extended-78-hepatectomy-in-a-mouse-surgical-model

Extended 78&#37; Hepatectomy in a Mouse Surgical Model

Partial 2/3 hepatectomy in mice is used in research to study the liver's regenerative capacity and explore outcomes of liver resection in a number of ...

Beth Israel Deaconess Medical Center and Harvard Medical School

&#x8BB8;&#x591A;&#x4EBA;&#x63A8;&#x6D4B;&#x8FD9;&#x5FAE;&#x5999;&#x7684;&#x708E;&#x75C7;&#x548C;&#x514D;&#x75AB;&#x6D3B;&#x6027;&#x5728;&#x672F;&#x4E2D;&#x671F;&#x95F4;&#x68C0;&#x6D4B;&#x5230;&#x94FE;&#x63A5;&#x5230;&#x4E0D;&#x5229;&#x7684; postkidney &#x79FB;&#x690D;&#x4E34;&#x5E8A;&#x6210;&#x679C;&#x3002;&#x4E3A;&#x6B64;&#x76EE;&#x7684;&#xFF0C;&#x540C;&#x79CD;&#x5F02;&#x4F53;&#x80BE;&#x79FB;&#x690D;&#x8840;&#x7BA1;&#x518D;&#x704C;&#x6CE8;&#x540E;&#x708E;&#x75C7;&#x3001; &#x8BF1;&#x53D1;&#x708E;&#x75C7;&#x7C98;&#x9644;&#x5206;&#x5B50;&#x3001; &#x514D;&#x75AB;&#x6FC0;&#x6D3B;&#xFF0C;&#x4EE5;&#x53CA; 15 &#x5206;&#x949F;&#x8868;&#x8FBE;&#x8840;&#x7BA1;&#x518D;&#x704C;&#x6CE8; &#xFF08;&#x96F6;&#x5C0F;&#x65F6;&#xFF09; &#x6765;&#x786E;&#x5B9A;&#x662F;&#x5426;&#x8FD9;&#x79CD;&#x5206;&#x6790;&#x53EF;&#x4EE5;&#x5E2E;&#x52A9;&#x9884;&#x6D4B;&#x53D1;&#x751F;&#x7684;&#x5EF6;&#x8FDF;&#x7684;&#x79FB;&#x690D;&#x529F;&#x80FD; (DGF)&#xFF0C;&#x6025;&#x6027;&#x6392;&#x65A5;&#x53CD;&#x5E94; (AR) &#x548C;&#x79FB;&#x690D;&#x529F;&#x80FD;&#x5728;&#x672F;&#x4E2D;&#x6D3B;&#x68C0;&#x83B7;&#x5F97;&#x8FDE;&#x7EED;&#x4ECE; 75 6 &#x5BC6;&#x82CF;&#x91CC;&#x5DDE;&#x7684;&#x8D28;&#x91CF;&#x6267;&#x884C;&#x5F81;&#x5F97; 15 &#x5206;&#x949F;&#x7684;&#x80BE;&#x79FB;&#x690D;&#x540E;&#x7684;&#x6297;&#x51CB;&#x4EA1;&#x57FA;&#x56E0;&#x8868;&#x8FBE;&#x5206;&#x6790;&#x3002;&#x5B9E;&#x65F6;&#x8367;&#x5149;&#x5B9A;&#x91CF; PCR &#x4E3A; 15 &#x9009;&#x62E9;&#x57FA;&#x56E0;&#x7684;&#x8F6C;&#x5F55;&#x548C;&#x7531;&#x6807;&#x51C6;&#x7EC4;&#x7EC7;&#x75C5;&#x7406;&#x5B66;&#x5206;&#x6790;&#x8FD9;&#x4E9B;&#x7A7F;&#x523A;&#x6D3B;&#x68C0;&#x3002;&#x79FB;&#x690D;&#x672F;&#x540E;&#x7684;&#x4E34;&#x5E8A;&#x7ED3;&#x679C;&#x8FD8;&#x5728;&#x672F;&#x4E2D;&#x8F6C;&#x5F55;&#x7B80;&#x4ECB;&#x53CA;&#x4E34;&#x5E8A;&#x79FB;&#x690D;&#x65F6;&#x53EF;&#x7528;&#x7684;&#x53C2;&#x6570;&#x65B9;&#x9762;&#x8FDB;&#x884C;&#x5206;&#x6790;&#x3002;&#x8FD9;&#x9879;&#x7814;&#x7A76;&#x6F14;&#x793A;&#x914D;&#x7F6E;&#x6709;&#x9650;&#x548C;&#x5047;&#x8BF4;&#x9A71;&#x52A8;&#x57FA;&#x4E8E;&#x805A;&#x5408;&#x9176;&#x94FE;&#x53CD;&#x5E94;&#x7684;&#x8F6C;&#x5F55;&#x6587;&#x4EF6;&#x96F6;&#x5C0F;&#x65F6;&#x80BE;&#x6D3B;&#x68C0;&#x9884;&#x6D4B;&#x79FB;&#x690D;&#x672F;&#x540E;&#x7684;&#x4E34;&#x5E8A;&#x7ED3;&#x679C;&#xFF0C;&#x5305;&#x62EC; DGF&#x3001; &#x65E9;&#x671F; AR &#x548C;&#x80BE;&#x529F;&#x80FD; 6 mo posttransplantation &#x7684;&#x8D28;&#x91CF;&#x3002;&#x5BF9;&#x4E8E;&#x4E00;&#x4E9B;&#x4E34;&#x5E8A;&#x7684;&#x7EC8;&#x7ED3;&#x70B9;&#xFF0C;&#x8054;&#x5408;&#x7684;&#x4F7F;&#x7528;&#x5206;&#x5B50;&#x5206;&#x6790;&#x548C;&#x8FDB;&#x4E00;&#x6B65;&#x7684;&#x79FB;&#x690D;&#x65F6;&#x53EF;&#x7528;&#x7684;&#x65E2;&#x5B9A;&#x4E34;&#x5E8A;&#x6307;&#x6807;&#x63D0;&#x9AD8;&#x8D28;&#x91CF;&#x7684;&#x9884;&#x540E;&#x3002;&#x8F6C;&#x5F55;&#x5206;&#x6790;&#x6570;&#x636E;&#x63D0;&#x4F9B;&#x7ED9;&#x4E86;&#x9884;&#x6D4B;&#x6A21;&#x578B;&#xFF0C;&#x7279;&#x522B;&#x662F;&#x5728; AR &#x548C;&#x80BE;&#x529F;&#x80FD; 6 mo posttransplantation &#x7EDD;&#x5BF9;&#x5FC5;&#x8981;&#x6570;&#x636E;&#x3002;

