100 research outputs found
An evaluation of urinary microRNA reveals a high sensitivity for bladder cancer
Background: Urinary biomarkers are needed to improve the care and reduce the cost of managing bladder cancer. Current
biomarkers struggle to identify both high and low-grade cancers due to differing molecular pathways. Changes in microRNA (miR) expression are seen in urothelial carcinogenesis in a phenotype-specific manner. We hypothesised that urinary miRs reflecting low- and high-grade pathways could detect bladder cancers and overcome differences in genetic events seen within the disease.
Methods: We investigated urinary samples (n ¼ 121) from patients with bladder cancer (n ¼ 68) and age-matched controls (n ¼ 53). Fifteen miRs were quantified using real-time PCR.
Results: We found that miR is stable within urinary cells despite adverse handling and detected differential expression of 10 miRs from patients with cancer and controls (miRs 15a/15b/24-1/27b/100/135b/203/212/328/1224, ANOVA Po0.05). Individually, miR-1224-3p had the best individual performance with specificity, positive and negative predictive values and concordance of 83%, 83%, 75% and 77%, respectively. The combination of miRs-135b/15b/1224-3p detected bladder cancer with a high sensitivity (94.1%), sufficient specificity (51%) and was correct in 86% of patients (concordance).
Conclusion: The use of this panel in patients with haematuria would have found 94% of urothelial cell carcinoma, while reducing cystoscopy rates by 26%. However, two invasive cancers (3%) would have been missed
Integrated Epigenome Profiling of Repressive Histone Modifications, DNA Methylation and Gene Expression in Normal and Malignant Urothelial Cells
Epigenetic regulation of gene expression is commonly altered in human cancer. We have observed alterations of DNA
methylation and microRNA expression that reflect the biology of bladder cancer. This common disease arises by distinct
pathways with low and high-grade differentiation. We hypothesized that epigenetic gene regulation reflects an interaction
between histone and DNA modifications, and differences between normal and malignant urothelial cells represent
carcinogenic events within bladder cancer. To test this we profiled two repressive histone modifications (H3K9m3 and
H3K27m3) using ChIP-Seq, cytosine methylation using MeDIP and mRNA expression in normal and malignant urothelial cell
lines. In genes with low expression we identified H3K27m3 and DNA methylation each in 20–30% of genes and both marks
in 5% of genes. H3K9m3 was detected in 5–10% of genes but was not associated with overall expression. DNA methylation
was more closely related to gene expression in malignant than normal cells. H3K27m3 was the epigenetic mark most
specifically correlated to gene silencing. Our data suggest that urothelial carcinogenesis is accompanied by a loss of control
of both DNA methylation and H3k27 methylation. From our observations we identified a panel of genes with cancer
specific-epigenetic mediated aberrant expression including those with reported carcinogenic functions and members
potentially mediating a positive epigenetic feedback loop. Pathway enrichment analysis revealed genes marked by H3K9m3
were involved with cell homeostasis, those marked by H3K27m3 mediated pro-carcinogenic processes and those marked
with cytosine methylation were mixed in function. In 150 normal and malignant urothelial samples, our gene panel correctly
estimated expression in 65% of its members. Hierarchical clustering revealed that this gene panel stratified samples
according to the presence and phenotype of bladder cancer
Changes in circulating microRNA levels associated with prostate cancer
BACKGROUND: The aim of this study was to investigate the hypothesis that changes in circulating microRNAs (miRs) represent
potentially useful biomarkers for the diagnosis, staging and prediction of outcome in prostate cancer.
METHODS: Real-time polymerase chain reaction analysis of 742 miRs was performed using plasma-derived circulating microvesicles
of 78 prostate cancer patients and 28 normal control individuals to identify differentially quantified miRs.
