Surrogate phenotype definition for alcohol use disorders: a genome-wide search for linkage and association-1

<p><b>Copyright information:</b></p><p>Taken from "Surrogate phenotype definition for alcohol use disorders: a genome-wide search for linkage and association"</p><p></p><p>BMC Genetics 2005;6(Suppl 1):S55-S55.</p><p>Published online 30 Dec 2005</p><p>PMCID:PMC1866728.</p><p></p

Surrogate phenotype definition for alcohol use disorders: a genome-wide search for linkage and association-0

<p><b>Copyright information:</b></p><p>Taken from "Surrogate phenotype definition for alcohol use disorders: a genome-wide search for linkage and association"</p><p></p><p>BMC Genetics 2005;6(Suppl 1):S55-S55.</p><p>Published online 30 Dec 2005</p><p>PMCID:PMC1866728.</p><p></p>e band, block 2: late time window – 1–2.5 Hz wave band, block 3: early time window – 3–7 Hz wave band) are connected. Within each block measures are taken at different locations on the skull. The dotted line represents the mean of all measures. Blue, ERP-M taking into account structure + magnitude: measures of block 1 are much larger than eothers (block 2 and 3), independent from location on the skull. Red, ERP-P taking into account structure: measures of the central and parietal midline channel are larger than those of the frontal channels, this pattern is congruent across blocks

Surrogate phenotype definition for alcohol use disorders: a genome-wide search for linkage and association-2

<p><b>Copyright information:</b></p><p>Taken from "Surrogate phenotype definition for alcohol use disorders: a genome-wide search for linkage and association"</p><p></p><p>BMC Genetics 2005;6(Suppl 1):S55-S55.</p><p>Published online 30 Dec 2005</p><p>PMCID:PMC1866728.</p><p></p

DataSheet_1_A genome-wide association study on hematopoietic stem cell transplantation reveals novel genomic loci associated with transplant outcomes.docx

IntroductionData on genomic susceptibility for adverse outcomes after hematopoietic stem cell transplantation (HSCT) for recipients are scarce.MethodsWe performed a genome wide association study (GWAS) to identify genes associated with survival/mortality, relapse, and severe graft-versus-host disease (sGvHD), fitting proportional hazard and subdistributional models to data of n=1,392 recipients of European ancestry from three centres.ResultsThe single nucleotide polymorphism (SNP) rs17154454, intronic to the neuronal growth guidant semaphorin 3C gene (SEMA3C), was genome-wide significantly associated with event-free survival (p=7.0x10-8) and sGvHD (p=7.5x10-8). Further associations were detected for SNPs in the Paxillin gene (PXN) with death without prior relapse or sGvHD, as well as for SNPs of the Plasmacytoma Variant Translocation 1 gene (PVT1, a long non-coding RNA gene), the Melanocortin 5 Receptor (MC5R) gene and the WW Domain Containing Oxidoreductase gene (WWOX), all associated with the occurrence of sGvHD. Functional considerations support the observed associations.DiscussionThus, new genes were identified, potentially influencing the outcome of HSCT.</p

DataSheet_2_A genome-wide association study on hematopoietic stem cell transplantation reveals novel genomic loci associated with transplant outcomes.docx

IntroductionData on genomic susceptibility for adverse outcomes after hematopoietic stem cell transplantation (HSCT) for recipients are scarce.MethodsWe performed a genome wide association study (GWAS) to identify genes associated with survival/mortality, relapse, and severe graft-versus-host disease (sGvHD), fitting proportional hazard and subdistributional models to data of n=1,392 recipients of European ancestry from three centres.ResultsThe single nucleotide polymorphism (SNP) rs17154454, intronic to the neuronal growth guidant semaphorin 3C gene (SEMA3C), was genome-wide significantly associated with event-free survival (p=7.0x10-8) and sGvHD (p=7.5x10-8). Further associations were detected for SNPs in the Paxillin gene (PXN) with death without prior relapse or sGvHD, as well as for SNPs of the Plasmacytoma Variant Translocation 1 gene (PVT1, a long non-coding RNA gene), the Melanocortin 5 Receptor (MC5R) gene and the WW Domain Containing Oxidoreductase gene (WWOX), all associated with the occurrence of sGvHD. Functional considerations support the observed associations.DiscussionThus, new genes were identified, potentially influencing the outcome of HSCT.</p

PI3K Inhibition Enhances Doxorubicin-Induced Apoptosis in Sarcoma Cells

<div><p>We searched for a drug capable of sensitization of sarcoma cells to doxorubicin (DOX). We report that the dual PI3K/mTOR inhibitor PI103 enhances the efficacy of DOX in several sarcoma cell lines and interacts with DOX in the induction of apoptosis. PI103 decreased the expression of <em>MDR1</em> and <em>MRP1</em>, which resulted in DOX accumulation. However, the enhancement of DOX-induced apoptosis was unrelated to DOX accumulation. Neither did it involve inhibition of mTOR. Instead, the combination treatment of DOX plus PI103 activated Bax, the mitochondrial apoptosis pathway, and caspase 3. Caspase 3 activation was also observed in xenografts of sarcoma cells in nude mice upon combination of DOX with the specific PI3K inhibitor GDC-0941. Although the increase in apoptosis did not further impact on tumor growth when compared to the efficient growth inhibition by GDC-0941 alone, these findings suggest that inhibition of PI3K may improve DOX-induced proapoptotic effects in sarcoma. Taken together with similar recent studies of neuroblastoma- and glioblastoma-derived cells, PI3K inhibition seems to be a more general option to sensitize tumor cells to anthracyclines.</p> </div

Correlation of <i>p</i>_{<i>META-GSA</i>} and <i>p</i>_<i>SPP</i> in scenario no. 8.

<p>The numbers of simulations out of a total of 500 are depicted. Gene sets are classified as significant (p ≤ 0.05) or not significant using SPP and META-GSA.</p

META-GSA: a tool for meta-analysis based on GSAs for GWASs.

<p>Genome-wide association study (GWAS); gene-set analysis (GSA); meta-analysis of GSAs (META-GSA); gene set of interest (GS, containing genes 3,5,…); complementary gene set (GS’, containing genes 1, 2, 4,…); gene-level statistic of gene <i>g</i> and study <i>s (Γ</i>_{<i>g</i>,<i>s</i>}<i>)</i>; “enrichment score” (ES) as test statistic for GSA in study <i>s</i>.</p

GDC-0941 inhibits tumor growth and increases DOX-mediated effects on caspase 3 activity.

<p><b>A)</b> Inhibition of RD tumor growth (in %) in nude mice treated with 1.2 mg/kg DOX (i.p. every third day for 22 days; n = 19), 75 mg/kg GDC-0941 (orally every day for 22 days; n = 9), the combination of both drugs (n = 12) at the time points indicated. Vehicle-treated animals served a controls (n = 18). <b>B)</b> Caspase 3 positive cells (in %) in tumors of nude mice isolated after 22 days of treatment with DOX and/or GDC-0941 or solvent. Data represent mean+SEM. *<i>P</i><0.05 by ANOVA/Tukey’s testing.</p

Inhibition of mTOR does not sensitize RD cells to DOX-induced apoptosis.

<p><b>A) and B)</b> RD cells were treated for 24h with 1 µM DOX and/or 1 µM everolimus (ever; respective left panels) or with 1 µM DOX and/or 20 µM LY294002 (respective right panels) or solvent. <b>A)</b> Annexin V positive RD cells were analysed by FACS. Data represent mean+SEM of two independent experiments performed in duplicates. n.s. not significant by Students <i>t</i>-test. <b>B)</b> Western blot analyses.</p