human-pluripotent-stem-cell-based-developmental-toxicity-assays-for

Human Pluripotent Stem Cell Based Developmental Toxicity Assays for Chemical Safety Screening and Systems Biology Data Generation

Efficient protocols to differentiate human pluripotent stem cells to various tissues in combination with -omics technologies opened up new horizons for in ...

Technical university of Dortmund

Technical University of Dortmund

Small cell lung cancer (SCLC) is usually classified into a two-stage system, limited (LD) and extensive disease (ED). However, the criteria for these two categories remain controversial. The widely used Veterans Administration Lung Study Group (VALG) definition of LD includes patients with primary tumor and nodal involvement limited to one hemithorax. In contrast, the International Association for the Study of Lung Cancer (IASLC) recommends that LD should additionally include all patients without distant metastasis. As a consequence, since treatment modalities for LD and ED could be different, individual clinical outcome of SCLC patients may be influenced by the staging system chosen. Among 109 consecutive SCLC patients treated in our clinic between 1989 and 1999 (mean age 68+/-9.1 years, 81% male) 23 patients (21%) could be either classified as LD or ED (LD-ED), depending on the staging system used. The prognosis of this overlapping group (LD-ED: median survival 291 days) was not statistically different from patients with limited disease defined by VALG criteria (LD-VALG: 385 days, log-rank test P = 0.42). On the other hand the survival difference between LD-ED patients and the ED-IASLC population was relevant (ED-IASLC: 208 days, P = 0.05), indicating that LD-ED patients should rather be included in the LD category. This is further supported by the results of a multivariate Cox regression analysis with all clinically relevant data. Only stage as defined by IASLC criteria was an independent prognostic factor in the likelihood-ratio-forward (hazard ratio = 1.94, CI = 1.26-2.99; P = 0.005) and backward model (hazard ratio = 1.76, CI: 1.12-2.76; P = 0.012), confirming the higher discriminatory power of the IASLC definition. In conclusion, the IASLC staging criteria for SCLC patients have a higher prognostic impact and are therefore preferable in clinical practice and future therapeutic trials.

Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer--what limits limited disease?

The tyrosine-kinase receptor c-kit and its ligand stem cell factor are coexpressed in many small cell lung cancer (SCLC) cell lines, leading to the hypothesis that this coexpression constitutes an autocrine growth loop. To further evaluate the frequency and pathogenic relevance of c-kit expression, tumor tissue together with the corresponding clinical data of SCLC patients was analyzed.

Characterization of c-kit expression in small cell lung cancer: prognostic and therapeutic implications.

Apurinic/apyrimidinic endonuclease (APE alias Ref-1) is a key enzyme in the base excision repair pathway. Besides its function in DNA repair, APE serves to maintain several transcription factors in an active reduced state such as c-Fos, c-Jun, NF-kappaB, p53 and HIF-1alpha, all of which have been shown to play a role in tumorigenesis. Because of the importance of APE in maintaining genomic stability and gene regulation, we examined whether APE expression is associated with survival and histopathological parameters of patients with ovarian cancer.

Nuclear expression of apurinic/apyrimidinic endonuclease increases with progression of ovarian carcinomas.

Studies in rodents suggest the presence of a hepatopancreatic stem cell in adult pancreas that may give rise to liver cells in vivo. The aim of the present study was to determine the ability of human islet-derived cells to adopt a hepatic phenotype in vivo. Cultured human islet-derived progenitor cells that did not express albumin in vitro were stained with the red fluorescent dye PKH26 and injected into the liver of severe combined immunodeficiency mice. After 3 or 12 weeks, red fluorescent cells were detected in 11 of 15 livers and were mostly single cells that were well integrated into the liver tissue. Human albumin was found in 8 of 11 animals by immunohistochemistry, and human albumin mRNA was detected in 4 of 10 host livers. The mechanism underlying this phenomenon seems to be transdifferentiation, because human and mouse albumin were found to be expressed in distinct cells in the host liver.

In vitro cultured islet-derived progenitor cells of human origin express human albumin in severe combined immunodeficiency mouse liver in vivo.

