Introducing Clicker Training as a Cognitive Enrichment for Laboratory Mice

Establishing new refinement strategies in laboratory animal science is a central goal in fulfilling the requirements of Directive 2010/63/EU. Previous ...

Johannes Gutenberg-Universität Mainz

The expression of tapasin is critical for an optimized MHC class I assembly and stable MHC class I surface expression. Thus, impaired MHC class I antigen expression of tumors can be attributable to tapasin downregulation. In order to understand the molecular mechanisms of deficient tapasin expression, the mouse tapasin promoter region and its 5'-flanking sequences were characterized. The mouse tapasin promoter lacks the TATA box and its transcription is initiated at multiple sites within a 51-nucleotide stretch. Sequence analyses revealed transcription factor binding motifs for NF-kappaB, GATA, E2F, p300, AP1, SP1 and IRF-1/2. Detailed analysis of deletion mutants and elimination of transcription factor binding motifs demonstrated an important role of NF-kappaB at position -468 for its basal activity, whereas E2F at position -229 represses constitutive promoter activity. Furthermore, the IRF-1/2 binding site is required for gamma interferon inducibility of the tapasin promoter in vitro, but also negatively interferes with its constitutive activity. Thus, characterization of the tapasin promoter represents the molecular basis for the understanding of the heterogeneous expression levels of tapasin under physiological and pathophysiological conditions.

Cloning and functional analyses of the mouse tapasin promoter.

Because of its amplification and/or overexpression in many human tumors, the HER-2/neu proto-oncogene represents an attractive target for T-cell-mediated vaccination strategies. However, overexpression of oncogenes is often associated with defective expression of components of the MHC class I antigen-processing machinery (APM), thereby resulting in an immune escape phenotype of oncogene-transformed cells. To determine whether HER-2/neu influences the MHC class I antigen-processing pathway, the expression pattern of different APM components was examined in murine in vitro models of constitutive and tetracycline-controlled HER-2/neu expression. In comparison with HER-2/neu(-) control cells, HER-2/neu(+) fibroblasts exhibit reduced levels of MHC class I surface antigens that were associated with impaired expression and/or function of the peptide transporter associated with antigen processing, the proteasome subunits low molecular weight protein 2 and low molecular weight protein 10, the proteasome activators PA28alpha and PA28beta, and tapasin. These APM abnormalities resulted in reduced sensitivity to lysis by CTLs. The HER-2/neu-mediated immune escape phenotype could be corrected by IFN-gamma treatment. The clinical relevance of this finding was supported by an inverse correlation between HER-2/neu and the peptide transporter associated with antigen-processing protein expression as determined by immunhistochemical analysis of a series of HER-2/neu(-) and HER-2/neu(+) breast cancer specimens. Thus, a functional link between deficient APM component expression and HER-2/neu overexpression is proposed that might influence the design of HER-2/neu-targeted T-cell-based immunotherapeutic strategies.

HER-2/neu-mediated regulation of components of the MHC class I antigen-processing pathway.

