cr&iacute;tico de curaci&oacute;n de la fractura. La supresi&oacute;n de CITED2 temprano despu&eacute;s de la fractura puede permitir una &oacute;ptima iniciaci&oacute;n de la respuesta curativa.

Identificaci&oacute;n de CITED2 como un regulador negativo de la curaci&oacute;n de la fractura.

Inducible NO synthase (iNOS) is a hallmark of chronic inflammation that is also overexpressed in melanoma and other cancers. Whereas iNOS is a known effector of myeloid-derived suppressor cell (MDSC)-mediated immunosuppression, its pivotal position at the interface of inflammation and cancer also makes it an attractive candidate regulator of MDSC recruitment. We hypothesized that tumor-expressed iNOS controls MDSC accumulation and acquisition of suppressive activity in melanoma. CD11b(+)GR1(+) MDSC derived from mouse bone marrow cells cultured in the presence of MT-RET-1 mouse melanoma cells or conditioned supernatants expressed STAT3 and reactive oxygen species (ROS) and efficiently suppressed T cell proliferation. Inhibition of tumor-expressed iNOS with the small molecule inhibitor L-NIL blocked accumulation of STAT3/ROS-expressing MDSC, and abolished their suppressive function. Experiments with vascular endothelial growth factor (VEGF)-depleting Ab and recombinant VEGF identified a key role for VEGF in the iNOS-dependent induction of MDSC. These findings were further validated in mice bearing transplantable MT-RET-1 melanoma, in which L-NIL normalized elevated serum VEGF levels; downregulated activated STAT3 and ROS production in MDSC; and reversed tumor-mediated immunosuppression. These beneficial effects were not observed in iNOS knockout mice, suggesting L-NIL acts primarily on tumor- rather than host-expressed iNOS to regulate MDSC function. A significant decrease in tumor growth and a trend toward increased tumor-infiltrating CD8(+) T cells were also observed in MT-RET transgenic mice bearing spontaneous tumors. These data suggest a critical role for tumor-expressed iNOS in the recruitment and induction of functional MDSC by modulation of tumor VEGF secretion and upregulation of STAT3 and ROS in MDSC.

Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release.

Endoscopic placement of a laryngeal keel has traditionally required the use of a Lichtenberger endo-extralaryngeal needle passer, which is not universally available. We discuss a safe and technically simple alternate technique using an endoscopic suture retriever through a percutaneously placed angiocatheter that obviates the need for the Lichtenberger instrument.

Endoscopic suture retriever for endolaryngeal keel placement in treatment of anterior glottic webs.

While viral antigens in human papillomavirus (HPV)-related oropharyngeal cancer (HPVOPC) are attractive targets for immunotherapy, the effects of existing standard-of-care therapies on immune responses to HPV are poorly understood. We serially sampled blood from patients with stage III-IV oropharyngeal cancer undergoing concomitant chemoradiotherapy with or without induction chemotherapy. Circulating immunocytes including CD4(+) and CD8(+) T cells, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSC) were profiled by flow cytometry. Antigen-specific T-cell responses were measured in response to HPV16 E6 and E7 peptide pools. The role of PD-1 signaling in treatment-related immunosuppression was functionally defined by performing HPV-specific T-cell assays in the presence of blocking antibody. While HPV-specific T-cell responses were present in 13 of 18 patients before treatment, 10 of 13 patients lost these responses within 3 months after chemoradiotherapy. Chemoradiotherapy decreased circulating T cells and markedly elevated MDSCs. PD-1 expression on CD4(+) T cells increased by nearly 2.5-fold after chemoradiotherapy, and ex vivo culture with PD-1-blocking antibody enhanced HPV-specific T-cell responses in 8 of 18 samples tested. Chemoradiotherapy suppresses circulating immune responses in patients with HPVOPC by unfavorably altering effector:suppressor immunocyte ratios and upregulating PD-1 expression on CD4(+) T cells. These data strongly support testing of PD-1-blocking agents in combination with standard-of-care chemoradiotherapy for HPVOPC.

Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer.

