Genome-Wide Meta-Analysis Identifies Variants in DSCAM and PDLIM3 that correlate with efficacy outcomes in metastatic renal cell carcinoma patients treated with sunitinib

Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p Personalised Therapeutic

The Effect of Shot Biopsy on Behavior, Salivary Cortisol, and Heart Rate in Slaughter Pigs

This paper describes behavioral and. physiological responses of pigs to shot biopsy, an experimental method used to study muscle tissue processes or to:predict meat quality. One biopsy sample from the longissimus muscle was obtained from 23-wk-old gilts (n = 10) using a cannula connected to a captive bolt. Ten other gilts were used as a control and received a sham shot. One week later, a second biopsy was taken from the same gilts, Behavioral and salivary cortisol responses to both biopsies were similar (P > .10). Pigs flinched in response to the biopsies. Salivary cortisol concentrations were increased (P <.05) 15 min after the biopsy as compared with pretreatment levels, but absolute levels were not different (P > .10) from the control group; In both biopsy and control groups, heart rate increased ( P <.001) in response to the presence of the technician. In response to the first biopsy, heart rate increased(P <.01) as compared with the rate during the 5-s period before the biopsy, but heart rate did not increase in response to the second biopsy. The biopsy pigs showed a decrease (P <.05) in initiating contact with the technician in the second test. We conclude that shot biopsy had a significant acute effect on behavior and heart rate. Therefore, the usefulness of this technique in studies in which the behavioral and heart rate responses are measured is limited

Traglast von Verbund-Durchlauftraegern fuer den Hoch- und Industriebau unter besonderer Beruecksichtigung einer nachgiebigen Verduebelung

Available from TIB Hannover: RR 7808(124) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEArbeitsgemeinschaft Industrieller Forschungsvereinigungen e.V., Koeln (Germany)DEGerman

Description of the EuroTARGET cohort: A European collaborative project on TArgeted therapy in renal cell cancer-GEnetic- and tumor-related biomarkers for response and toxicity

Contains fulltext : 177333.pdf (publisher's version ) (Open Access)OBJECTIVE: For patients with metastatic renal cell cancer (mRCC), treatment choice is mainly based on clinical parameters. With many treatments available and the limited response to treatment and associated toxicities, there is much interest in identifying better biomarkers for personalized treatment. EuroTARGET aims to identify and characterize host- and tumor-related biomarkers for prediction of response to tyrosine kinase inhibitor therapy in mRCC. Here, we describe the EuroTARGET mRCC patient cohort. METHODS AND MATERIALS: EuroTARGET is a European collaborative project designed as an observational study for which patients with mRCC were recruited prospectively in 62 centers. In addition, 462 patients with mRCC from previous studies were included. Detailed clinical information (baseline and follow-up) from all patients was entered in web-based case record forms. Blood was collected for germline DNA and pharmacokinetic/pharmacodynamic analyses and, where available, fresh-frozen tumor material was collected to perform tumor DNA, RNA, kinome, and methylome analyses. RESULTS: In total, 1,210 patients with mRCC were included. Of these, 920 received a tyrosine kinase inhibitor as first-line targeted treatment (sunitinib [N = 713, 78%], sorafenib [N = 41, 4%], or pazopanib [N = 166, 18%]) and had at least 6 months of outcome assessment (median follow-up 15.3 months [interquartile range: 8.5-30.2 months]). Germline DNA samples were available from 824 of these patients, fresh-frozen tumor material from 142 patients, fresh-frozen normal kidney tissue from 95 patients, and tissue microarrays created from formalin-fixed paraffin-embedded tumor material from 247 patients. Of the 920 patients, germline DNA variant chip data were successfully generated for 811 patients (Illumina HumanOmniExpress BeadChip). For 80 patients, next-generation exome sequencing of germline and tumor DNA was performed, tumor RNA sequencing was performed for 124 patients, kinome activity measured and processed for 121 patients (PamChip), and methylome data (Illumina Infinium HumanMethylation450 BeadChip) were created for 116 RCC tissues (and 23 normal kidney tissues). For 73 out of the 920 patients, all platform data types were generated. In addition, 40 patients were included in a pharmacokinetic/pharmacodynamic phase IV substudy. CONCLUSIONS: Analysis of EuroTARGET cohort data will contribute to personalization of therapy for patients with mRCC. The extensive clinical data and multiplatform EuroTARGET data will be freely available