V-&#x96C7;&#x5458;&#x518D;&#x57F9;&#x8BAD;&#x5C40;-b2 &#x9020;&#x8840;&#x767D;&#x8840;&#x75C5;&#x75C5;&#x6BD2;&#x764C;&#x57FA;&#x56E0;&#x540C;&#x6E90; 2 &#xFF08;ERBB2 &#xFF1B; &#x540C;&#x4E49;&#x8BCD; HER2&#xFF0C;&#x7EBD;&#xFF09; &#x5BF9;&#x8DE8;&#x819C;&#x7CD6;&#x86CB;&#x767D;&#x916A;&#x6C28;&#x9178;&#x6FC0;&#x9176;&#x7279;&#x5B9A;&#x7684;&#x6D3B;&#x52A8;&#xFF0C;&#x4F5C;&#x4E3A;&#x4E0D;&#x540C;&#x7684;&#x4FE1;&#x53F7;&#x8F6C;&#x5BFC;&#x8FC7;&#x7A0B;&#x4E2D;&#x7684;&#x4E3B;&#x8981;&#x4EA4;&#x6362;&#x673A;&#x4E0E;&#x8FDB;&#x884C;&#x7F16;&#x7801;&#x3002;&#x5728;&#x5927;&#x91CF;&#x7684;&#x4EBA;&#x7C7B;&#x764C;&#x75C7;&#xFF0C;&#x5305;&#x62EC;&#x4E73;&#x817A;&#x764C;&#x3001; &#x5375;&#x5DE2;&#x53CA;&#x80BE;&#x810F;&#x764C;&#x53D1;&#x73B0; ERBB2 &#x6269;&#x589E;&#x548C;&#x8868;&#x8FBE;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x76EE;&#x6807;&#x662F;&#x63A2;&#x6D4B; ERBB2 &#x8C03;&#x8282;&#x9776;&#x57FA;&#x56E0;&#x7684;&#x5168;&#x57FA;&#x56E0;&#x7EC4;&#x89C4;&#x6A21;&#x53CA;&#x5176;&#x81F4;&#x7624;&#x6027;&#x7684;&#x5F71;&#x54CD;&#x4F5C;&#x51FA;&#x8D21;&#x732E;&#x3002;ERBB2 &#x8F6C;&#x67D3;&#x548C;&#x91CE;&#x751F;&#x578B;&#x5C0F;&#x9F20;&#x6210;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x7684;&#x57FA;&#x56E0;&#x5DEE;&#x5F02;&#x8868;&#x8FBE;&#x8C31;&#x76D1;&#x6D4B;&#x91C7;&#x7528; DNA &#x82AF;&#x7247;&#x3002;&#x6240;&#x9009;&#x57FA;&#x56E0;&#x7684;&#x8868;&#x8FBE;&#x8C03;&#x63A7;&#x7ECF; RT-PCR &#x68C0;&#x6D4B;&#x6838;&#x5B9E;&#xFF0C;&#x5E76;&#x7531;&#x5370;&#x8FF9;&#x5206;&#x6790;&#x9A8C;&#x8BC1;&#x3002;&#x57FA;&#x56E0;&#x7EC4;&#x5E7F;&#x6CDB;&#x7684;&#x57FA;&#x56E0;&#x8868;&#x8FBE;&#x8C31;&#x786E;&#x5B9A; (i) &#x5DF2;&#x77E5;&#x76EE;&#x6807;&#x7684; ERBB2 &#x4FE1;&#x53F7;&#x3001; (ii) &#x57FA;&#x56E0;&#x4E0E;&#x80BF;&#x7624;&#x7684;&#x5173;&#x7CFB;&#x53D7;&#x7275;&#x8FDE;&#xFF0C;&#x4F46;&#x8FC4;&#x4ECA;&#x672A;&#x4E0E; ERBB2 &#x4FE1;&#x53F7;&#x4EE5;&#x53CA; (iii) &#x672A;&#x4E0E;&#x6076;&#x6027;&#x8F6C;&#x5316;&#xFF0C;&#x5305;&#x62EC;&#x4E0D;&#x5E26;&#x6279;&#x6CE8;&#x529F;&#x80FD;&#x7684;&#x65B0;&#x57FA;&#x56E0;&#x5173;&#x8054;&#x7684;&#x57FA;&#x56E0;&#x5173;&#x8054;&#x3002;&#x6211;&#x4EEC;&#x8FD8;&#x53D1;&#x73B0;&#x81F3;&#x5C11;&#x4E00;&#x5C0F;&#x90E8;&#x5206;&#x7684; coexpressed &#x57FA;&#x56E0;&#x5BF9;&#x57FA;&#x56E0;&#x7EC4;&#x4E0E;&#x5BC6;&#x5207;&#x76F8;&#x5173;&#x3002;ERBB2 &#x8FC7;&#x8868;&#x8FBE;&#x6291;&#x5236;&#x8F6C;&#x5F55;&#x7684;&#x53CD;&#x8840;&#x7BA1;&#x589E;&#x751F;&#x7684;&#x56E0;&#x7D20; &#xFF08;&#x4F8B;&#x5982;&#xFF0C;Sparc&#xFF0C;Timp3&#xFF0C;Serpinf1)&#xFF0C;&#x4F46;&#x8BF1;&#x5BFC;&#x7684;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x56E0;&#x5B50; &#xFF08;&#x4F8B;&#x5982;&#xFF0C;Klf5&#xFF0C;Tnfaip2&#xFF0C;Sema3c&#xFF09; &#x7684;&#x8868;&#x8FBE;&#x3002;&#x4F9D;&#x8D56;&#x7684; ERBB2 &#x57FA;&#x56E0;&#x8C03;&#x63A7;&#x5206;&#x6790;&#x63ED;&#x793A;&#x6F5C;&#x5728;&#x7684;&#x8BCA;&#x65AD;&#x6807;&#x5FD7;&#x7269;&#x548C;&#x5047;&#x5B9A;&#x7684;&#x6CBB;&#x7597;&#x9776;&#x70B9;&#x7684;&#x6C47;&#x7F16;&#x3002;Colocalize &#x57FA;&#x56E0;&#x7EC4;&#x4E2D;&#x7684; coexpressed &#x57FA;&#x56E0;&#x7684;&#x9274;&#x5B9A;&#x53EF;&#x80FD;&#x8868;&#x660E;&#x9700;&#x8981;&#x8FDB;&#x4E00;&#x6B65;&#x7814;&#x7A76;&#xFF0C;&#x4EE5;&#x8BC4;&#x4F30;&#x529F;&#x80FD; coregulation &#x7684;&#x57FA;&#x56E0;&#x8C03;&#x63A7;&#x673A;&#x5236;&#x3002;&#xFF08;&#x53EF;&#x4EE5;&#x5728; http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html &#x56FD;&#x9645;&#x764C;&#x75C7;&#x6742;&#x5FD7;&#x7F51;&#x7AD9;&#x4E0A;&#x627E;&#x5230;&#x8865;&#x5145;&#x6750;&#x6599;&#x7684;&#x8FD9;&#x7BC7;&#x6587;&#x7AE0;&#xFF09;&#x3002;

