10 results on '"Ward, Douglas"'
Search Results
2. PD-L2 Is Constitutively Expressed in Normal and Malignant Urothelium.
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Dowell, Alexander C., Munford, Haydn, Goel, Anshita, Gordon, Naheema S., James, Nicholas D., Cheng, K. K., Zeegers, Maurice P., Ward, Douglas G., and Bryan, Richard T.
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UROTHELIUM ,BLADDER ,PROGRAMMED cell death 1 receptors ,PROGRAMMED death-ligand 1 ,TRANSITIONAL cell carcinoma - Abstract
The use of immune checkpoint blockade, in particular PD-1 and PD-L1 inhibitors, is now commonplace in many clinical settings including the treatment of muscle-invasive bladder cancer (MIBC). Notwithstanding, little information exists regarding the expression of the alternative PD-1 ligand, PD-L2 in urothelial bladder cancer (UBC). We therefore set out to characterise the expression of PD-L2 in comparison to PD-L1. Firstly, we assessed PD-L2 expression by immunohistochemistry and found widespread expression of PD-L2 in UBC, albeit with reduced expression in MIBC. We further investigated these findings using RNA-seq data from a cohort of 575 patients demonstrating that PDCD1LG2 (PD-L2) is widely expressed in UBC and correlated with CD274 (PD-L1). However, in contrast to our immunohistochemistry findings, expression was significantly increased in advanced disease. We have also provided detailed evidence of constitutive PD-L2 expression in normal urothelium and propose a mechanism by which PD-L2 is cleaved from the cell surface in MIBC. These data provide a comprehensive assessment of PD-L2 in UBC, showing PD-L2 is abundant in UBC and, importantly, constitutively present in normal urothelium. These data have implications for future development of immune checkpoint blockade, and also the understanding of the function of the immune system in the normal urinary bladder. [ABSTRACT FROM AUTHOR]
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- 2021
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3. Urine DNA for monitoring chemoradiotherapy response in muscle‐invasive bladder cancer: a pilot study.
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Gordon, Naheema S., Baxter, Laura A., Goel, Anshita, Arnold, Roland, Kaur, Baljit, Liu, Wenyu, Pirrie, Sarah J., Hussain, Syed, Viney, Richard, Ford, Daniel, Zarkar, Anjali, Wood, Mary A., Mitin, Timur, Thompson, Reid F., James, Nicholas D., Ward, Douglas G., and Bryan, Richard T.
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BLADDER cancer ,CANCER invasiveness ,CHEMORADIOTHERAPY ,DNA ,PILOT projects ,URINE - Abstract
We undertook a pilot study to evaluate whether measuring common BC-associated mutations in urinary DNA can contribute to the monitoring of treatment responses in patients with organ-confined MIBC treated with curative intent. Abbreviations BC bladder cancer cpDNA chloroplast DNA MIBC muscle-invasive bladder cancer SNV single-nucleotide variant VAF variant allele frequency Accumulating evidence implies the utility of DNA-based urine biomarkers for initial detection of bladder cancer (BC) and surveillance of non-muscle-invasive BC [1,2]. In summary, two out of the four patients who relapsed (three local, one distant, 3-9 months after completing treatment) had undetectable urinary VAFs on treatment completion. [Extracted from the article]
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- 2022
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4. Multiplex PCR and Next Generation Sequencing for the Non-Invasive Detection of Bladder Cancer
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Ward, Douglas G., Baxter, Laura, Gordon, Naheema S., Ott, Sascha, Savage, Richard S., Beggs, Andrew D., James, Jonathan D., Lickiss, Jennifer, Green, Shaun, Wallis, Yvonne, Wei, Wenbin, James, Nicholas D., Zeegers, Maurice P., Cheng, K. K., Mathews, Glenn M., Patel, Prashant, Griffiths, Michael, Bryan, Richard T., RS: CAPHRI - R5 - Optimising Patient Care, RS: NUTRIM - R4 - Gene-environment interaction, and Complexe Genetica
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Male ,Physiology ,Science ,Urology ,Gene Identification and Analysis ,Artificial Gene Amplification and Extension ,Urine ,urologic and male genital diseases ,Research and Analysis Methods ,Polymerase Chain Reaction ,Biochemistry ,Sensitivity and Specificity ,Extraction techniques ,Genetics ,Medicine and Health Sciences ,Cancer Detection and Diagnosis ,Point Mutation ,Humans ,Molecular Biology Techniques ,Mutation Detection ,Molecular Biology ,DNA extraction ,Aged ,Aged, 80 and over ,Biology and Life Sciences ,Cancers and Neoplasms ,High-Throughput Nucleotide Sequencing ,DNA, Neoplasm ,Bladder Cancer ,Body Fluids ,Neoplasm Proteins ,Genitourinary Tract Tumors ,Oncology ,Urinary Bladder Neoplasms ,Mutation ,Medicine ,Female ,Anatomy ,Multiplex Polymerase Chain Reaction ,Biomarkers ,Research Article - Abstract