The tyrosine-kinase receptor c-kit (CD117) and its ligand stem cell factor are considered to be co-expressed in various solid tumors, including adenocarcinomas of the lung. The frequency of c-kit expression and its association with clinical parameters has not yet been evaluated in a larger population of lung adenocarcinomas. Therefore, tumor tissue of 95 consecutive patients with adenocarcinoma of the lung was stained using a polyclonal c-kit antibody. c-kit expression was correlated with relevant clinical parameters obtained by chart review. Positive c-kit expression in tumor tissue was observed in 61 of 95 patients (64%). Univariate analysis showed a significant effect of T (p = 0.003), N (p = 0.001) and M stage (p < 0.001) as well as of performance status (p = 0.001), surgical resection (p < 0.001), and LDH serum levels (p = 0.016) on survival. In contrast, c-kit protein expression was non- significant (p = 0.913). However, multivariate Cox regression with the influential parameters revealed a significant effect of c-kit expression on survival. Forward stepwise selection showed a 1.77-fold increased risk to die (hazard ratio, HR; 95% confidence interval, CI: 1.00-3.14, p = 0.047) for patients with c-kit-positive tumors. Similar data for c-kit expression were obtained by backward stepwise selection (HR: 1.78; 95% CI: 1.00-3.16; p = 0.044). In conclusion, the receptor tyrosine kinase c-kit is frequently expressed in adenocarcinomas of the lung and has a relevant effect on patient survival. The results of this study support clinical trials targeting the c-kit receptor with specific c-kit inhibitors (e.g. imatinib).

c-kit expression in adenocarcinomas of the lung.

Cellule mesenchimali del pancreas sviluppo esprimono il marcatore delle cellule staminali neurali nestina e fattore della trascrizione isolotto-1 (Isl-1). Usando definito condizioni di cultura che abbiamo isolati su una singola cella base nestina producendo cellule da isole pancreatiche umane. Queste cellule sono state immortalate con vettori lentivirali che codifica per la telomerasi e mBmi. Sono positivi per Isl-1 e della nestina e hanno il potenziale per adottare un fenotipo del pancreas endocrino con espressione di fattori di trascrizione critici inclusi Ipf-1, Isl-1, Ngn-3, Pax4, Pax6, Nkx2.2 e Nkx6.1 cos&igrave; come l&#39;isolotto ormoni insulina, glucagone e somatostatina. Inoltre, possono essere differenziati in cellule produttrici di albumina umana in vivo quando innestate in un fegato di topo SCID. In conformit&agrave; con un fenotipo mesenchimale, le cellule sono state anche in grado di adottare fenotipi adipocytic o osteocytic in vitro. In conclusione, colte isolotti pancreatici contengono nestina e Isl-1 cellule staminali mesenchimali positive con molteplici capacit&agrave; evolutiva.

Multipotenziale nestina e Isl-1 positive cellule staminali mesenchimali isolate da isole pancreatiche umane.

&#x5728;&#x53D1;&#x5C55;&#x4E2D;&#x56FD;&#x5BB6;&#x7684;&#x80F0;&#x817A;&#x4E2D;&#x7684;&#x95F4;&#x8D28;&#x7EC6;&#x80DE;&#x8868;&#x8FBE;&#x795E;&#x7ECF;&#x5E72;&#x7EC6;&#x80DE;&#x6807;&#x8BB0;&#x5DE2;&#x86CB;&#x767D;&#x548C;&#x8F6C;&#x5F55;&#x56E0;&#x5B50;&#x80F0;&#x5C9B;-1 (Isl-1&#xFF09;&#x3002;&#x4F7F;&#x7528;&#x5DE2;&#x751F;&#x4EA7;&#x4ECE;&#x4EBA;&#x80F0;&#x5C9B;&#x7EC6;&#x80DE;&#x7684;&#x5355;&#x4E2A;&#x5355;&#x5143;&#x683C;&#x7684;&#x57FA;&#x7840;&#x4E0A;&#x5B9A;&#x4E49;&#x6211;&#x4EEC;&#x5B64;&#x7ACB;&#x7684;&#x6587;&#x5316;&#x6761;&#x4EF6;&#x3002;&#x8FD9;&#x4E9B;&#x7EC6;&#x80DE;&#x88AB;&#x6C38;&#x751F;&#x4E0E;&#x7AEF;&#x7C92;&#x9176;&#x548C; mBmi &#x7F16;&#x7801;&#x7684;&#x6162;&#x75C5;&#x6BD2;&#x8F7D;&#x4F53;&#x3002;&#x4ED6;&#x4EEC;&#x662F;&#x79EF;&#x6781;&#x7684; Isl 1 &#x548C;&#x5DE2;&#xFF0C;&#x5E76;&#x6709;&#x53EF;&#x80FD;&#x91C7;&#x53D6;&#x5305;&#x62EC;&#x68EE;&#x6797;&#x5C0F;&#x7EC4; 1&#x3001; Isl 1&#x3001; &#x4E0B;&#x4E00;&#x4EE3;&#x7F51;&#x7EDC; 3&#x3001; Pax4&#x3001; Pax6&#x3001; Nkx2.2&#xFF0C;&#x548C; Nkx6.1&#xFF0C;&#x4EE5;&#x53CA;&#x80F0;&#x5C9B;&#x6FC0;&#x7D20;&#x80F0;&#x5C9B;&#x7D20;&#x3001; &#x80F0;&#x9AD8;&#x8840;&#x7CD6;&#x7D20;&#x3001; &#x548C;&#x751F;&#x957F;&#x6291;&#x7D20;&#x7684;&#x5173;&#x952E;&#x8F6C;&#x5F55;&#x56E0;&#x5B50;&#x7684;&#x8868;&#x8FBE;&#x4E0E;&#x80F0;&#x817A;&#x5185;&#x5206;&#x6CCC;&#x8868;&#x578B;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x5B83;&#x4EEC;&#x53EF;&#x4EE5;&#x5206;&#x5316;&#x4E3A;&#x4EBA;&#x4F53;&#x767D;&#x86CB;&#x767D;&#x751F;&#x4EA7;&#x7EC6;&#x80DE;&#x4F53;&#x5185;&#x79FB;&#x690D;&#x5230; SCID &#x5C0F;&#x9F20;&#x809D;&#x810F;&#x65F6;&#x3002;&#x6839;&#x636E;&#x95F4;&#x8D28;&#x8868;&#x578B;&#xFF0C;&#x5355;&#x5143;&#x683C;&#x4E5F;&#x80FD;&#x591F;&#x901A;&#x8FC7;&#x4F53;&#x5916;&#x6210;&#x6216;&#x5B54;&#x9699;&#x578B;&#x3002;&#x6700;&#x540E;&#xFF0C;&#x4F53;&#x5916;&#x57F9;&#x517B;&#x7684;&#x80F0;&#x5C9B;&#x5305;&#x542B;&#x7684;&#x5DE2;&#x548C; Isl-1 &#x79EF;&#x6781;&#x7684;&#x9AA8;&#x9AD3;&#x95F4;&#x5145;&#x8D28;&#x5E72;&#x7EC6;&#x80DE;&#x5177;&#x6709;&#x591A;&#x53D1;&#x5C55;&#x80FD;&#x529B;&#x3002;