&#x8BC6;&#x522B;&#x548C;&#x9A8C;&#x8BC1;&#x7684;&#x5C0F;&#x8BF4; ERBB2 &#x7EBD; HER2&#xFF09; &#x5305;&#x62EC;&#x57FA;&#x56E0;&#x53C2;&#x4E0E;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x7684;&#x76EE;&#x6807;&#x3002;

V-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2; synonyms HER2, NEU) encodes a transmembrane glycoprotein with tyrosine kinase-specific activity that acts as a major switch in different signal-transduction processes. ERBB2 amplification and overexpression have been found in a number of human cancers, including breast, ovary and kidney carcinoma. Our aim was to detect ERBB2-regulated target genes that contribute to its tumorigenic effect on a genomewide scale. The differential gene expression profile of ERBB2-transfected and wild-type mouse fibroblasts was monitored employing DNA microarrays. Regulated expression of selected genes was verified by RT-PCR and validated by Western blot analysis. Genome wide gene expression profiling identified (i) known targets of ERBB2 signaling, (ii) genes implicated in tumorigenesis but so far not associated with ERBB2 signaling as well as (iii) genes not yet associated with oncogenic transformation, including novel genes without functional annotation. We also found that at least a fraction of coexpressed genes are closely linked on the genome. ERBB2 overexpression suppresses the transcription of antiangiogenic factors (e.g., Sparc, Timp3, Serpinf1) but induces expression of angiogenic factors (e.g., Klf5, Tnfaip2, Sema3c). Profiling of ERBB2-dependent gene regulation revealed a compendium of potential diagnostic markers and putative therapeutic targets. Identification of coexpressed genes that colocalize in the genome may indicate gene regulatory mechanisms that require further study to evaluate functional coregulation. (Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.)

Identification and validation of novel ERBB2 (HER2, NEU) targets including genes involved in angiogenesis.

V-erb-b2 leuc&eacute;mie &eacute;rythroblastiques viral oncogene homologue 2 (ERBB2 ; synonymes HER2, NEU) encode une glycoprot&eacute;ine transmembranaire avec l&#39;activit&eacute; tyrosine kinase sp&eacute;cifique qui agit comme un commutateur important dans des processus de transduction des signaux diff&eacute;rents. La surexpression et ERBB2 amplification ont retrouv&eacute; dans un certain nombre de cancers humains, y compris le cancer du sein, ovaire et du rein. Notre objectif &eacute;tait de d&eacute;tecter les g&egrave;nes cibles r&eacute;glement&eacute;es ERBB2 qui contribuent &agrave; son effet tumorig&egrave;ne sur une &eacute;chelle de genomewide. Le profil d&#39;expression g&eacute;nique diff&eacute;rentielle des fibroblastes de souris transfect&eacute;es ERBB2 et sauvage a &eacute;t&eacute; suivi en utilisant des puces &agrave; ADN. Expression contr&ocirc;l&eacute;e de certains g&egrave;nes a &eacute;t&eacute; v&eacute;rifi&eacute;e par RT-PCR et valid&eacute;e par immunobuvardage. Profilage de l&#39;expression g&eacute;nique large de g&eacute;nome a identifi&eacute; des cibles (i) connues de signalisation ERBB2, (ii) les g&egrave;nes impliqu&eacute;s dans la tumorigen&egrave;se mais pour l&#39;instant pas associ&eacute; ERBB2 signalisation ainsi que (iii) les g&egrave;nes ne sont pas encore associ&eacute;s &agrave; la transformation oncog&eacute;nique, y compris les nouveaux g&egrave;nes sans annotation fonctionnelle. Nous avons aussi constat&eacute; qu&#39;au moins une fraction des g&egrave;nes dynorphin sont &eacute;troitement li&eacute;s sur le g&eacute;nome. La surexpression ERBB2 supprime la transcription des facteurs anti-angiog&eacute;niques (p. ex., Sparc, Timp3, Serpinf1), mais induit l&#39;expression de facteurs angiog&eacute;niques (p. ex., Klf5, Tnfaip2, Sema3c). Profilage de la r&eacute;gulation du g&egrave;ne ERBB2 d&eacute;pendant a r&eacute;v&eacute;l&eacute; un compendium des marqueurs diagnostiques potentiels et cibles th&eacute;rapeutiques putatifs. Identification des g&egrave;nes dynorphin colocalis&eacute;es dans le g&eacute;nome peut indiquer les m&eacute;canismes de r&eacute;gulation g&eacute;nique n&eacute;cessitant encore &eacute;tude visant &agrave; &eacute;valuer la co-r&eacute;gulation fonctionnelle. (&Eacute;l&eacute;ments suppl&eacute;mentaires pour cet article figurent sur le site de l&#39;International Journal of Cancer &agrave; http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.)

Identification et validation de roman ERBB2 (HER2, NEU) cibles, y compris les g&egrave;nes impliqu&eacute;s dans l&#39;angiogen&egrave;se.

Identifizierung und Validierung neuartiger ErbB2 (HER2, NEU), einschlie&#xDF;lich der Ziele Gene an der Angiogenese beteiligt.