&#x5173;&#x4E8E;&#x80BE;&#x79FB;&#x690D;&#x540E;&#x8840;&#x7BA1;&#x518D;&#x704C;&#x6CE8;&#x548C;&#x4E34;&#x5E8A;&#x7ED3;&#x679C;&#x7684;&#x672F;&#x4E2D;&#x5206;&#x5B50;&#x72B6;&#x6001;&#x3002;

Many hypothesize that subtle inflammation and immune activity detected in the intraoperative period are linked to adverse postkidney transplant clinical outcomes. To this end, renal allografts were analyzed for expression of pro-inflammatory, inflammation-induced adhesion molecules, immune activation as well as anti-apoptotic genes expressed 15 min after vascular reperfusion (zero-hour) to determine whether this analysis can aid in predicting the occurrence of delayed graft function (DGF), acute rejection (AR), and the quality of graft function at 6 mo. Intraoperative biopsies were obtained from 75 consecutively performed renal allografts in which consent was obtained 15 min after vascular reperfusion. These biopsies were analyzed by quantitative real-time PCR for transcription of 15 select genes and by standard histopathology. Posttransplant clinical outcomes were also analyzed in respect to intraoperative transcriptional profiles and clinical parameters available at the time of transplantation. This study demonstrates that a limited and hypothesis-driven PCR-based transcriptional profile of the zero-hour kidney biopsy predicts posttransplant clinical outcomes including DGF, early AR, and the quality of renal function 6 mo posttransplantation. For some clinical endpoints, the combined use of molecular analysis and established clinical indicators available at the time of transplantation further enhances the quality of prognosis. The transcriptional profiling data provide absolutely essential data to the predictive models, particularly with respect to AR and renal function 6 mo posttransplantation.

On the intraoperative molecular status of renal allografts after vascular reperfusion and clinical outcomes.