&#x591A;&#x5DE2;&#x86CB;&#x767D;&#x548C; Isl 1 &#x79EF;&#x6781;&#x9AA8;&#x9AD3;&#x95F4;&#x5145;&#x8D28;&#x5E72;&#x7EC6;&#x80DE;&#x5206;&#x79BB;&#x4EBA;&#x80F0;&#x5C9B;&#x3002;

Mesenchymal cells in the developing pancreas express the neural stem cell marker nestin and the transcription factor islet-1 (Isl-1). Using defined culture conditions we isolated on a single cell basis nestin producing cells from human pancreatic islets. These cells were immortalized with lentiviral vectors coding for telomerase and mBmi. They are positive for Isl-1 and nestin and have the potential to adopt a pancreatic endocrine phenotype with expression of critical transcription factors including Ipf-1, Isl-1, Ngn-3, Pax4, Pax6, Nkx2.2, and Nkx6.1 as well as the islet hormones insulin, glucagon, and somatostatin. In addition, they can be differentiated into human albumin producing cells in vivo when grafted into a SCID mouse liver. In accordance with a mesenchymal phenotype, the cells were also able to adopt adipocytic or osteocytic phenotypes in vitro. In conclusion, cultured pancreatic islets contain nestin and Isl-1 positive mesenchymal stem cells with multipotential developmental capacity.

Multipotential nestin and Isl-1 positive mesenchymal stem cells isolated from human pancreatic islets.

Cellules m&#xE9;senchymateuses dans le pancr&#xE9;as d&#xE9;velopper exprimer l&#x26;#39;neuronal cellules souches marqueur nestine et le facteur de transcription &#xEE;lot-1 (Isl-1). Utilisation de conditions de culture d&#xE9;finies, nous avons isol&#xE9; sur quelques cellules unicellulaires nestine base de production de &#xEE;lots pancr&#xE9;atiques humains. Ces cellules ont &#xE9;t&#xE9; immortalis&#xE9;es avec des vecteurs lentiviraux codant pour la t&#xE9;lom&#xE9;rase et MBMI. Ils sont positifs pour Isl-1 et la nestine et ont le potentiel d&#x26;#39;adopter un ph&#xE9;notype pancr&#xE9;atique endocrine avec l&#x26;#39;expression de facteurs de transcription essentiels, y compris IPF-1, Isl-1, Ngn-3, Pax4, Pax6, Nkx2.2, et Nkx6.1 ainsi que l&#x26;#39;&#xEE;lot hormones insuline, le glucagon, et la somatostatine. En outre, ils peuvent &#xEA;tre diff&#xE9;renci&#xE9;es en cellules productrices de l&#x26;#39;albumine humaine in vivo lorsque greff&#xE9; sur un foie de souris SCID. Conform&#xE9;ment &#xE0; un ph&#xE9;notype m&#xE9;senchymateux, les cellules &#xE9;taient &#xE9;galement en mesure d&#x26;#39;adopter des ph&#xE9;notypes adipocytaire ou ost&#xE9;ocytique in vitro. En conclusion, les &#xEE;lots pancr&#xE9;atiques de culture contiennent nestine et Isl-1 positives des cellules souches m&#xE9;senchymateuses avec une capacit&#xE9; de d&#xE9;veloppement multipotentielle.