Omologo virale oncogene di leucemia erythroblastic V-erb-b2 2 (ERBB2; sinonimi HER2, NEU) codifica per una glicoproteina transmembrana con attivit&agrave; specifiche della chinasi della tirosina che agisce come un interruttore principale in diversi processi di trasduzione del segnale. Sovraespressione e amplificazione di ERBB2 sono stati trovati in un certo numero di tumori umani, tra cui il carcinoma del seno, ovaio e reni. Il nostro scopo era di individuare geni bersaglio ERBB2-regolato che contribuiscono al suo effetto tumorigeno su una scala di genomewide. Il profilo di espressione genica differenziale dei fibroblasti del mouse transfected ERBB2 e wild-type &egrave; stato monitorato che impiegano i microarrays del DNA. Regolamentato espressione di geni selezionati &egrave; stato verificato mediante RT-PCR e convalidato mediante analisi Western blot. Genome wide gene expression profiling identificato obiettivi (i) noti di segnalazione ERBB2, (ii) geni implicati nella tumorigenesi ma finora non associato con ERBB2 segnalazione nonch&eacute; (iii) i geni associati non ancora trasformazione oncogenica, compresi nuovi geni senza annotazione funzionale. Abbiamo anche trovato che almeno una frazione di geni Rsc8p sono strettamente collegati sul genoma. Sovraespressione di ERBB2 sopprime la trascrizione di fattori antiangiogenetici (ad es., Sparc, Timp3, Serpinf1), ma induce espressione di fattori angiogenetici (ad es., Klf5, Tnfaip2, Sema3c). Profilatura di regolazione del gene ERBB2-dipendente, ha rivelato un compendio di potenziali marcatori diagnostici e putativi bersagli terapeutici. Identificazione di geni Rsc8p che colocalize nel genoma pu&ograve; indicare meccanismi regolatori gene che richiedono ulteriori studi per valutare la coregolamentazione funzionale. (Materiale supplementare per questo articolo pu&ograve; essere trovato al http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html sito Web di International Journal of Cancer).

Identificazione e validazione del romanzo ERBB2 (HER2, NEU) obiettivi tra cui geni coinvolti nell&#39;angiogenesi.