BackgroundHighly sensitive and specific urine-based tests to detect either primary or recurrent bladder cancer have proved elusive to date. Our ever increasing knowledge of the genomic aberrations in bladder cancer should enable the development of such tests based on urinary DNA.MethodsDNA was extracted from urine cell pellets and PCR used to amplify the regions of the TERT promoter and coding regions of FGFR3, PIK3CA, TP53, HRAS, KDM6A and RXRA which are frequently mutated in bladder cancer. The PCR products were barcoded, pooled and paired-end 2 x 250 bp sequencing performed on an Illumina MiSeq. Urinary DNA was analysed from 20 non-cancer controls, 120 primary bladder cancer patients (41 pTa, 40 pT1, 39 pT2+) and 91 bladder cancer patients post-TURBT (89 cancer-free).ResultsDespite the small quantities of DNA extracted from some urine cell pellets, 96% of the samples yielded mean read depths >500. Analysing only previously reported point mutations, TERT mutations were found in 55% of patients with bladder cancer (independent of stage), FGFR3 mutations in 30% of patients with bladder cancer, PIK3CA in 14% and TP53 mutations in 12% of patients with bladder cancer. Overall, these previously reported bladder cancer mutations were detected in 86 out of 122 bladder cancer patients (70% sensitivity) and in only 3 out of 109 patients with no detectable bladder cancer (97% specificity).ConclusionThis simple, cost-effective approach could be used for the non-invasive surveillance of patients with non-muscle-invasive bladder cancers harbouring these mutations. The method has a low DNA input requirement and can detect low levels of mutant DNA in a large excess of normal DNA. These genes represent a minimal biomarker panel to which extra markers could be added to develop a highly sensitive diagnostic test for bladder cancer.
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- 2016
5. Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: a 23‐gene panel with utility for non‐invasive diagnosis and risk stratification.
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Ward, Douglas G., Gordon, Naheema S., Boucher, Rebecca H., Pirrie, Sarah J., Baxter, Laura, Ott, Sascha, Silcock, Lee, Whalley, Celina M., Stockton, Joanne D., Beggs, Andrew D., Griffiths, Mike, Abbotts, Ben, Ijakipour, Hanieh, Latheef, Fathimath N., Robinson, Robert A., White, Andrew J., James, Nicholas D., Zeegers, Maurice P., Cheng, K. K., and Bryan, Richard T.
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GENETIC mutation , *BLADDER cancer , *CIRCULATING tumor DNA , *DNA , *CHLOROPLAST DNA , *SOMATIC mutation , *GENE frequency - Abstract
Objectives: To develop a focused panel of somatic mutations (SMs) present in the majority of urothelial bladder cancers (UBCs), to investigate the diagnostic and prognostic utility of this panel, and to compare the identification of SMs in urinary cell‐pellet (cp)DNA and cell‐free (cf)DNA as part of the development of a non‐invasive clinical assay. Patients and Methods: A panel of SMs was validated by targeted deep‐sequencing of tumour DNA from 956 patients with UBC. In addition, amplicon and capture‐based targeted sequencing measured mutant allele frequencies (MAFs) of SMs in 314 urine cpDNAs and 153 urine cfDNAs. The association of SMs with grade, stage, and clinical outcomes was investigated by univariate and multivariate Cox models. Concordance between SMs detected in tumour tissue and cpDNA and cfDNA was assessed. Results: The panel comprised SMs in 23 genes: TERT (promoter), FGFR3,PIK3CA,TP53,ERCC2,RHOB,ERBB2,HRAS,RXRA,ELF3,CDKN1A,KRAS,KDM6A,AKT1,FBXW7,ERBB3,SF3B1,CTNNB1,BRAF, C3orf70,CREBBP,CDKN2A, and NRAS; 93.5–98.3% of UBCs of all grades and stages harboured ≥1 SM (mean: 2.5 SMs/tumour). RAS mutations were associated with better overall survival (P = 0.04). Mutations in RXRA, RHOB and TERT (promoter) were associated with shorter time to recurrence (P < 0.05). MAFs in urinary cfDNA and cpDNA were highly correlated; using a capture‐based approach, >94% of tumour SMs were detected in both cpDNA and cfDNA. Conclusions: SMs are reliably detected in urinary cpDNA and cfDNA. The technical capability to identify very low MAFs is essential to reliably detect UBC, regardless of the use of cpDNA or cfDNA. This 23‐gene panel shows promise for the non‐invasive diagnosis and risk stratification of UBC. [ABSTRACT FROM AUTHOR]
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- 2019
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6. Molecular Subtypes of T1 Bladder Cancer: Biomolecular Characteristics Versus Clinical Utility.
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Ward, Douglas G., Arnold, Roland, and Bryan, Richard T.