Multipotentielle Nestin et Isl-1 positives Cellules souches m&#xE9;senchymateuses Isol&#xE9; &#xE0; partir des &#xEE;lots pancr&#xE9;atiques humains

Mesenchymale Zellen in der Bauchspeicheldr&uuml;se entwickeln express die neuronalen Stammzellen Markierung nestin und die Transkription Faktor Inselchen-1 (Isl-1). Mit definierten Kulturbedingungen, die wir isoliert auf eine einzelne Zelle Grundlage nestin produzierenden Zellen aus menschlichen Pankreas Inselchen. Diese Zellen wurden mit Lentiviralen Vektoren Kodierung f&uuml;r Telomerase und mBmi verewigt. Sie sind positiv f&uuml;r Isl-1 und nestin und haben das Potenzial, einen pankreatischen endokrinen Ph&auml;notyp mit Ausdruck der kritischen Transkriptionsfaktoren, die Ipf-1, Isl-1, Ngn-3, Pax4 Pax6, Nkx2.2, und Nkx6.1 sowie die Inselchen hormone Insulin, Glukagon und Somatostatin anzunehmen. Dar&uuml;ber hinaus k&ouml;nnen sie in menschliches Albumin-produzierenden Zellen in-vivo wenn in einem SCID-Maus-Leber veredelt unterschieden werden. Gem&auml;&szlig; einem Mesenchymale Ph&auml;notyp konnten die Zellen auch in-vitro-adipocytic oder osteocytic Ph&auml;notypen zu verabschieden. Abschlie&szlig;end enthalten kultivierte Pankreas Inselchen nestin und Isl-1 positiven mesenchymalen Stammzellen mit multipotenzielle Entwicklungsst&ouml;rungen Kapazit&auml;t.

Multipotenzielle nestin und Isl-1 positive mesenchymale Stammzellen aus menschlichen Pankreas Inseln isoliert.