V erb b2 &#x8D64;&#x82BD;&#x767D;&#x8840;&#x75C5;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x76F8;&#x540C;&#x7269; 2 (ERBB2; &#x30B7;&#x30CE;&#x30CB;&#x30E0; HER2 &#x30CE;&#x30A4;) &#x7570;&#x306A;&#x308B;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x30D7;&#x30ED;&#x30BB;&#x30B9;&#x306E;&#x4E3B;&#x8981;&#x306A;&#x30B9;&#x30A4;&#x30C3;&#x30C1;&#x3068;&#x3057;&#x3066;&#x52D5;&#x4F5C;&#x30C1;&#x30ED;&#x30B7;&#x30F3;&#x306E;&#x30AD;&#x30CA;&#x30FC;&#x30BC;&#x56FA;&#x6709;&#x306E;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D3;&#x30C6;&#x30A3;&#x3068;&#x819C;&#x8CAB;&#x901A;&#x578B;&#x306E;&#x7CD6;&#x86CB;&#x767D;&#x3092;&#x30A8;&#x30F3;&#x30B3;&#x30FC;&#x30C9;&#x3057;&#x307E;&#x3059;&#x3002;ERBB2 &#x5897;&#x5E45;&#x3068;&#x904E;&#x5270;&#x767A;&#x73FE;&#x306F;&#x3001;&#x4E73;&#x304C;&#x3093;&#x3001;&#x5375;&#x5DE3;&#x3001;&#x814E;&#x81D3;&#x764C;&#x3092;&#x542B;&#x3080;&#x4EBA;&#x9593;&#x306E;&#x304C;&#x3093;&#x306E;&#x6570;&#x3067;&#x767A;&#x898B;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005; &#x306E;&#x76EE;&#x6A19;&#x306F;&#x30B2;&#x30CE;&#x30E0;&#x30EF;&#x30A4;&#x30C9; &#x30B9;&#x30B1;&#x30FC;&#x30EB;&#x305D;&#x306E;&#x767A;&#x764C;&#x6027;&#x52B9;&#x679C;&#x306B;&#x8CA2;&#x732E; ERBB2 &#x8ABF;&#x6574;&#x3055;&#x308C;&#x305F;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x907A;&#x4F1D;&#x5B50;&#x3092;&#x691C;&#x51FA;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x3060;&#x3063;&#x305F;&#x3002;ERBB2 &#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30D5;&#x30A7;&#x30AF;&#x30C8;&#x304A;&#x3088;&#x3073;&#x91CE;&#x751F;&#x578B;&#x30DE;&#x30A6;&#x30B9;&#x7DDA;&#x7DAD;&#x82BD;&#x7D30;&#x80DE;&#x306E;&#x5DEE;&#x52D5;&#x907A;&#x4F1D;&#x5B50;&#x767A;&#x73FE;&#x30D7;&#x30ED;&#x30D5;&#x30A1;&#x30A4;&#x30EB;&#x306F;&#x3001;DNA &#x30DE;&#x30A4;&#x30AF;&#x30ED; &#x30A2;&#x30EC;&#x30A4;&#x3092;&#x7528;&#x3044;&#x305F;&#x76E3;&#x8996;&#x3060;&#x3063;&#x305F;&#x3002;&#x9078;&#x629E;&#x3057;&#x305F;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x767A;&#x73FE;&#x3055;&#x308C;&#x305F; RT-PCR &#x306B;&#x3088;&#x3063;&#x3066;&#x3092;&#x78BA;&#x8A8D;&#x3001;&#x897F;&#x90E8;&#x306E;&#x3057;&#x307F;&#x306E;&#x5206;&#x6790;&#x306B;&#x3088;&#x3063;&#x3066;&#x691C;&#x8A3C;&#x3057;&#x307E;&#x3059;&#x3002;&#x30B2;&#x30CE;&#x30E0;&#x5E83;&#x3044;&#x907A;&#x4F1D;&#x5B50;&#x767A;&#x73FE;&#x30D7;&#x30ED;&#x30D5;&#x30A1;&#x30A4;&#x30EA;&#x30F3;&#x30B0; ERBB2 &#x30B7;&#x30B0;&#x30CA;&#x30EA;&#x30F3;&#x30B0;&#x3001;(ii) &#x907A;&#x4F1D;&#x5B50;&#x306F;&#x816B;&#x760D;&#x5F62;&#x6210;&#x306B;&#x95A2;&#x4E0E;&#x3059;&#x308B;&#x306A;&#x304F; ERBB2 (iii) &#x306F;&#x307E;&#x3060;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x65B0;&#x898F;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x6A5F;&#x80FD;&#x30A2;&#x30CE;&#x30C6;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x306A;&#x3057;&#x3092;&#x542B;&#x3080;&#x767A;&#x764C;&#x907A;&#x4F1D;&#x5B50;&#x3060;&#x3051;&#x3067;&#x306A;&#x304F;&#x3001;&#x30B7;&#x30B0;&#x30CA;&#x30EA;&#x30F3;&#x30B0;&#x3068;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x3053;&#x308C;&#x307E;&#x3067;&#x306E;&#x3068;&#x3053;&#x308D;&#x306E; (i) &#x65E2;&#x77E5;&#x306E;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x3092;&#x7279;&#x5B9A;&#x3057;&#x307E;&#x3059;&#x3002;&#x307E;&#x305F;&#x5C11;&#x306A;&#x304F;&#x3068;&#x3082;&#x6570;&#x5206;&#x306E;&#x5171;&#x767A;&#x73FE;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x30B2;&#x30CE;&#x30E0;&#x4E0A;&#x5BC6;&#x63A5;&#x306B;&#x30EA;&#x30F3;&#x30AF;&#x3055;&#x308C;&#x307E;&#x3059;.ERBB2 &#x306E;&#x904E;&#x5270;&#x767A;&#x73FE;&#x306F;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x963B;&#x5BB3;&#x5264;&#x306E;&#x8981;&#x56E0; &#xFF08;&#x4F8B;&#x3048;&#x3070;&#x3001;Sparc, Timp3, Serpinf1) &#x306E;&#x8EE2;&#x5199;&#x3092;&#x6291;&#x5236;&#x3059;&#x308B;&#x304C;&#x3001;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x56E0;&#x5B50; (&#x4F8B;&#x3048;&#x3070;&#x3001;Klf5&#x3001;Tnfaip2&#x3001;Sema3c) &#x306E;&#x767A;&#x73FE;&#x3092;&#x8A98;&#x5C0E;&#x3057;&#x307E;&#x3059;&#x3002;ERBB2 &#x4F9D;&#x5B58;&#x578B;&#x907A;&#x4F1D;&#x5B50;&#x8ABF;&#x7BC0;&#x306E;&#x30D7;&#x30ED;&#x30D5;&#x30A1;&#x30A4;&#x30EA;&#x30F3;&#x30B0;&#x306B;&#x306F;&#x3001;&#x6F5C;&#x5728;&#x7684;&#x306A;&#x8A3A;&#x65AD;&#x30DE;&#x30FC;&#x30AB;&#x30FC;&#x3068;&#x63A8;&#x5B9A;&#x3055;&#x308C;&#x308B;&#x6CBB;&#x7642;&#x6A19;&#x7684;&#x306E;&#x5927;&#x8981;&#x660E;&#x3089;&#x304B;&#x306B;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x30B2;&#x30CE;&#x30E0;&#x4E2D;&#x306E; colocalize &#x5171;&#x767A;&#x73FE;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x540C;&#x5B9A;&#x6A5F;&#x80FD; coregulation &#x3092;&#x8A55;&#x4FA1;&#x3059;&#x308B;&#x7814;&#x7A76;&#x3092;&#x3055;&#x3089;&#x306B;&#x5FC5;&#x8981;&#x306A;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x8ABF;&#x7BC0;&#x6A5F;&#x69CB;&#x3092;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;(&#x3053;&#x306E;&#x8CC7;&#x6599;&#x306E;&#x88DC;&#x8DB3;&#x8CC7;&#x6599;&#x764C;&#x56FD;&#x969B;&#x30B8;&#x30E3;&#x30FC;&#x30CA;&#x30EB;&#x306E;&#x30A6;&#x30A7;&#x30D6;&#x30B5;&#x30A4;&#x30C8; http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html &#x3067;&#x898B;&#x3064;&#x3051;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3059;&#x3002;)