Beaucoup l&#39;hypoth&egrave;se cette inflammation subtile et activit&eacute; immunitaire d&eacute;tect&eacute;e dans la p&eacute;riode perop&eacute;ratoire sont li&eacute;s aux r&eacute;sultats cliniques de transplantation postkidney ind&eacute;sirables. &Agrave; cette fin, les allogreffes r&eacute;nales ont &eacute;t&eacute; analys&eacute;s pour l&#39;expression des mol&eacute;cules d&#39;adh&eacute;sion pro-inflammatoires, induite par l&#39;inflammation, activation immunitaire ainsi que des g&egrave;nes anti-apoptotiques exprim&eacute;s 15 min apr&egrave;s reperfusion vasculaire (z&eacute;ro heure) pour d&eacute;terminer si cette analyse peut aider &agrave; pr&eacute;dire l&#39;apparition de la fonction de greffon retard&eacute;e (DGF), le rejet aigu (AR) et la qualit&eacute; de la fonction du greffon &agrave; 6 mois. biopsies perop&eacute;ratoires ont &eacute;t&eacute; obtenues de 75 cons&eacute;cutivement ex&eacute;cut&eacute; allogreffes r&eacute;nales dans lesquelles le consentement a &eacute;t&eacute; obtenu 15 min apr&egrave;s reperfusion vasculaire. Ces biopsies ont &eacute;t&eacute; analys&eacute;s par PCR en temps r&eacute;el quantitative pour la transcription des g&egrave;nes select 15 et histopathologique standard. Posttransplantation r&eacute;sultats cliniques ont &eacute;t&eacute; &eacute;galement analys&eacute;es par rapport aux profils transcriptionnelles perop&eacute;ratoires et param&egrave;tres cliniques disponibles au moment de la transplantation. Cette &eacute;tude d&eacute;montre qu&#39;un profil transcriptionnel limit&eacute; et sur des hypoth&egrave;ses bas&eacute;es sur la PCR de la biopsie r&eacute;nale zero-hour pr&eacute;dit posttransplantation r&eacute;sultats cliniques, y compris DGF, AR au d&eacute;but et la qualit&eacute; de post-transplantation de fonction r&eacute;nale 6 mo. Pour certains param&egrave;tres cliniques, l&#39;utilisation combin&eacute;e de l&#39;analyse mol&eacute;culaire et &eacute;tablis les indicateurs cliniques disponibles au moment de la transplantation plus am&eacute;liore la qualit&eacute; du pronostic. Les donn&eacute;es de profilage transcriptionnelles fournissent des donn&eacute;es absolument essentielles pour les mod&egrave;les pr&eacute;dictifs, particuli&egrave;rement en ce qui concerne l&#39;AR et post-transplantation de fonction r&eacute;nale 6 mo.

Sur l&#39;&eacute;tat mol&eacute;culaire perop&eacute;ratoire des allogreffes r&eacute;nales apr&egrave;s reperfusion vasculaire et les r&eacute;sultats cliniques.

Auf der intraoperativen molekularen Status des Nieren-Transplantate nach vaskul&#xE4;ren Reperfusion und klinische Ergebnisse.

Molti hanno ipotizzato che l&#39;infiammazione sottile e attivit&agrave; immunitaria rilevata nel periodo intraoperatorio sono legati a risultati clinici avversi trapianto postkidney. A tal fine, allograft renale sono stati analizzati per l&#39;espressione delle molecole di adesione pro-infiammatorie, infiammazione indotta, attivazione immunitaria cos&igrave; come anti-apoptotic geni espressi 15 min dopo riperfusione vascolare (ora zero) per determinare se questa analisi possono aiutare a predire l&#39;occorrenza di funzione innesto ritardato (DGF), rigetto acuto (AR) e la qualit&agrave; della funzione di innesto a 6 Mo. biopsie intraoperatorie sono state ottenute da 75 consecutivamente eseguita allograft renale in cui il consenso &egrave; stato ottenuto 15 min dopo riperfusione vascolare. Queste biopsie sono state analizzate da PCR quantitativa in tempo reale per la trascrizione dei geni selezionare 15 e di istopatologia standard. Infettivo risultati clinici sono stati analizzati anche rispetto ai profili trascrizionali intraoperatorie e parametri clinici disponibili al momento del trapianto. Questo studio dimostra che un limitata e basata su ipotesi basate su PCR transcriptional profilo della biopsia renale zero-hour predice esiti clinici infettivo DGF, AR precoce e la qualit&agrave; di posttransplantation mo 6 la funzione renale. Per alcuni endpoint clinici, l&#39;uso combinato di analisi molecolare e stabiliti gli indicatori clinici disponibili al momento del trapianto ulteriormente migliora la qualit&agrave; della prognosi. I dati di profilatura trascrizionali forniscono dati assolutamente essenziali per i modelli predittivi, specialmente per quanto riguarda AR e posttransplantation mo 6 la funzione renale.

Sullo stato molecolare intraoperatorio del allograft renale dopo riperfusione vascolare e gli esiti clinici.