&#x958B;&#x767A;&#x81B5;&#x81D3;&#x306E;&#x9593;&#x8449;&#x7CFB;&#x7D30;&#x80DE;&#x306F;&#x795E;&#x7D4C;&#x5E79;&#x7D30;&#x80DE;&#x30DE;&#x30FC;&#x30AB;&#x30FC;&#x3067;&#x3042;&#x308B;&#x30CD;&#x30B9;&#x30C1;&#x30F3;&#x3068;&#x8EE2;&#x5199;&#x56E0;&#x5B50;&#x81B5;&#x5CF6;-1&#xFF08;ISL-1&#xFF09;&#x3092;&#x8868;&#x73FE;&#x3057;&#x307E;&#x3059;&#x3002;&#x5B9A;&#x7FA9;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x57F9;&#x990A;&#x6761;&#x4EF6;&#x3092;&#x7528;&#x3044;&#x3066;&#x3001;&#x6211;&#x3005;&#x306F;&#x30D2;&#x30C8;&#x81B5;&#x5CF6;&#x304B;&#x3089;&#x306E;&#x5358;&#x4E00;&#x7D30;&#x80DE;&#x306E;&#x57FA;&#x5E95;&#x30CD;&#x30B9;&#x30C1;&#x30F3;&#x7523;&#x751F;&#x7D30;&#x80DE;&#x3067;&#x9694;&#x96E2;&#x3055;&#x308C;&#x308B;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x7D30;&#x80DE;&#x306F;&#x3001;&#x30C6;&#x30ED;&#x30E1;&#x30E9;&#x30FC;&#x30BC;&#x3068;mBmi&#x30B3;&#x30FC;&#x30C7;&#x200B;&#x200B;&#x30A3;&#x30F3;&#x30B0;&#x30EC;&#x30F3;&#x30C1;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x30D9;&#x30AF;&#x30BF;&#x30FC;&#x3067;&#x4E0D;&#x6B7B;&#x5316;&#x3055;&#x308C;&#x305F;&#x3002;&#x5F7C;&#x3089;&#x306F;&#x3001;ISL-1&#x304A;&#x3088;&#x3073;&#x30CD;&#x30B9;&#x30C1;&#x30F3;&#x967D;&#x6027;&#x3067;&#x3042;&#x308B;&#x3068;IPF-1&#x3001;ISL-1&#x3001;NGN-3&#x3001;PAX4&#x3001;Pax6&#x306E;&#x3001;Nkx2.2&#x3001;&#x304A;&#x3088;&#x3073;Nkx6.1&#x3092;&#x542B;&#x3080;&#x91CD;&#x8981;&#x306A;&#x8EE2;&#x5199;&#x56E0;&#x5B50;&#x306E;&#x767A;&#x73FE;&#x3068;&#x81B5;&#x5185;&#x5206;&#x6CCC;&#x8868;&#x73FE;&#x578B;&#x3092;&#x63A1;&#x7528;&#x3059;&#x308B;&#x53EF;&#x80FD;&#x6027;&#x3092;&#x79D8;&#x3081;&#x3066;&#x3044;&#x308B;&#x306A;&#x3069;&#x306E;&#x81B5;&#x5CF6;&#x30DB;&#x30EB;&#x30E2;&#x30F3;&#x3001;&#x30A4;&#x30F3;&#x30B9;&#x30EA;&#x30F3;&#x3001;&#x30B0;&#x30EB;&#x30AB;&#x30B4;&#x30F3;&#x3001;&#x304A;&#x3088;&#x3073;&#x30BD;&#x30DE;&#x30C8;&#x30B9;&#x30BF;&#x30C1;&#x30F3;&#x3002; SCID&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x809D;&#x81D3;&#x306B;&#x79FB;&#x690D;&#x3059;&#x308B;&#x3068;&#x304D;&#x306B;&#x52A0;&#x3048;&#x3066;&#x3001;&#x305D;&#x308C;&#x3089;&#x306F;in vivo&#x3067;&#x30D2;&#x30C8;&#x30A2;&#x30EB;&#x30D6;&#x30DF;&#x30F3;&#x7523;&#x751F;&#x7D30;&#x80DE;&#x306B;&#x5206;&#x5316;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3059;&#x3002;&#x9593;&#x8449;&#x8868;&#x73FE;&#x578B;&#x306B;&#x5F93;&#x3063;&#x3066;&#x3001;&#x7D30;&#x80DE;&#x306F;&#x307E;&#x305F;&#x3001;in vitro&#x3067;&#x306E;&#x8102;&#x80AA;&#x7D30;&#x80DE;&#x3084;&#x9AA8;&#x7D30;&#x80DE;&#x306E;&#x8868;&#x73FE;&#x578B;&#x3092;&#x63A1;&#x7528;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3057;&#x305F;&#x3002;&#x7D50;&#x8AD6;&#x3068;&#x3057;&#x3066;&#x306F;&#x3001;&#x57F9;&#x990A;&#x3055;&#x308C;&#x305F;&#x81B5;&#x5CF6;&#x306F;&#x3001;&#x30CD;&#x30B9;&#x30C1;&#x30F3;&#x3068;&#x591A;&#x80FD;&#x6027;&#x767A;&#x9054;&#x80FD;&#x529B;&#x3092;&#x6301;&#x3064;ISL-1&#x967D;&#x6027;&#x306E;&#x9593;&#x8449;&#x7CFB;&#x5E79;&#x7D30;&#x80DE;&#x304C;&#x542B;&#x307E;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;

&#x30D2;&#x30C8;&#x81B5;&#x5CF6;&#x304B;&#x3089;&#x5358;&#x96E2;&#x3055;&#x308C;&#x305F;&#x591A;&#x80FD;&#x6027;&#x30CD;&#x30B9;&#x30C1;&#x30F3;&#x304A;&#x3088;&#x3073;ISL-1&#x967D;&#x6027;&#x306E;&#x9593;&#x8449;&#x7CFB;&#x5E79;&#x7D30;&#x80DE;