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BLADDER cancer , *TRANSITIONAL cell carcinoma , *PATIENT selection - Published
- 2020
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7. The Sirenic Links between Diabetes, Obesity, and Bladder Cancer.
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Gill, Emily, Sandhu, Gurimaan, Ward, Douglas G., Perks, Claire M., and Bryan, Richard T.
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BLADDER cancer ,SOMATOMEDIN ,TYPE 2 diabetes ,OBESITY ,DIABETES - Abstract
There is considerable evidence of a positive association between the incidence of type 2 diabetes mellitus (T2DM) and obesity with bladder cancer (BCa), with the link between T2DM and obesity having already been established. There also appear to be potential associations between Pleckstrin homology domain containing S1 (PLEKHS1) and the Insulin-like Growth Factor (IGF) axis. Seven literature searches were carried out to investigate the backgrounds of these potential links. PLEKHS1 is a candidate biomarker in BCa, with mutations that are easily detectable in urine and increased expression seemingly associated with worse disease states. PLEKHS1 has also been implicated as a potential mediator for the onset of T2DM in people with obesity. The substantial evidence of the involvement of IGF in BCa, the role of the IGF axis in obesity and T2DM, and the global prevalence of T2DM and obesity suggest there is scope for investigating the links between these components. Preliminary findings on the relationship between PLEKHS1 and the IGF axis signal possible associations with BCa progression. This indicates that PLEKHS1 plays a role in the pathogenesis of BCa that may be mediated by members of the IGF axis. Further detailed research is needed to establish the relationship between PLEKHS1 and the IGF axis in BCa and determine how these phenomena overlap with T2DM and obesity. [ABSTRACT FROM AUTHOR]
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- 2021
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8. Bladder Cancers Arise from Distinct Urothelial Sub-populations.
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Bryan, Richard T. and Ward, Douglas G.
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BLADDER cancer , *ANIMAL models of carcinogenesis , *CARCINOMA in situ , *TRANSITIONAL cell carcinoma , *HETEROGENEITY , *KERATIN , *CELL populations - Published
- 2015
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9. Circulating Tumour DNA Detection By The Urine-Informed Analysis Of Archival Serum Samples From Muscle-Invasive Bladder Cancer Patients.
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BinHumaid, Faisal S., Goel, Anshita, Gordon, Naheema S., Abbotts, Ben, Cheng, K.K., Zeegers, Maurice P., James, Nicholas D., Altaweel, Waleed M., Seyam, Raouf M., Meyer, Brian F., Arnold, Roland, Ward, Douglas G., and Bryan, Richard T.
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CIRCULATING tumor DNA , *CANCER invasiveness , *BLOOD serum analysis , *BLADDER cancer , *CANCER patients - Published
- 2024
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10. Expression of Engrailed-2 (EN2) protein in bladder cancer and its potential utility as a urinary diagnostic biomarker.
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Morgan, Richard, Bryan, Richard T., Javed, Saqib, Launchbury, Francesca, Zeegers, Maurice P., Cheng, K.K., James, Nicholas D., Wallace, D. Michael A., Hurst, Carolyn D., Ward, Douglas G., Knowles, Margaret A., and Pandha, Hardev
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PROTEIN analysis , *BIOMARKERS , *GENE expression , *IMMUNOHISTOCHEMISTRY , *POLYMERASE chain reaction , *STATISTICS , *TUMOR classification , *URINALYSIS , *WESTERN immunoblotting , *DATA analysis , *RECEIVER operating characteristic curves , *DATA analysis software , *DESCRIPTIVE statistics , *DIAGNOSIS ,BLADDER tumors - Abstract
Abstract: Despite significant advances in our understanding of the molecular pathology of bladder cancer, it remains a significant health problem with high morbidity and mortality associated with muscle-invasive bladder cancer (stages T2+), and high costs associated with the surveillance of non-muscle-invasive bladder cancer (NMIBC, stages Ta/T1/Tis). Moreover, current diagnostic biomarkers are suboptimal and of poor utility for low grade disease and surveillance. In this study, we show that the Engrailed-2 (EN2) transcription factor is expressed in, and secreted by, bladder cancer cell lines and patient tumour specimens, justifying an evaluation of urinary EN2 as a diagnostic biomarker in bladder cancer using archived samples from an established biospecimen collection. In patients with NMIBC, urinary EN2 was detected in most cases with an overall sensitivity of 82% and specificity of 75%. The sensitivity for stage Ta and T1 tumours was 71% and 76%, respectively, and 94% for stage T2+ tumours. This compares favourably with existing markers. The sensitivity for tumour grades 1, 2 and 3 was 69%, 78% and 87%, respectively. Thus urinary EN2 has the potential to be a more sensitive and specific protein biomarker for NMIBC than currently available tests. [Copyright &y& Elsevier]
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- 2013
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