&#x8B58;&#x5225;&#x304A;&#x3088;&#x3073;&#x691C;&#x8A3C; &#xFF08;HER2&#x3001;&#x30CE;&#x30A4;&#xFF09; &#x5C0F;&#x8AAC; ERBB2 &#x306E;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x306B;&#x95A2;&#x4E0E;&#x3059;&#x308B;&#x907A;&#x4F1D;&#x5B50;&#x3092;&#x542B;&#x3080;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x3002;

V erb b2 erythroblastic &#xBC31;&#xD608;&#xBCD1; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; oncogene &#xCCB4; 2 (ERBB2; &#xB3D9;&#xC758;&#xC5B4; HER2, NEU) &#xB2E4;&#xB978; &#xC2E0;&#xD638; &#xC804;&#xB2EC; &#xACFC;&#xC815;&#xC5D0;&#xC11C; &#xC8FC;&#xC694; &#xC2A4;&#xC704;&#xCE58; &#xC5ED;&#xD560; &#xD558;&#xB294; &#xD2F0;&#xB85C;&#xC2E0; &#xD0A4; &#xB2C8; &#xC544; &#xC81C; &#xAD00;&#xB828; &#xD65C;&#xB3D9; &#xB9C9; &#xD6A1;&#xB2E8; &#xB2F9;&#xB2E8;&#xBC31;&#xC9C8;&#xC744; &#xC778;&#xCF54;&#xB529;&#xD569;&#xB2C8;&#xB2E4;. ERBB2 &#xC99D;&#xD3ED; &#xBC0F; overexpression &#xB2E4;&#xC591; &#xD55C; &#xC778;&#xAC04;&#xC758; &#xC554;, &#xC720; &#xBC29;, &#xB09C;&#xC18C; &#xBC0F; &#xC2E0;&#xC7A5; &#xC554; &#xC885; &#xB4F1;&#xC5D0;&#xC11C; &#xBC1C;&#xACAC; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xC758; &#xBAA9;&#xD45C;&#xB294; genomewide &#xADDC;&#xBAA8;&#xC758; tumorigenic &#xD6A8;&#xACFC;&#xC5D0; &#xAE30;&#xC5EC; &#xD558;&#xB294; ERBB2 &#xADDC;&#xC81C; &#xB300;&#xC0C1; &#xC720;&#xC804;&#xC790;&#xB97C; &#xAC80;&#xCD9C; &#xD588;&#xB2E4;. ERBB2 &#xD398; &#xBC0F; &#xC57C;&#xC0DD;-&#xD0C0;&#xC785; &#xB9C8;&#xC6B0;&#xC2A4; &#xC12C;&#xC720; &#xC544; &#xC138;&#xD3EC;&#xC758; &#xC720;&#xC804;&#xC790; &#xCC28;&#xB3D9; &#xC2DD; &#xD504;&#xB85C;&#xD544; DNA microarrays &#xCC44;&#xC6A9; &#xBAA8;&#xB2C8;&#xD130;&#xB9C1; &#xD588;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC120;&#xD0DD; &#xB41C; &#xC720;&#xC804;&#xC790;&#xC758; &#xB808; &#xADE4; &#xB808;&#xC774;&#xD2B8; &#xB41C; &#xD45C;&#xD604; RT-PCR&#xC5D0; &#xC758;&#xD574; &#xD655;&#xC778; &#xB418;&#xC5C8;&#xACE0; &#xC11C;&#xCABD; &#xC624; &#xC810; &#xBD84;&#xC11D; &#xD558; &#xC5EC; &#xC720;&#xD6A8;&#xC131;&#xC744; &#xAC80;&#xC0AC; &#xD569;&#xB2C8;&#xB2E4;. &#xAC8C;&#xB188; &#xB113;&#xC740; &#xC9C4; &#xC2DD; &#xD504;&#xB85C; &#xD30C;&#xC77C;&#xB9C1; ERBB2 &#xC2E0;&#xD638;, (ii) &#xC720;&#xC804;&#xC790; tumorigenesis&#xC5D0; &#xC5F0;&#xB8E8; &#xD558;&#xC9C0;&#xB9CC; &#xC9C0;&#xAE08;&#xAE4C;&#xC9C0; ERBB2 &#xC2E0;&#xD638; &#xBFD0;&#xB9CC; &#xC544;&#xB2C8;&#xB77C;, (iii) &#xC544;&#xC9C1; &#xAE30;&#xB2A5; &#xC5C6;&#xC774; &#xC18C;&#xC124; &#xC720;&#xC804;&#xC790;&#xB97C; &#xD3EC;&#xD568; &#xD558; &#xC5EC; &#xAE08;&#xD558;&#xB294; &#xBCC0;&#xD658; &#xC5F0;&#xAD00; &#xC720;&#xC804;&#xC790;&#xC640; &#xAD00;&#xB828; &#xB418;&#xC9C0; &#xC54A;&#xC740;&#xC758; (i) &#xC54C;&#xB824;&#xC9C4;&#xB41C; &#xB300;&#xC0C1; &#xD655;&#xC778;. &#xC6B0;&#xB9AC;&#xB294; &#xB610;&#xD55C; coexpressed &#xC720;&#xC804;&#xC790;&#xC758; &#xC801;&#xC5B4;&#xB3C4; &#xC77C;&#xBD80;&#xBD84;&#xC740; &#xAC8C;&#xB188;&#xC5D0; &#xBC00;&#xC811; &#xD558; &#xAC8C; &#xC5F0;&#xACB0; &#xB41C; &#xBC1C;&#xACAC;. ERBB2 overexpression &#xD56D; &#xD608;&#xAD00; &#xC2E0;&#xC0DD; &#xC694;&#xC778; (&#xC608;&#xB97C; &#xB4E4;&#xC5B4;, &#xC2A4;&#xD30D;, Timp3, Serpinf1)&#xC758; &#xC804;&#xC0AC;&#xB97C; &#xC5B5;&#xC81C; &#xD558;&#xC9C0;&#xB9CC; angiogenic &#xC694;&#xC778; (&#xC608;&#xB97C; &#xB4E4;&#xC5B4;, Klf5, Tnfaip2, Sema3c)&#xC758; &#xC2DD;&#xC744; &#xC720;&#xB3C4; &#xD55C;&#xB2E4;. ERBB2 &#xC885;&#xC18D; &#xC720;&#xC804;&#xC790; &#xC870;&#xC808;&#xC758; &#xD504;&#xB85C; &#xD30C;&#xC77C;&#xB9C1; &#xC7A0;&#xC7AC;&#xC801;&#xC778; &#xC9C4;&#xB2E8; &#xB9C8;&#xCEE4; &#xBC0F; &#xC0C1; &#xCE58;&#xB8CC; &#xB300;&#xC0C1;&#xC758; &#xC81C; &#xC694;&#xB97C; &#xACF5;&#xAC1C; &#xD588;&#xB2E4;. &#xAC8C;&#xB188;&#xC5D0; &#xC788;&#xB294; colocalize coexpressed &#xC720;&#xC804;&#xC790;&#xC758; &#xC2DD;&#xBCC4; &#xCD94;&#xAC00; &#xAE30;&#xB2A5; coregulation&#xC744; &#xD3C9;&#xAC00; &#xD558;&#xB294; &#xC5F0;&#xAD6C;&#xC5D0; &#xD544;&#xC694;&#xD55C; &#xC720;&#xC804;&#xC790; &#xADDC;&#xC81C; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xB098;&#xD0C0;&#xB0BC; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. (&#xC774; &#xAE30;&#xC0AC;&#xC5D0; &#xB300; &#xD55C; &#xBCF4;&#xCDA9; &#xC790;&#xB8CC;&#xB294; http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html&#xC5D0; &#xAD6D;&#xC81C; &#xC554; &#xC800;&#xB110; &#xC6F9;&#xC0AC;&#xC774;&#xD2B8;&#xC5D0;&#xC11C; &#xCC3E;&#xC744; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.)