Aging skin is among the most common patient concerns in a facial plastic surgery practice. Ultraviolet (UV)-induced damage expedites the pace of intrinsic aging, resulting in many of the visible signs of aging, such as rough skin texture, pigmentation irregularities, fine and deep wrinkling, and inelasticity. Primary prevention of UV and environmental damage with proper skin care and the use of sunscreen are critical. There is great interest in topically applied products to reverse or delay the visible signs of photoaging. We discuss the most common topically applied agents for photoaging, reviewing their mechanisms and supporting evidence.

Skin Care.

We examined the development of racial categorizations of faces spanning the European-East Asian ("White-Asian") categorical continuum in children between the ages of four and nine as well as adults. We employed a stimulus set that independently varied skin color and other aspects of facial physiognomy, allowing the contribution of each to be assessed independently and in interaction with each other. Results demonstrated substantial development across this age range in children's ability to draw on both sorts of cue, with over twice as much variance explained by stimulus variation in adults than children. Nonetheless, children were clearly sensitive to both skin color and other aspects of facial physiognomy, suggesting that understanding of the White-Asian category boundary develops in a somewhat different way than understanding of the White-Black category boundary, in which attention to features other than skin color appear only somewhat later. Discussion focuses on the implications of these findings for theories of social categorization.

The Development of White-Asian Categorization: Contributions from Skin Color and Other Physiognomic Cues.

Human papillomavirus (HPV), particularly HPV16 and HPV18, can cause cancers in diverse anatomical sites, including the anogenital and oropharyngeal (throat) regions. Therefore, development of safe and clinically effective therapeutic vaccines is an important goal. Herein, we show that a recombinant fusion protein of a humanized antibody to CD40 fused to HPV16.E6/7 (αCD40-HPV16.E6/7) can evoke HPV16.E6/7-specific CD8(+) and CD4(+) T-cell responses in head-and-neck cancer patients in vitro and in human CD40 transgenic (hCD40Tg) mice in vivo The combination of αCD40-HPV16.E6/7 and poly(I:C) efficiently primed HPV16.E6/7-specific T cells, particularly CD8(+) T cells, in hCD40Tg mice. Inclusion of montanide enhanced HPV16.E6/7-specific CD4(+), but not CD8(+), T-cell responses. Poly(I:C) plus αCD40-HPV16.E6/7 was sufficient to mount both preventative and therapeutic immunity against TC-1 tumors in hCD40Tg mice, significantly increasing the frequency of HPV16-specific CD8(+) CTLs in the tumors, but not in peripheral blood. In line with this, tumor volume inversely correlated with the frequency of HPV16.E6/7-specific CD8(+) T cells in tumors, but not in blood. These data suggest that CD40-targeting vaccines for HPV-associated malignancies can provide a highly immunogenic platform with a strong likelihood of clinical benefit. Data from this study offer strong support for the development of CD40-targeting vaccines for other cancers in the future. Cancer Immunol Res; 4(10); 823-34. ©2016 AACR.

Article	Year
Evidence for non-traditional activation of complement factor C3 during murine liver regeneration. Molecular immunology\| PubMed ID: 18452991	2008
Identification of CITED2 as a negative regulator of fracture healing. Biochemical and biophysical research communications\| PubMed ID: 19607804	2009
Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 22529296	2012
Endoscopic suture retriever for endolaryngeal keel placement in treatment of anterior glottic webs. The Annals of otology, rhinology, and laryngology\| PubMed ID: 25204710	2015
Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer. Cancer research\| PubMed ID: 25320012	2014
Skin Care. Facial plastic surgery clinics of North America\| PubMed ID: 26208767	2015
The Development of White-Asian Categorization: Contributions from Skin Color and Other Physiognomic Cues. PloS one\| PubMed ID: 27355683	2016
Therapeutic HPV Cancer Vaccine Targeted to CD40 Elicits Effective CD8+ T-cell Immunity. Cancer immunology research\| PubMed ID: 27485136	2016

Amelia Clark

Biography

JoVE Journal Publications

Other Publications