&#xAC1C;&#xBC1C; &#xCDCC; &#xC7A5; &#xC911;&#xAC04; &#xC5FD; &#xC138;&#xD3EC;&#xB294; &#xC2E0;&#xACBD; &#xC904;&#xAE30; &#xC138;&#xD3EC; &#xD45C;&#xC2DD; nestin&#xACFC; &#xC804;&#xC0AC; &#xC778;&#xC790; &#xC12C;-1 (Isl-1) &#xD45C;&#xD604;. &#xC778;&#xAC04;&#xC758; &#xCDCC; &#xC7A5; &#xB3C5;&#xB3C4;&#xC5D0;&#xC11C; &#xC140; &#xC0DD;&#xC0B0; nestin &#xB2E8;&#xC77C; &#xC140; &#xAE30;&#xC900;&#xC5D0; &#xC6B0;&#xB9AC; &#xACE0;&#xB9BD; &#xBB38;&#xD654; &#xC870;&#xAC74; &#xC815;&#xC758; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC;. &#xC774;&#xB7EC;&#xD55C; &#xC140; lentiviral &#xBCA1;&#xD130; telomerase &#xBC0F; Mbmi&#xC5D0; &#xB300; &#xD55C; &#xCF54;&#xB529;&#xC73C;&#xB85C; &#xBD88;&#xBA78; &#xD558; &#xAC8C; &#xD588;&#xB2E4;. &#xADF8;&#xB4E4;&#xC740; Isl-1&#xC5D0; &#xB300; &#xD55C; &#xAE0D;&#xC815;&#xC801;&#xC774; &#xACE0; nestin&#xC640; &#xD45C;&#xD604;&#xC758; Ipf 1, Isl 1, Ngn-3, Pax4, Pax6, Nkx2.2, &#xBC0F; nkx6.1&#xB85C; &#xC11C;&#xB294; &#xC12C; &#xD638;&#xB974;&#xBAAC; &#xC778;&#xC290;&#xB9B0;, &#xAE00; &#xB8E8;&#xCE74; &#xACE4;, &#xBC0F; somatostatin&#xB97C; &#xD3EC;&#xD568; &#xD558; &#xC5EC; &#xC911;&#xC694; &#xD55C; &#xC804;&#xC0AC; &#xC778;&#xC790;&#xC640; &#xCDCC; &#xC7A5; &#xB0B4; &#xBD84; &#xBE44; &#xD615;&#xC744; &#xCC44;&#xD0DD; &#xAC00;&#xB2A5;&#xC131;&#xC774; &#xC788;&#xB2E4;. &#xB610;&#xD55C;, &#xADF8;&#xB4E4;&#xC740; &#xC778;&#xAC04;&#xC758; &#xC54C; &#xBD80; &#xBBFC; &#xC0DD;&#xC0B0; SCID &#xB9C8;&#xC6B0;&#xC2A4; &#xAC04;&#xC5D0; &#xC735;&#xD569; &#xD558;&#xC600;&#xC2B5;&#xB2C8;&#xB2E4; &#xB54C; in vivo &#xC138;&#xD3EC;&#xB85C; &#xBD84;&#xD654; &#xB420; &#xC218; &#xC788;&#xB2E4;. &#xC5FD; &#xD615;&#xC5D0; &#xB530;&#xB77C; &#xC140; &#xB610;&#xD55C; &#xC0DD;&#xCCB4; &#xC678;&#xC5D0;&#xC11C; adipocytic &#xB610;&#xB294; osteocytic&#xC5D0; &#xD574;&#xB2F9; &#xD558;&#xB294; &#xACE0;&#xAE30;&#xB97C; &#xCC44;&#xD0DD;&#xD560; &#xC218; &#xC788;&#xC5C8;&#xB2E4;. &#xB05D;&#xC73C;&#xB85C;, &#xAD50;&#xC591;&#xB41C; &#xCDCC; &#xC7A5; &#xB3C5;&#xB3C4; multipotential &#xBC1C;&#xB2EC; &#xC6A9;&#xB7C9; nestin&#xC640; Isl 1 &#xAE0D;&#xC815;&#xC801;&#xC778; &#xC911;&#xAC04; &#xC5FD; &#xC904;&#xAE30; &#xC138;&#xD3EC;&#xB97C; &#xD3EC;&#xD568;.

Multipotential nestin&#xC640; Isl 1 &#xAE0D;&#xC815;&#xC801;&#xC778; &#xC911;&#xAC04; &#xC5FD; &#xC904;&#xAE30; &#xC138;&#xD3EC; &#xC778;&#xAC04;&#xC758; &#xCDCC; &#xC7A5; &#xB3C5;&#xB3C4;&#xC5D0;&#xC11C; &#xACA9;&#xB9AC;.

