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Single Nucleotide Polymorphism(SNP)Study. ICORG 08-40, V4

ABSTRACT: Primary Objective: Correlation of the skin and/or eye toxicity grade secondary to Cetuximab or Panitumumab and the SNP profile of the Epidermal Growth Factor Receptor (EGFR) domain III region. Secondary Objectives: Correlation of SNP profile with indicators of tumour response parameters, such as radiological response, duration of response, time to progression (TTP), overall survival (OS) time, incidence of non-dermatological adverse events.

DISEASE(S): Non-small Cell Lung Cancer,Colorectal Cancer,Colorectal Neoplasms,Carcinoma, Non-small-cell Lung

PROVIDER: 2135070 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Phase II Study with Symadex (C-1311) in Patients with Metastatic Colorectal Cancer after Oxaliplatin and/or Irinotecan Failure

Project description:Primary objectives: Evaluate the overall response rate (CR+PR) using RECIST criteria. Primary: Overall response rate (ORR) = complete response (CR) + partial response (PR) using RECIST criteria. Secondary: Time to progression (TTP) and duration of response.

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TTP mRNA targets identified by global analysis of stabilized transcripts in TTP-deficient fibroblasts

Project description:Tristetraprolin (TTP) is a tandem CCCH zinc finger protein that was identified through its rapid induction by mitogens in fibroblasts. Studies of TTP-deficient mice, and cells derived from them, showed that TTP could bind to certain AU-rich elements in mRNAs, leading to increases in the rates of mRNA deadenylation and destruction. Known physiological target mRNAs for TTP include tumor necrosis factor alpha (TNF), granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin 2 beta (IL2 beta). Here we used microarray analysis of RNA from wild-type and TTP-deficient fibroblast cell lines to identify transcripts with different decay rates, after serum stimulation and actinomycin D treatment. Of 250 mRNAs apparently stabilized in the absence of TTP, 23 contained conserved TTP binding sites; 10 of these were shown by secondary analyses to be stabilized. The most dramatically affected transcript encoded the protein Ier3, recently implicated in the physiological control of blood pressure. The Ier3 transcript contained several conserved TTP binding sites that could bind TTP directly, and conferred TTP sensitivity to the mRNA in cell transfection studies. These studies have identified several new, physiologically relevant TTP target transcripts in fibroblasts; these target mRNAs encode proteins from a variety of functional classes. Keywords: mRNA degradation, time course, knockout experiment

2006-10-17 | GSE5324 | GEO

Transcriptomic Analysis Of Micropapillary High Grade T1 Urothelial Bladder Cancer

Project description:Management of high-grade T1 (HGT1) micropapillary bladder cancer (MPBC) is controversial. An accurate genomic characterization might help predict outcome. We analyze the transcriptomic profile of MPBC in a clinically annotated HGT1 cohort establishing correlation with clinical outcome.A retrospective analysis of prospectively clinically followed series of HGT1; 23 patients with MPBC and 64 without MPBC (reference set). We identified a set of genes differentially expressed (DE). Associations between; clinical variables and gene expression (GE) levels (Wilcoxon’s rank sum); GE and time to progression (TTP) in univariate analysis (Log rank); GE levels adjusting for clinical variables (Cox regression) were evaluated.We identified a 26-gene signature that characterized MPBC in HGT1. Several genes including CD36, FAPB3 and RAETE1 were significantly associated with TTP. High expression of FABP3 and CD36 were associated with shorter TTP (P=0.045 and P=0.08 (NS)) as was low expression of RAET1E (P=0.01). Limitations include the lack of specific quantification of the percentage of MPBC tumor >10%.

2021-01-31 | GSE136401 | GEO

RNA-Seq analysis of wild-type and ttpA-C240ins mutant D. discoideum amebae during short-term nutrient deprivation

Project description:In many eukaryotes, mRNAs containing specific AU-rich motifs are regulated by proteins of the tristetraprolin (TTP) family, which bind to these motifs through a tandem zinc finger (TZF) domain. This binding leads to promotion of subsequent deadenylation and decay, partly through a conserved carboxyl-terminal CNOT1 binding domain. We explored the physiological role of the single TTP family member (TtpA) expressed in Dictyostelium discoideum. This study shows the effect of an insertional mutation in the TZF domain (ttpA-C240ins), which disrupted the TZF RNA binding domain, evaluated in amebae in axenic conditions in growth medium during surface culture, and during short term (2 and 6 hours) nutrient deprivation. RNA-Seq analysis was performed on WT and mutant cells in parallel during this short time course.

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A Link between the N363S Glucocorticoid Receptor Polymorphism and Altered Gene Expression Related to Human Disease

Project description:A single nucleotide polymorphism (SNP) in the human glucocorticoid receptor (GR), N363S, has been the focus of several clinical studies, and some epidemiological data link this SNP to increased glucocorticoid sensitivity, coronary artery disease and increased body mass index (BMI). However, molecular studies in vitro using reporter gene expression systems have failed to define a link between this polymorphism and altered glucocorticoid receptor function. To address the biological relevancy of N363S in glucocorticoid receptor mechanisms and function, we established stable U-2 OS (human osteosarcoma) cell lines expressing wild type hGR or N363S using a tetracycline-regulated expression system. Functional assays with reporter gene systems revealed only minor differences between the wild type hGR and N363S receptors under a variety of conditions that probe for GR function. However, examination of this polymorphism by human gene microarray analysis showed, for the first time, that there are significant differences between wild type hGR and the N363S SNP in their ability to selectively regulate gene expression. Several of these genes may define the link between the N363S SNP and human disease. Keywords: human glucocorticoid receptor, N363S single nucleotide polymorphism, microarray gene analysis

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