&#x591A;&#x304F;&#x306F;&#x305D;&#x306E;&#x5FAE;&#x5999;&#x306A;&#x708E;&#x75C7;&#x4EEE;&#x8AAC;&#x3057;&#x3001;&#x8853;&#x4E2D;&#x306E;&#x671F;&#x9593;&#x306B;&#x691C;&#x51FA;&#x3055;&#x308C;&#x305F;&#x514D;&#x75AB;&#x6D3B;&#x52D5;&#x304C;&#x6709;&#x5BB3; postkidney &#x79FB;&#x690D;&#x306E;&#x81E8;&#x5E8A;&#x7D50;&#x679C;&#x306B;&#x30EA;&#x30F3;&#x30AF;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x306E;&#x672B;&#x5C3E;&#x306B;&#x540C;&#x7A2E;&#x79FB;&#x690D;&#x814E;&#x306E;&#x30D7;&#x30ED;&#x708E;&#x75C7;&#x3001;&#x708E;&#x75C7;&#x8A98;&#x8D77;&#x63A5;&#x7740;&#x5206;&#x5B50;&#x3001;&#x514D;&#x75AB;&#x6D3B;&#x6027;&#x5316; 15 &#x5206;&#x518D;&#x704C;&#x6D41;&#x9045;&#x5EF6;&#x79FB;&#x690D;&#x6A5F;&#x80FD; (&#x57FA;&#x91D1;&#x7DCF;&#x5C40;) &#x306E;&#x767A;&#x751F;&#x3092;&#x4E88;&#x6E2C;&#x3059;&#x308B;&#x3053;&#x3068;&#x3067;&#x3053;&#x306E;&#x5206;&#x6790;&#x3092;&#x52A9;&#x3051;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x308B;&#x304B;&#x3069;&#x3046;&#x304B;&#x3001;&#x6025;&#x6027;&#x62D2;&#x7D76;&#x53CD;&#x5FDC; (AR) &#x3068; 6 mo &#x3092;&#x8853;&#x4E2D;&#x751F;&#x691C; 75 &#x304B;&#x3089;&#x9023;&#x7D9A;&#x3057;&#x3066;&#x5F97;&#x3089;&#x308C;&#x305F;&#x79FB;&#x690D;&#x7247;&#x6A5F;&#x80FD;&#x306E;&#x54C1;&#x8CEA;&#x3067; 15 &#x5206;&#x306E;&#x540C;&#x610F;&#x3092;&#x5F97;&#x3089;&#x308C;&#x305F;&#x814E;&#x540C;&#x7A2E;&#x79FB;&#x690D;&#x3092;&#x5B9F;&#x884C;&#x3092;&#x6C7A;&#x5B9A;&#x3059;&#x308B;&#x8840;&#x7BA1;&#x969C;&#x5BB3;&#x5F8C; (0 &#x6642;&#x9593;) &#x767A;&#x73FE;&#x6297;&#x30A2;&#x30DD;&#x30C8;&#x30FC;&#x30B7;&#x30B9;&#x907A;&#x4F1D;&#x5B50;&#x8868;&#x73FE;&#x306E;&#x305F;&#x3081;&#x8840;&#x7BA1;&#x518D;&#x704C;&#x6D41;&#x5F8C;&#x5206;&#x6790;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x751F;&#x691C;&#x3067;&#x306F;&#x6A19;&#x6E96;&#x306E;&#x75C5;&#x7406; 15 &#x9078;&#x629E;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x8EE2;&#x5199;&#x306E;&#x305F;&#x3081;&#x306E;&#x5B9A;&#x91CF;&#x7684;&#x30EA;&#x30A2;&#x30EB;&#x30BF;&#x30A4;&#x30E0; PCR &#x306B;&#x3088;&#x308A;&#x5206;&#x6790;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x592B;&#x5A66;&#x9593;&#x9020;&#x8840;&#x81E8;&#x5E8A;&#x8EE2;&#x5E30;&#x306F;&#x307E;&#x305F;&#x8853;&#x4E2D;&#x8EE2;&#x5199;&#x30D7;&#x30ED;&#x30D5;&#x30A1;&#x30A4;&#x30EB;&#x3068;&#x81E8;&#x5E8A;&#x30D1;&#x30E9;&#x30E1;&#x30FC;&#x30BF;&#x30FC;&#x306E;&#x79FB;&#x690D;&#x6642;&#x306B;&#x5229;&#x7528;&#x3067;&#x304D;&#x308B;&#x70B9;&#x3067;&#x5206;&#x6790;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x672C;&#x7814;&#x7A76;&#x306F;&#x3001;&#x9650;&#x3089;&#x308C;&#x305F;&#x3068;&#x4EEE;&#x8AAC;&#x99C6;&#x52D5; PCR &#x57FA;&#x3065;&#x304B;&#x305B;&#x3066;&#x3044;&#x305F;&#x8EE2;&#x5199;&#x30D7;&#x30ED;&#x30D5;&#x30A1;&#x30A4;&#x30EB; &#x30BC;&#x30ED;&#x6642;&#x9593;&#x814E;&#x751F;&#x691C;&#x306E;&#x57FA;&#x91D1;&#x7DCF;&#x5C40;&#x3001;&#x65E9;&#x671F;&#x306E; AR &#x3068;&#x814E;&#x6A5F;&#x80FD; 6 mo posttransplantation &#x306E;&#x54C1;&#x8CEA;&#x3092;&#x542B;&#x3080;&#x592B;&#x5A66;&#x9593;&#x9020;&#x8840;&#x306E;&#x81E8;&#x5E8A;&#x7D50;&#x679C;&#x3092;&#x4E88;&#x6E2C;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;&#x3044;&#x304F;&#x3064;&#x304B;&#x306E;&#x81E8;&#x5E8A;&#x306E;&#x30A8;&#x30F3;&#x30C9;&#x30DD;&#x30A4;&#x30F3;&#x30C8;&#x306B;&#x3064;&#x3044;&#x3066;&#x3001;&#x5206;&#x5B50;&#x89E3;&#x6790;&#x3068;&#x78BA;&#x7ACB;&#x3055;&#x308C;&#x305F;&#x81E8;&#x5E8A;&#x6307;&#x6A19;&#x306E;&#x79FB;&#x690D;&#x3055;&#x3089;&#x306B;&#x4E00;&#x5EA6;&#x306B;&#x5229;&#x7528;&#x3067;&#x304D;&#x308B;&#x306E;&#x4F75;&#x7528;&#x4E88;&#x5F8C;&#x306E;&#x8CEA;&#x3092;&#x9AD8;&#x3081;&#x307E;&#x3059;&#x3002;&#x8EE2;&#x5199;&#x30D7;&#x30ED;&#x30D5;&#x30A1;&#x30A4;&#x30EA;&#x30F3;&#x30B0; &#x30C7;&#x30FC;&#x30BF;&#x306F;&#x7D76;&#x5BFE;&#x306B;&#x4E0D;&#x53EF;&#x6B20;&#x306E;&#x30C7;&#x30FC;&#x30BF;&#x4E88;&#x6E2C;&#x30E2;&#x30C7;&#x30EB;&#x306F;&#x3001;&#x7279;&#x306B;&#x306B;&#x95A2;&#x3057;&#x3066; AR &#x3068;&#x814E;&#x6A5F;&#x80FD; 6 mo posttransplantation &#x3092;&#x63D0;&#x4F9B;&#x3057;&#x307E;&#x3059;&#x3002;