Las c&#xE9;lulas mesenquimales en el p&#xE1;ncreas en desarrollo expresan el marcador de las c&#xE9;lulas madre neurales nestina y el factor de transcripci&#xF3;n islote-1 (COL-1). Usando definidas las condiciones de cultivo se aislaron las c&#xE9;lulas en una sola c&#xE9;lula nestin base de producci&#xF3;n de islotes pancre&#xE1;ticos humanos. Estas c&#xE9;lulas se han inmortalizado con vectores lentivirales que codifican para la telomerasa y MBMI. Ellos son positivos para Isl-1 y nestina y tienen el potencial para adoptar un fenotipo endocrina del p&#xE1;ncreas con la expresi&#xF3;n de factores de transcripci&#xF3;n cr&#xED;ticos, entre ellos IPF-1, Isl-1, NGN-3, PAx4, Pax6, Nkx2.2 y Nkx6.1 as&#xED; como el islote hormonas insulina, glucag&#xF3;n y somatostatina. Adem&#xE1;s, se pueden diferenciarse en c&#xE9;lulas humanas productoras de alb&#xFA;mina in vivo cuando se injerta en un h&#xED;gado de rat&#xF3;n SCID. De acuerdo con un fenotipo mesenquimal, las c&#xE9;lulas fueron tambi&#xE9;n capaces de adoptar fenotipos adipocytic o osteocitos in vitro. En conclusi&#xF3;n, los islotes pancre&#xE1;ticos contienen cultivos de nestin y Isl-1 en las c&#xE9;lulas madre mesenquimales positivos con capacidad de desarrollo pluripotencial.

Multipotencial Nestin e ISL-1 c&#xE9;lulas positivas madre mesenquimales aisladas de los islotes pancre&#xE1;ticos humanos

HER3 (erbB-3) is a member of the epidermal growth factor receptor (EGFR) family. After dimerization with other members of the EGFR family several signal transduction cascades can be activated, including phosphoinosite 3'-kinase (PI3-K)/Akt and extracellular signal-regulated kinase (ERK1/2). Here, we studied a possible association between HER3 expression and prognosis in patients with ovarian cancer.

ErbB-3 predicts survival in ovarian cancer.

Approximately 5,000 of 6 million annual visitors of the Oktoberfest in Munich have to undergo medical treatment. Patients with alcohol intoxication without trauma or further complications are all treated in a specialized medical camp. We studied these patients in order to identify risk factors and to assess the relevance of the Glasgow Coma Score (GCS) and of ethanol blood concentrations for patient management. In 2004 totally 405 patients suffering from ethanol intoxication without trauma were treated in the medical camp. A complete set of the following data was obtained from all 405 patients: GCS, ethanol blood concentration, age, sex, blood pressure (mean, systolic and diastolic), body temperature, heart rate, blood sugar, GOT, gamma-GT, and CK. A multivariate logistic regression model was applied to identify risk factors predicting patients at increased risk of hospitalization. Low GCS (< or =8 vs. >8, OR: 4.18, CI: 1.96-8.65) low age (20-29 vs. > or =30 years, OR: 2.35, CI: 1.05-5.65) and male gender (male vs. female, OR: 3.58, CI: 1.36-9.34) independently predicted patients that had to be hospitalized. All other parameters including ethanol blood concentrations were not explanatory. Patients with GCS < or = 8 (n = 66) had a lower median blood pressure (P = 0.0312) and showed a smaller increase in blood pressure during the observation period compared to patients with GCS > 8 (P < 0.001), suggesting that this subgroup may require longer recovery periods. Men aged 20-29 years were at highest risk for hospital admission. Increased risk could not be explained by higher ethanol blood concentrations in this subgroup. Importantly, GCS < 6 does not justify endotracheal intubation in ethanol intoxicated patients, when further complications, such as trauma, can be excluded.

Munich Oktoberfest experience: remarkable impact of sex and age in ethanol intoxication.

From our recent work on the three-dimensional structure of epoxide hydrolases we theoretically deduced the likelihood of a two-step catalytic mechanism that we and others have subsequently experimentally confirmed. Analysis of the rate of the two steps by us and by others show that the first step-responsible for removal of the reactive epoxide from the system-works extraordinarily fast (typically three orders of magnitude faster than the second step), sucking up the epoxide like a sponge. Regeneration of the free enzyme (the second step of the catalytic mechanism) is slow. This becomes a toxicological problem only at doses of the epoxide that titrate the enzyme out. Our genotoxicity work shows that indeed this generates a practical threshold below which no genotoxicity is observed. This shows that-contrary to old dogma-practical thresholds exist for definable genotoxic carcinogens.

Detoxication strategy of epoxide hydrolase-the basis for a novel threshold for definable genotoxic carcinogens.

Members of the Bcl-2 family act as master regulators of mitochondrial homeostasis and apoptosis. We analyzed whether ERBB2 influences the prognosis of breast cancer by influencing the proapoptotic versus antiapoptotic balance of Bcl-2 family members.

ERBB2 induces an antiapoptotic expression pattern of Bcl-2 family members in node-negative breast cancer.