RESULTS: A total of 12 miRs were differentially quantified in prostate cancer patients compared with controls, including 9 in patients
without metastases. In all, 11 miRs were present in significantly greater amounts in prostate cancer patients with metastases
compared with those without metastases. The association of miR-141 and miR-375 with metastatic prostate cancer was confirmed
using serum-derived exosomes and microvesicles in a separate cohort of patients with recurrent or non-recurrent disease following
radical prostatectomy. An analysis of five selected miRs in urine samples found that miR-107 and miR-574-3p were quantified at
significantly higher concentrations in the urine of men with prostate cancer compared with controls.
CONCLUSION: These observations suggest that changes in miR concentration in prostate cancer patients may be identified by analysing
various body fluids. Moreover, circulating miRs may be used to diagnose and stage prostate cance
Competing mortality in patients diagnosed with bladder cancer: evidence of undertreatment in the elderly and female patients
Background: Bladder cancer (BC) predominantly affects the elderly and is often the cause of death among patients with muscleinvasive disease. Clinicians lack quantitative estimates of competing mortality risks when considering treatments for BC. Our aim was to determine the bladder cancer-specific mortality (CSM) rate and other-cause mortality (OCM) rate for patients with newly diagnosed BC.
Methods: Patients (n ¼ 3281) identified from a population-based cancer registry diagnosed between 1994 and 2009. Median
follow-up was 48.15 months (IQ range 18.1–98.7). Competing risk analysis was performed within patient groups and outcomes compared using Gray’s test.
Results: At 5 years after diagnosis, 1246 (40%) patients were dead: 617 (19%) from BC and 629 (19%) from other causes. The 5-year BC mortality rate varied between 1 and 59%, and OCM rate between 6 and 90%, depending primarily on the tumour type and patient age. Cancer-specific mortality was highest in the oldest patient groups. Few elderly patients received radical treatment for invasive cancer (52% vs 12% for patients o60 vs 480 years, respectively). Female patients with high-risk non-muscle-invasive BC had worse CSM than equivalent males (Gray’s Po0.01).
Conclusion: Bladder CSM is highest among the elderly. Female patients with high-risk tumours are more likely to die of their
disease compared with male patients. Clinicians should consider offering more aggressive treatment interventions among older
patients
Suitability of PSA-detected localised prostate cancers for focal therapy: Experience from the ProtecT study
This article is available through a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. Copyright @ 2011 Cancer Research UK.Background: Contemporary screening for prostate cancer frequently identifies small volume, low-grade lesions. Some clinicians have advocated focal prostatic ablation as an alternative to more aggressive interventions to manage these lesions. To identify which patients might benefit from focal ablative techniques, we analysed the surgical specimens of a large sample of population-detected men undergoing radical prostatectomy as part of a randomised clinical trial. Methods: Surgical specimens from 525 men who underwent prostatectomy within the ProtecT study were analysed to determine tumour volume, location and grade. These findings were compared with information available in the biopsy specimen to examine whether focal therapy could be provided appropriately. Results: Solitary cancers were found in prostatectomy specimens from 19% (100 out of 525) of men. In addition, 73 out of 425 (17%) men had multiple cancers with a solitary significant tumour focus. Thus, 173 out of 525 (33%) men had tumours potentially suitable for focal therapy. The majority of these were small, well-differentiated lesions that appeared to be pathologically insignificant (38–66%). Criteria used to select patients for focal prostatic ablation underestimated the cancer's significance in 26% (34 out of 130) of men and resulted in overtreatment in more than half. Only 18% (24 out of 130) of men presumed eligible for focal therapy, actually had significant solitary lesions. Conclusion: Focal therapy appears inappropriate for the majority of men presenting with prostate-specific antigen-detected localised prostate cancer. Unifocal prostate cancers suitable for focal ablation are difficult to identify pre-operatively using biopsy alone. Most lesions meeting criteria for focal ablation were either more aggressive than expected or posed little threat of progression.National Institute for Health Researc