&#xC2DD;&#xBCC4; &#xBC0F; &#xAC80;&#xC99D;&#xC744; &#xD558;&#xB294; &#xC18C;&#xC124;&#xC758; ERBB2 (HER2, NEU) &#xD608;&#xAD00; &#xC2E0;&#xC0DD;&#xC5D0; &#xAD00;&#xB828; &#xB41C; &#xC720;&#xC804;&#xC790;&#xB97C; &#xD3EC;&#xD568; &#xD558; &#xC5EC; &#xB300;&#xC0C1;.

V-erb-b2 Leucemia Eritrobl&aacute;stica hom&oacute;logo del oncogene virales 2 (ERBB2; sin&oacute;nimos HER2, NEU) codifica una glicoprote&iacute;na transmembrana con actividad de tirosina quinasa espec&iacute;fica que act&uacute;a como un interruptor principal en los diferentes procesos de transducci&oacute;n de la se&ntilde;al. Sobreexpresi&oacute;n y ERBB2 amplificaci&oacute;n se han encontrado en un n&uacute;mero de c&aacute;nceres humanos, incluyendo el carcinoma de mama, ovario y ri&ntilde;&oacute;n. Nuestro objetivo era detectar genes de Diana ERBB2-regulado que contribuyen a su efecto tumor&iacute;geno en una escala de genomewide. El perfil de expresi&oacute;n g&eacute;nica diferencial de fibroblastos de rat&oacute;n ERBB2-transfectadas y salvaje-tipo supervisaron utilizando microarrays de DNA. Expresi&oacute;n regulada de los genes seleccionados fue verificado por RT-PCR y validado por an&aacute;lisis de Western blot. Perfil de la expresi&oacute;n de la amplia g&eacute;nica del genoma identificado objetivos (i) conocidos de se&ntilde;alizaci&oacute;n de ERBB2, (ii) genes implicados en la tumorig&eacute;nesis pero hasta ahora no asociado ERBB2 se&ntilde;alizaci&oacute;n as&iacute; como (iii) genes no relacionados con la transformaci&oacute;n oncog&eacute;nica, incluyendo nuevos genes sin anotaci&oacute;n funcional. Tambi&eacute;n se encontr&oacute; que al menos una fracci&oacute;n de genes coexpressed est&aacute;n vinculadas en el genoma. Sobreexpresi&oacute;n de ERBB2 suprime la transcripci&oacute;n de factores antiangiog&eacute;nicos (p. ej., Sparc, Timp3, Serpinf1) pero induce la expresi&oacute;n de factores angiog&eacute;nicos (p. ej., Klf5, Tnfaip2, Sema3c). Perfiles de regulaci&oacute;n g&eacute;nica de ERBB2-dependiente revelaron un compendio de posibles marcadores diagn&oacute;sticos y posibles dianas terap&eacute;uticas. Identificaci&oacute;n de genes coexpressed que colocalize en el genoma puede indicar los mecanismos de regulaci&oacute;n de genes que requieren m&aacute;s estudio para evaluar la corregulaci&oacute;n funcional. (Material complementario para este art&iacute;culo puede encontrarse en el sitio web del International Journal of Cancer en http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html).