&#x540C;&#x7A2E;&#x79FB;&#x690D;&#x814E;&#x8840;&#x7BA1;&#x518D;&#x704C;&#x6D41;&#x3068;&#x81E8;&#x5E8A;&#x8EE2;&#x5E30;&#x5F8C;&#x306E;&#x8853;&#x4E2D;&#x306E;&#x5206;&#x5B50;&#x72B6;&#x614B;&#x306B;&#x3002;

&#xB9CE;&#xC740; &#xAC00;&#xC124;&#xC744; &#xADF8; &#xBBF8;&#xBB18;&#xD55C; &#xC5FC;&#xC99D; &#xBC0F; &#xBA74;&#xC5ED; &#xD65C;&#xB3D9; &#xC790;&#xAC00; &#xAE30;&#xAC04;&#xC5D0;&#xC11C; &#xBD88;&#xB9AC; &#xD55C; postkidney &#xC774;&#xC2DD; &#xC784;&#xC0C1; &#xACB0;&#xACFC;&#xC5D0; &#xC5F0;&#xACB0; &#xB429;&#xB2C8;&#xB2E4;. &#xC774; &#xC704;&#xD574; &#xC2E0;&#xC7A5; allografts &#xD608;&#xAD00; reperfusion &#xD6C4; &#xD504;&#xB85C;-&#xC5FC;&#xC99D; &#xC131;, &#xC5FC;&#xC99D; &#xC720;&#xBC1C; &#xC811;&#xCC29; &#xBD84;&#xC790;, &#xBA74;&#xC5ED; &#xD65C;&#xC131;&#xD654; &#xBFD0;&#xB9CC; &#xC544;&#xB2C8;&#xB77C; &#xD608;&#xAD00; reperfusion (0 &#xC2DC;&#xAC04;) &#xAE09;&#xC131; &#xAC70;&#xBD80; (AR) &#xBC0F; &#xC790;&#xAC00; biopsies 75&#xC5D0;&#xC11C; &#xC5F0;&#xC18D;&#xC801;&#xC73C;&#xB85C; &#xAC00;&#xC838;&#xC628; 6 &#xBAA8;&#xC5D0; &#xC774;&#xC2DD; &#xD568;&#xC218;&#xC758; &#xD488;&#xC9C8; &#xC2E0;&#xC7A5; allografts&#xB294; &#xB3D9;&#xC758; 15 &#xBD84; &#xC5BB;&#xC740; &#xC218;&#xD589;&#xC774; &#xBD84;&#xC11D; &#xC9C0;&#xC5F0;&#xB41C; &#xC774;&#xC2DD; &#xD568;&#xC218; (DGF)&#xC758; &#xBC1C;&#xC0DD; &#xC608;&#xCE21;&#xC5D0; &#xB3C4;&#xC6C0; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;, &#xC5EC;&#xBD80;&#xC744; &#xD655;&#xC778; &#xD6C4; 15 &#xBD84;&#xC744; &#xD45C;&#xD604; &#xD558;&#xB294; &#xC548;&#xD2F0;-apoptotic &#xC720;&#xC804;&#xC790;&#xC758; &#xD45C;&#xD604;&#xC5D0; &#xB300; &#xD55C; &#xBD84;&#xC11D; &#xD588;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; biopsies 15 &#xC120;&#xD0DD; &#xC720;&#xC804;&#xC790;&#xC758; &#xC804;&#xC0AC;&#xC5D0; &#xB300; &#xD55C; &#xC2E4;&#xC2DC;&#xAC04; &#xC591;&#xC774; &#xB9CE;&#xC740; PCR &#xBC0F; &#xD45C;&#xC900; histopathology &#xBD84;&#xC11D; &#xD588;&#xB2E4;. Posttransplant &#xC784;&#xC0C1; &#xACB0;&#xACFC; &#xB610;&#xD55C; &#xC790;&#xAC00; transcriptional &#xD504;&#xB85C;&#xD544; &#xBC0F; &#xC774;&#xC2DD; &#xC2DC; &#xC0AC;&#xC6A9; &#xAC00;&#xB2A5;&#xD55C; &#xC784;&#xC0C1; &#xB9E4;&#xAC1C; &#xBCC0;&#xC218;&#xB97C; &#xBD84;&#xC11D; &#xD588;&#xB2E4;. &#xC774; &#xC5F0;&#xAD6C; &#xC81C;&#xD55C; &#xBC0F; &#xAC00;&#xC124; &#xAE30;&#xBC18; PCR &#xAE30;&#xBC18; transcriptional &#xD504;&#xB85C;&#xD544; 0 &#xC2DC;&#xAC04; &#xC2E0;&#xC7A5; &#xC0DD; &#xAC80; DGF &#xCD08;&#xAE30; &#xC544;&#xCE78;&#xC18C;&#xC640; &#xC2E0;&#xC7A5; &#xAE30;&#xB2A5; 6 &#xBAA8; posttransplantation&#xC758; &#xD488;&#xC9C8;&#xC744; &#xD3EC;&#xD568; &#xD55C; posttransplant &#xC784;&#xC0C1; &#xACB0;&#xACFC; &#xC608;&#xCE21; &#xD558;&#xB294; &#xBC29;&#xBC95;&#xC744; &#xBCF4;&#xC5EC; &#xC90D;&#xB2C8;&#xB2E4;. &#xC77C;&#xBD80; &#xC784;&#xC0C1; &#xB05D;&#xC810;&#xC5D0; &#xB300; &#xD55C; &#xBD84;&#xC790; &#xBD84;&#xC11D; &#xBC0F; &#xC124;&#xB9BD;&#xB41C; &#xC784;&#xC0C1; &#xC9C0;&#xD45C; &#xCD94;&#xAC00; &#xC774;&#xC2DD;&#xC758; &#xC2DC;&#xAC04;&#xC5D0; &#xC0AC;&#xC6A9;&#xD560; &#xC218; &#xACB0;&#xD569; &#xD558; &#xC5EC; &#xC0AC;&#xC6A9; &#xC608; &#xC9C0;&#xC758; &#xD488;&#xC9C8;&#xC744; &#xD5A5;&#xC0C1; &#xC2DC;&#xD0B5;&#xB2C8;&#xB2E4;. Transcriptional &#xD504;&#xB85C; &#xD30C;&#xC77C;&#xB9C1; &#xB370;&#xC774;&#xD130;&#xB294; &#xD2B9;&#xD788; AR &#xBC0F; &#xC2E0;&#xC7A5; &#xAE30;&#xB2A5; 6 &#xBAA8; posttransplantation&#xC5D0; &#xB300;&#xD574; &#xC608;&#xCE21; &#xBAA8;&#xB378;&#xC744; &#xC808;&#xB300;&#xC801;&#xC73C;&#xB85C; &#xC911;&#xC694; &#xD55C; &#xB370;&#xC774;&#xD130;&#xB97C; &#xC81C;&#xACF5;&#xD569;&#xB2C8;&#xB2E4;.