Recently, growing attention has been directed toward stem cell metabolism, with the key observation that the plasticity of stem cells also reflects the plasticity of their energy substrate metabolism. There seems to be a clear link between the self-renewal state of stem cells, in which cells proliferate without differentiation, and the activity of specific metabolic pathways. Differentiation is accompanied by a shift from anaerobic glycolysis to mitochondrial respiration. This metabolic switch of differentiating stem cells is required to cover the energy demands of the different organ-specific cell types. Among other metabolic signatures, amino acid and carbohydrate metabolism is most prominent in undifferentiated embryonic stem cells, whereas the fatty acid metabolic signature is unique in cardiomyocytes derived from embryonic stem cells. Identifying the specific metabolic pathways involved in pluripotency and differentiation is critical for further progress in the field of developmental biology and regenerative medicine. The recently generated knowledge on metabolic key processes may help to generate mature stem cell-derived somatic cells for therapeutic applications without the requirement of genetic manipulation. In the present review, the literature about metabolic features of stem cells and their cardiovascular cell derivatives as well as the specific metabolic gene signatures differentiating between stem and differentiated cells are summarized and discussed.

Unique metabolic features of stem cells, cardiomyocytes, and their progenitors.

Nanotechnology offers enormous potential for technological progress. Fortunately, early and intensive efforts have been invested in investigating toxicology and safety aspects of this new technology. However, despite there being more than 6,000 publications on nanotoxicology, some key questions still have to be answered and paradigms need to be challenged. Here, we present a view on the field of nanotoxicology to stimulate the discussion on major knowledge gaps and the critical appraisal of concepts or dogma. First, in the ongoing debate as to whether nanoparticles may harbour a specific toxicity due to their size, we support the view that there is at present no evidence of 'nanospecific' mechanisms of action; no step-change in hazard was observed so far for particles below 100 nm in one dimension. Therefore, it seems unjustified to consider all consumer products containing nanoparticles a priori as hazardous. Second, there is no evidence so far that fundamentally different biokinetics of nanoparticles would trigger toxicity. However, data are sparse whether nanoparticles may accumulate to an extent high enough to cause chronic adverse effects. To facilitate hazard assessment, we propose to group nanomaterials into three categories according to the route of exposure and mode of action, respectively: Category 1 comprises nanomaterials for which toxicity is mediated by the specific chemical properties of its components, such as released ions or functional groups on the surface. Nanomaterials belonging to this category have to be evaluated on a case-by-case basis, depending on their chemical identity. Category 2 focuses on rigid biopersistent respirable fibrous nanomaterials with a specific geometry and high aspect ratio (so-called WHO fibres). For these fibres, hazard assessment can be based on the experiences with asbestos. Category 3 focuses on respirable granular biodurable particles (GBP) which, after inhalation, may cause inflammation and secondary mutagenicity that may finally lead to lung cancer. After intravenous, oral or dermal exposure, nanoscaled GBPs investigated apparently did not show 'nanospecific' effects so far. Hazard assessment of GBPs may be based on the knowledge available for granular particles. In conclusion, we believe the proposed categorization system will facilitate future hazard assessments.

Article	Year
Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer--what limits limited disease? Lung cancer (Amsterdam, Netherlands)\| PubMed ID: 12234695	2002
Characterization of c-kit expression in small cell lung cancer: prognostic and therapeutic implications. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 12538468	2003
Nuclear expression of apurinic/apyrimidinic endonuclease increases with progression of ovarian carcinomas. Gynecologic oncology\| PubMed ID: 14766249	2004
In vitro cultured islet-derived progenitor cells of human origin express human albumin in severe combined immunodeficiency mouse liver in vivo. Stem cells (Dayton, Ohio)\| PubMed ID: 15579634	2004
c-kit expression in adenocarcinomas of the lung. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine\| PubMed ID: 15627886	2004
Multipotential nestin and Isl-1 positive mesenchymal stem cells isolated from human pancreatic islets. Biochemical and biophysical research communications\| PubMed ID: 16713999	2006
ErbB-3 predicts survival in ovarian cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology\| PubMed ID: 16896008	2006
Munich Oktoberfest experience: remarkable impact of sex and age in ethanol intoxication. Archives of toxicology\| PubMed ID: 18987847	2008
Detoxication strategy of epoxide hydrolase-the basis for a novel threshold for definable genotoxic carcinogens. Nonlinearity in biology, toxicology, medicine\| PubMed ID: 19330105	2004
ERBB2 induces an antiapoptotic expression pattern of Bcl-2 family members in node-negative breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 20068093	2010
Unique metabolic features of stem cells, cardiomyocytes, and their progenitors. Circulation research\| PubMed ID: 24723659	2014
Manufactured nanomaterials: categorization and approaches to hazard assessment. Archives of toxicology\| PubMed ID: 25326817	2014

Jan Georg Hengstler

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