Identificaci&oacute;n y validaci&oacute;n de novela ERBB2 (HER2, NEU) objetivos incluyendo genes involucrados en la angiog&eacute;nesis.

A wavelet approach to detecting electrocautery noise in the ECG.

A software approach has been developed for detecting electrocautery noise in the electrocardiogram (ECG) using a wavelet decomposition of the signal. With this approach, a clinical monitoring expert system can be forewarned of potential artefacts in trend values derived from the ECG, allowing it to proceed with caution when making decisions based on these trends. In 15 operations spanning 38.5 hours of ECG data, we achieved a false positive rate of 0.71% and a false negative rate of 0.33%. While existing hardware approaches detect the source of the noise without any ability to assess its impact on the measured ECG, our software approach detects only the presence of noise in the signal itself. Furthermore, the software approach is cheaper and easier to implement in a clinical environment than existing hardware approaches.

A Wavelet Approach to Detecting Electrocautery Noise in the ECG.

HER-2/neu overexpression in tumor cells caused abnormalities of MHC class I surface expression due to impaired expression of components of the antigen-processing machinery (APM) including the low molecular weight proteins, the transporter associated with antigen processing (TAP), and the chaperone tapasin, whereas the expression of MHC class I heavy chain as well as β(2)-microglobulin was only marginally affected. This oncogene-mediated deficient APM component expression could be reverted by interferon-γ treatment, suggesting a deregulation rather than structural alterations as underlying molecular mechanisms. To determine the level of regulation, the transcriptional activity of APM components was analyzed in HER-2/neu(-) and HER-2/neu(+) cells. All major APM components were transcriptionally down-regulated in HER-2/neu(+) when compared with HER-2/neu(-) cells, which was accompanied by a reduced binding of RNA polymerase II to the APM promoters. Site-directed mutagenesis of the p300- and E2F-binding sites in the APM promoters did not reconstitute the oncogene-mediated decreased transcription rate with the exception of tapasin, which was restored in HER-2/neu(+) cells to levels of wild type tapasin promoter activity in HER-2/neu(-) fibroblasts. The E2F-directed control of tapasin expression was further confirmed by chromatin immunoprecipitation analyses showing that E2F1 and p300 bind to the tapasin and APM promoters in both cell lines. Moreover, siRNA-mediated silencing of E2F1 was associated with an increased tapasin expression, whereas transient overexpression of E2F1 launch a reduced tapasin transcription, suggesting that E2F1 is an essential transcription factor for tapasin.

Identification of E2F1 as an important transcription factor for the regulation of tapasin expression.

Most high-performance organic solar cells involve bulk-heterojunctions in order to increase the active donor-acceptor interface area. The power conversion efficiency depends critically on the nano-morphology of the blend and the interface. Spectroscopy of the sub-bandgap region, i.e., below the bulk absorption of the individual components, provides unique opportunities to study interface-related properties. We present absorption measurements in the sub-bandgap region of bulk heterojunctions made of poly(3-hexylthiophene-2,5-diyl) as an electron donor and [6,6]-phenyl-C61-butyric acid methyl ester (P3HT:PCBM) as an electron acceptor and compare them with quantum-chemical calculations and recently published data on the external quantum efficiency (EQE). The very weak absorption of the deep sub-bandgap region measured by the ultra-sensitive Photothermal Deflection Spectroscopy (PDS) features Urbach tails, polaronic transitions, conventional excitons, and possibly charge-transfer states. The quantum-chemical calculations allow characterizing some of the unsettled spectral features.

Felix Herrmann

Translational Animal Research Center,
University Medical Centre,
Translational Animal Research Center, University Medical Centre

Johannes Gutenberg-Universität Mainz

Introducing Clicker Training as a Cognitive Enrichment for Laboratory Mice

Felix Herrmann

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Translational Animal Research Center,University Medical Centre,Translational Animal Research Center, University Medical Centre

Johannes Gutenberg-Universität Mainz

Introducing Clicker Training as a Cognitive Enrichment for Laboratory Mice

Translational Animal Research Center,
University Medical Centre,
Translational Animal Research Center, University Medical Centre