&#xD608;&#xAD00; reperfusion &#xD6C4; &#xC784;&#xC0C1; &#xACB0;&#xACFC; &#xC2E0;&#xC7A5; allografts&#xC758; &#xC790;&#xAC00; &#xBD84;&#xC790; &#xC0C1;&#xD0DC;.

Muchos presumen inflamaci&oacute;n sutil y actividad inmunol&oacute;gica detectado en el per&iacute;odo intraoperatorio est&aacute;n vinculadas a los resultados cl&iacute;nicos adversos trasplante postkidney. Para ello, se analizaron aloinjertos renales para la expresi&oacute;n de mol&eacute;culas de adhesi&oacute;n proinflamatorias, inducida por la inflamaci&oacute;n, activaci&oacute;n inmune como anti-apoptotic genes expresados 15 minutos tras la reperfusi&oacute;n vascular (cero horas) para determinar si este an&aacute;lisis pueden ayudar a predecir la ocurrencia de la funci&oacute;n del injerto retrasada (DGF), rechazo agudo (AR) y la calidad de la funci&oacute;n del injerto en Missouri 6 biopsias intraoperatorias se obtuvieron de 75 consecutivamente realizaron aloinjertos renales que se obtuvo consentimiento 15 min tras la reperfusi&oacute;n vascular. Estas biopsias se analizaron mediante PCR cuantitativa en tiempo real para la transcripci&oacute;n de genes seleccionados 15 y por la histopatolog&iacute;a est&aacute;ndar. Tambi&eacute;n se analizaron los resultados cl&iacute;nicos postrasplante respecto a perfiles transcripcionales intraoperatorios y par&aacute;metros cl&iacute;nicos disponibles al momento del trasplante. Este estudio demuestra que una limitada basados en hip&oacute;tesis basadas en PCR transcripcional perfil y de la biopsia del ri&ntilde;&oacute;n de la cero horas predice los resultados cl&iacute;nicos postrasplante DGF, AR temprana, y la calidad de la funci&oacute;n renal 6 mo posttransplantation. Para algunas variables cl&iacute;nicas de evaluaci&oacute;n, el uso combinado de an&aacute;lisis molecular y establecidos los indicadores cl&iacute;nicos disponibles en el momento de trasplante m&aacute;s mejora la calidad del pron&oacute;stico. Los datos de generaci&oacute;n de perfiles transcripcionales proporcionan datos absolutamente esenciales para los modelos predictivos, particularmente con respecto a la AR y la funci&oacute;n renal 6 mo posttransplantation.

En el estado molecular intraoperatorio de aloinjertos renales despu&eacute;s de reperfusi&oacute;n vascular y los resultados cl&iacute;nicos.

Vascular smooth muscle cell (VSMC) proliferation and migration contribute significantly to atherosclerosis, postangioplasty restenosis, and transplant vasculopathy. Forkhead transcription factors belonging to the FoxO subfamily have been shown to inhibit growth and cell cycle progression in a variety of cell types. We hypothesized that forkhead proteins may play a role in VSMC biology. Under in vitro conditions, platelet-derived growth factor (PDGF)-BB, tumor necrosis factor-alpha, and insulin-like growth factor 1 stimulated phosphorylation of FoxO in human coronary artery smooth muscle cells via MEK1/2 and/or phosphatidylinositol 3-kinase-dependent signaling pathways. PDGF-BB, tumor necrosis factor-alpha, and insulin-like growth factor 1 treatment resulted in the nuclear exclusion of FoxO, whereas PDGF-BB alone down-regulated the FoxO target gene, p27(kip1), and enhanced cell survival and progression through the cell cycle. These effects were abrogated by overexpression of a constitutively active, phosphorylation-resistant mutant of the FoxO family member, TM-FKHRL1. The anti-proliferative effect of TM-FKHRL1 was partially reversed by small interfering RNA against p27(kip1). In a rat balloon carotid arterial injury model, adenovirus-mediated gene transfer of FKHRL1 caused an increase in the expression of p27(kip1) in the VSMC and inhibition of neointimal hyperplasia. These data suggest that FoxO activity inhibits VSMC proliferation and activation and that this signaling axis may represent a therapeutic target in vasculopathic disease states.

Forkhead transcription factors inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia.