Interaction of Copper-Amine With Southern Pine: Retention and Migration
The retention and leachability of copper in copper-amine (Cu-EA)-treated southern pine (SP) are influenced by the formulation and the composition of copper-amine treating solutions. The sources of copper used, Cu(OH)2, CuCO3, CuSO4, and Cu(NO3)2, in the copper-amine complex formulation affect the leachability of copper. Data show that copper-amine from CuSO4- and Cu(NO3)2-treated wood has less copper loss during laboratory water leaching than that from Cu(OH)2- and CuCO3-treated wood. Increasing the amine-to-copper molar ratio increases the copper retention by wood, but reduces the leach resistance of copper. The nature of amine ligands, such as monoethanolamine (primary amine), 2-methylamino-ethanol (secondary amine), and N, N-dimethyl-ethanolamine (tertiary amine), has some effect on copper retention and copper leaching. As the molecular weight of amine ligands increases, copper loss during leaching decreases
Identification of a hypoxia-regulated miRNA signature in bladder cancer and a role for miR-145 in hypoxia-dependent apoptosis
Background: Hypoxia leads to the stabilisation of the hypoxia-inducible factor (HIF) transcription factor that drives the expression of target genes including microRNAs (miRNAs). MicroRNAs are known to regulate many genes involved in tumourigenesis. The aim of this study was to identify hypoxia-regulated miRNAs (HRMs) in bladder cancer and investigate their functional significance.
Methods: Bladder cancer cell lines were exposed to normoxic and hypoxic conditions and interrogated for the expression of 384 miRNAs by qPCR. Functional studies were carried out using siRNA-mediated gene knockdown and chromatin immunoprecipitations. Apoptosis was quantified by annexin V staining and flow cytometry.
Results: The HRM signature for NMI bladder cancer lines includes miR-210, miR-193b, miR-145, miR-125-3p, miR-708 and miR-517a. The most hypoxia-upregulated miRNA was miR-145. The miR-145 was a direct target of HIF-1a and two hypoxia response elements were identified within the promoter region of the gene. Finally, the hypoxic upregulation of miR-145 contributed to increased apoptosis in RT4 cells.
Conclusions: We have demonstrated the hypoxic regulation of a number of miRNAs in bladder cancer. We have shown that miR-
145 is a novel, robust and direct HIF target gene that in turn leads to increased cell death in NMI bladder cancer cell lines
The small-nucleolar RNAs commonly used for microRNA normalisation correlate with tumour pathology and prognosis
Background:To investigate small-nucleolar RNAs (snoRNAs) as reference genes when measuring miRNA expression in tumour samples, given emerging evidence for their role in cancer.Methods:Four snoRNAs, commonly used for normalisation, RNU44, RNU48, RNU43 and RNU6B, and miRNA known to be associated with pathological factors, were measured by real-time polymerase chain reaction in two patient series: 219 breast cancer and 46 head and neck squamous cell carcinoma (HNSCC). SnoRNA and miRNA were then correlated with clinicopathological features and prognosis.Results:Small-nucleolar RNA expression was as variable as miRNA expression (miR-21, miR-210, miR-10b). Normalising miRNA PCR expression data to these recommended snoRNAs introduced bias in associations between miRNA and pathology or outcome. Low snoRNA expression correlated with markers of aggressive pathology. Low levels of RNU44 were associated with a poor prognosis. RNU44 is an intronic gene in a cluster of highly conserved snoRNAs in the growth arrest specific 5 (GAS5) transcript, which is normally upregulated to arrest cell growth under stress. Low-tumour GAS5 expression was associated with a poor prognosis. RNU48 and RNU43 were also identified as intronic snoRNAs within genes that are dysregulated in cancer.Conclusion:Small-nucleolar RNAs are important in cancer prognosis, and their use as reference genes can introduce bias when determining miRNA expression. © 2011 Cancer Research UK All rights reserved
MicroRNA-320c inhibits tumorous behaviors of bladder cancer by targeting Cyclin-dependent kinase 6
Diagnostic value of circulating tumor cell detection in bladder and urothelial cancer: systematic review and meta-analysis
- …