81 research outputs found
Updates on p53: modulation of p53 degradation as a therapeutic approach
The p53 pathway is aberrant in most human tumours with over 50% expressing mutant p53 proteins. The pathway is critically controlled by protein degradation. Here, we discuss the latest developments in the search for small molecules that can modulate p53 pathway protein stability and restore p53 activity for cancer therapy
Should We Abandon the t-Test in the Analysis of Gene Expression Microarray Data: A Comparison of Variance Modeling Strategies
High-throughput post-genomic studies are now routinely and promisingly investigated in biological and biomedical research. The main statistical approach to select genes differentially expressed between two groups is to apply a t-test, which is subject of criticism in the literature. Numerous alternatives have been developed based on different and innovative variance modeling strategies. However, a critical issue is that selecting a different test usually leads to a different gene list. In this context and given the current tendency to apply the t-test, identifying the most efficient approach in practice remains crucial. To provide elements to answer, we conduct a comparison of eight tests representative of variance modeling strategies in gene expression data: Welch's t-test, ANOVA [1], Wilcoxon's test, SAM [2], RVM [3], limma [4], VarMixt [5] and SMVar [6]. Our comparison process relies on four steps (gene list analysis, simulations, spike-in data and re-sampling) to formulate comprehensive and robust conclusions about test performance, in terms of statistical power, false-positive rate, execution time and ease of use. Our results raise concerns about the ability of some methods to control the expected number of false positives at a desirable level. Besides, two tests (limma and VarMixt) show significant improvement compared to the t-test, in particular to deal with small sample sizes. In addition limma presents several practical advantages, so we advocate its application to analyze gene expression data
The effects of transurethral resection and cystoprostatectomy on dissemination of epithelial cells in the circulation of patients with bladder cancer
This study was undertaken to evaluate the risk of haematogenous dissemination of epithelial cells induced by endoscopic resection and/or cystoprostatectomy for transitional cell carcinoma of the bladder. Thirty-three patients were studied. Thirty-one had different stages and grades of bladder cancer and two patients had benign bladder conditions. Twenty-five cancer patients required transurethral resection of their bladder tumour. Of those, 20 had superficial disease (pTaG1–G2: n = 19; pT1G2: n = 1) and five had muscle invasive tumours (pT2G3: n = 2; pT3aG3: n = 1; pT4G3: n = 2). Five patients underwent radical cystoprostatectomy for muscle invasive cancers (pT2G3: n = 3; pT3bG3: n = 1; pT4G3: n = 1) and one man received chemotherapy for metastatic disease. Venous blood (10 ml) was obtained from the antecubital fossa in each patient, before and 1–2 h after completion of surgery, and prior to treatment in the metastatic patient. An indirect immunocytochemical technique was used to detect circulating epithelial cells after centrifugation on Ficoll gradient and fixation of mononuclear cells on slides, using a monoclonal antibody directed against three cytokeratins: CK8, CK18 and CK19. Circulating epithelial cells were detected only in the patient with metastatic disease. None of the other patients had evidence of epithelial circulating cells before or after surgery. The results suggest that irrespective of disease stage and grade, neither endoscopic nor open bladder surgery leads to detectable dissemination of urothelial cells in the peripheral circulation. These procedures are therefore unlikely to increase the risk of progression and metastasis in transitional cell carcinoma of the bladder. © 1999 Cancer Research Campaig
Combined effects of single nucleotide polymorphisms TP53 R72P and MDM2 SNP309, and p53 expression on survival of breast cancer patients
Solanum americanum: reservoir for Potato virus Y and Cucumber mosaic virus in sweet pepper crops
Metabolic regulation by p53
We are increasingly aware that cellular metabolism plays a vital role in diseases such as cancer, and that p53 is an important regulator of metabolic pathways. By transcriptional activation and other means, p53 is able to contribute to the regulation of glycolysis, oxidative phosphorylation, glutaminolysis, insulin sensitivity, nucleotide biosynthesis, mitochondrial integrity, fatty acid oxidation, antioxidant response, autophagy and mTOR signalling. The ability to positively and negatively regulate many of these pathways, combined with feedback signalling from these pathways to p53, demonstrates the reciprocal and flexible nature of the regulation, facilitating a diverse range of responses to metabolic stress. Intriguingly, metabolic stress triggers primarily an adaptive (rather than pro-apoptotic) p53 response, and p53 is emerging as an important regulator of metabolic homeostasis. A better understanding of how p53 coordinates metabolic adaptation will facilitate the identification of novel therapeutic targets and will also illuminate the wider role of p53 in human biology
A multicenter randomized phase II study of sequential epirubicin/cyclophosphamide followed by docetaxel with or without celecoxib or trastuzumab according to HER2 status, as primary chemotherapy for localized invasive breast cancer patients
Hypoxia-inducible factor-1α expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas
Hypoxia-inducible factor-1 (HIF-1)α expression was studied in the gastric carcinogenesis sequence and as a prognostic factor in surgically resected gastric and gastro-oesophageal junction tumours. Protein expression was examined using immunohistochemistry on formalin-fixed biopsies of normal mucosa (n=20), Helicobacter pylori associated gastritis (n=24), intestinal metaplasia (n=24), dysplasia (n=12) and intestinal (n=19) and diffuse (n=21) adenocarcinoma. The relationship between HIF-1α expression and prognosis was assessed in resection specimens from 177 patients with gastric and gastro-oesophageal junction adenocarcinoma. Hypoxia-inducible factor-1α expression was not observed in normal gastric mucosa but increased in density (P<0.01) and intensity (P<0.01) with progression from H. pylori-associated gastritis, intestinal metaplasia, dysplasia to adenocarcinoma. The pattern of staining in the resection specimens was focally positive in 49 (28%) and at the invasive tumour edge in 41 (23%). Invasive edge expression was associated with lymph node metastases (P=0.034), advanced TNM stage (P=0.001) and was an adverse prognostic factor for cancer-specific survival (P=0.019). In univariate analysis and in comparison with tumours not expressing HIF-1α, invasive edge staining was associated with a hazard ratio of 1.6 (95% CI 1.0−2.5) and focally positive staining a hazard ratio of 0.7 (95% CI 0.5−1.2). Hypoxia-inducible factor-1α lost prognostic significance in multivariate analysis. The results suggest HIF-1α is involved in gastric carcinogenesis and disease progression, but is only a weak prognostic factor for survival
Integrating genetics and epigenetics in breast cancer: biological insights, experimental, computational methods and therapeutic potential
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