To determine the functional significance of physiological reactive oxygen species (ROS) levels in endothelium-dependent nitric oxide (NO)-mediated coronary vasodilatation.

Endothelium-dependent coronary vasodilatation requires NADPH oxidase-derived reactive oxygen species.

 Decreased expression and activity of endothelial nitric oxide synthase (eNOS) in response to inflammatory and metabolic insults is the hallmark of endothelial cell (EC) dysfunction that preludes the development of atherosclerosis and hypertension. We previously reported the atheroprotective properties of the ubiquitin-editing and anti-inflammatory protein A20, also known as TNFAIP3, in part through interrupting nuclear factor-kappa B (NF-κB) and interferon signaling in EC and protecting these cells from apoptosis. However, A20's effect on eNOS expression and function remains unknown. In this study, we evaluated the impact of A20 overexpression or knockdown on eNOS expression in EC, at baseline and after tumor necrosis factor (TNF) treatment, used to mimic inflammation.  A20 overexpression in human coronary artery EC (HCAEC) significantly increased basal eNOS mRNA (qPCR) and protein (western blot) levels and prevented their downregulation by TNF. Conversely, siRNA-induced A20 knockdown decreased eNOS mRNA levels, identifying A20 as a physiologic regulator of eNOS expression. By reporter assays, using deletion and point mutants of the human eNOS promoter, and knockdown of eNOS transcriptional regulators, we demonstrated that A20-mediated increase of eNOS was transcriptional and relied on increased expression of the transcription factor Krüppel-like factor (KLF2), and upstream of KLF2, on activation of extracellular signal-regulated kinase 5 (ERK5). Accordingly, ERK5 knockdown or inhibition significantly abrogated A20's ability to increase KLF2 and eNOS expression. In addition, A20 overexpression in HCAEC increased eNOS phosphorylation at Ser-1177, which is key for the function of this enzyme.  This is the first report demonstrating that overexpression of A20 in EC increases eNOS transcription in an ERK5/KLF2-dependent manner and promotes eNOS activating phosphorylation. This effect withstands eNOS downregulation by TNF, preventing EC dysfunction in the face of inflammation. This novel function of A20 further qualifies its therapeutic promise to prevent/treat atherosclerosis.

A20/TNFAIP3 Increases ENOS Expression in an ERK5/KLF2-Dependent Manner to Support Endothelial Cell Health in the Face of Inflammation.

Peripheral artery disease (PAD), a highly prevalent global disease, associates with significant morbidity and mortality in affected patients. Despite progress in endovascular and open revascularization techniques for advanced PAD, these interventions grapple with elevated rates of arterial restenosis and vein graft failure attributed to intimal hyperplasia (IH). Novel multiomics technologies, coupled with sophisticated analyses tools recently powered by advances in artificial intelligence, have enabled the study of atherosclerosis and IH with unprecedented single-cell and spatial precision. Numerous studies have pinpointed gene hubs regulating pivotal atherogenic and atheroprotective signaling pathways as potential therapeutic candidates. Leveraging advancements in viral and nonviral gene therapy (GT) platforms, gene editing technologies, and cutting-edge biomaterial reservoirs for delivery uniquely positions us to develop safe, efficient, and targeted GTs for PAD-related diseases. Gene therapies appear particularly fitting for ex vivo genetic engineering of IH-resistant vein grafts. This manuscript highlights currently available state-of-the-art multiomics approaches, explores promising GT-based candidates, and details GT delivery modalities employed by our laboratory and others to thwart mid-term vein graft failure caused by IH, as well as other PAD-related conditions. The potential clinical translation of these targeted GTs holds the promise to revolutionize PAD treatment, thereby enhancing patients' quality of life and life expectancy.

Article	Year
On the intraoperative molecular status of renal allografts after vascular reperfusion and clinical outcomes. Journal of the American Society of Nephrology : JASN\| PubMed ID: 15888558	2005
Forkhead transcription factors inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia. The Journal of biological chemistry\| PubMed ID: 15961397	2005
Endothelium-dependent coronary vasodilatation requires NADPH oxidase-derived reactive oxygen species. Arteriosclerosis, thrombosis, and vascular biology\| PubMed ID: 20702812	2010
A20/TNFAIP3 Increases ENOS Expression in an ERK5/KLF2-Dependent Manner to Support Endothelial Cell Health in the Face of Inflammation. Frontiers in cardiovascular medicine\| PubMed ID: 34026871	2021
Advancements in Omics and Breakthrough Gene Therapies: A Glimpse into the Future of Peripheral Artery Disease. Annals of vascular surgery\| PubMed ID: 38582204	2024

Christiane Ferran

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