T A Holland

Keele University, Newcastle-under-Lyme, England, United Kingdom

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Publications (8)25.55 Total impact

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    ABSTRACT: Recent studies have shown that loss of heterozygosity (LOH) on chromosome 10q is a frequent event in a number of tumour types including colorectal cancers. Because previous studies have used markers located mainly distally on chromosome 10, we have examined 114 sporadic colorectal adenocarcinomas for LOH using a panel of 9 highly polymorphic microsatellite markers spanning the long arm of chromosome 10. Using microdissected tumour material, LOH of one or more chromosome 10q markers was a frequent event (75 of 114; 66%). The highest frequency of loss (42 of 96; 44%) was observed at the marker D10S1790 located at 10q21.1. The mean age of presentation, of patients with LOH of D10S1790 was significantly (p = 0.0006) lower (67.1 years) compared to patients with retention of this marker (73.5 years). When we compared frequency of loss at this marker in patients presenting before 70 years of age (68%) to those above 70 years (23%) we observed a significant difference (p < 0.0001). Statistical analysis between loss, or instability at other markers and clinicopathological features did not show any significant associations. In addition LOH at D10S1790 was infrequent in adenomas (2 of 20; 10%) compared to adenocarcinomas (42 of 96; 44%) (p = 0.0047), suggesting that loss within this region is a late event in colorectal tumorigenesis. The association of loss at D10S1790 and an earlier age of presentation in adenocarcinomas suggests that this locus may harbor a tumour suppressor gene(s), which affects the rate of colorectal tumour progression. Identification of this region of genetic loss further refines our understanding of the paradigm in this tumour type of multiple-steps responsible for initiation and progression.
    International Journal of Cancer 06/2002; 99(6):829-33. · 6.20 Impact Factor
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    ABSTRACT: We investigated the expression of the cell cycle regulatory proteins cyclin D1 and p21(WAF1/CIP1) (p21) in human colorectal carcinomas using immunohistochemistry. Cyclin D1 was not detected in normal colonic epithelium; however, expression was observed in 74/126 (58.7%) of the tumour samples studied. Protein was detected in the nucleus in 22/126 (17.4%) and exclusively in the cytoplasm in 52/126 (41.3%) tumours. Nuclear expression of cyclin D1 was associated with poorly differentiated tumours (p = 0.035) and was more common in right- than in left-sided tumours (p = 0.005). Tumours displaying either, expression of cytoplasmic, (p = 0.05, HR 0.56, 95% CI 0.31-1.0) or nuclear (p = 0.021, HR 0.24, 95% CI 0.07-0.81) cyclin D1 were associated with improved patient survival compared with tumours negative for cyclin D1. p21 protein was strongly expressed mainly in the upper crypts of normal colonic epithelial cells, but in 63/126 (50%) of the tumour samples studied p21 expression was absent. Patients with tumours in which >50% of cells expressed p21 had improved survival compared to patients whose tumours were negative or had < or =50% of cells expressing p21 (p = 0.06, HR 0.33, 95% CI 0.1-1.0). We also observed a significant association between cyclin D1 subcellular localisation and p21 expression: 21/22 (95.5%) tumours expressing cyclin D1 in the nucleus also expressed p21, whereas only 17/52 (32.7%) of the tumours displaying exclusive cytoplasmic cyclin D1 staining were positive for p21 (p < 0.001). These data highlight the significance of exclusive cytoplasmic expression of cyclin D1 in colorectal cancer and lend support to recent in vitro studies suggesting that p21 protein may modulate the subcellular localisation of the cyclin D1 protein. Thus, deregulated expression of the cyclin D1 and p21 proteins are important in colorectal tumourigenesis and have implications for patient prognosis.
    International Journal of Cancer 09/2001; 95(5):302-6. · 6.20 Impact Factor
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    ABSTRACT: We investigated the expression of the cell cycle regulatory proteins cyclin D1 and p21WAF1/CIP1 (p21) in human colorectal carcinomas using immunohistochemistry. Cyclin D1 was not detected in normal colonic epithelium; however, expression was observed in 74/126 (58.7%) of the tumour samples studied. Protein was detected in the nucleus in 22/126 (17.4%) and exclusively in the cytoplasm in 52/126 (41.3%) tumours. Nuclear expression of cyclin D1 was associated with poorly differentiated tumours (p = 0.035) and was more common in right- than in left-sided tumours (p = 0.005). Tumours displaying either, expression of cytoplasmic, (p = 0.05, HR 0.56, 95% CI 0.31–1.0) or nuclear (p = 0.021, HR 0.24, 95% CI 0.07–0.81) cyclin D1 were associated with improved patient survival compared with tumours negative for cyclin D1. p21 protein was strongly expressed mainly in the upper crypts of normal colonic epithelial cells, but in 63/126 (50%) of the tumour samples studied p21 expression was absent. Patients with tumours in which >50% of cells expressed p21 had improved survival compared to patients whose tumours were negative or had ≤50% of cells expressing p21 (p = 0.06, HR 0.33, 95% CI 0.1–1.0). We also observed a significant association between cyclin D1 subcellular localisation and p21 expression: 21/22 (95.5%) tumours expressing cyclin D1 in the nucleus also expressed p21, whereas only 17/52 (32.7%) of the tumours displaying exclusive cytoplasmic cyclin D1 staining were positive for p21 (p < 0.001). These data highlight the significance of exclusive cytoplasmic expression of cyclin D1 in colorectal cancer and lend support to recent in vitro studies suggesting that p21 protein may modulate the subcellular localisation of the cyclin D1 protein. Thus, deregulated expression of the cyclin D1 and p21 proteins are important in colorectal tumourigenesis and have implications for patient prognosis. © 2001 Wiley-Liss, Inc.
    International Journal of Cancer 06/2001; 95(5):302 - 306. · 6.20 Impact Factor
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    ABSTRACT: The objective of this study was to determine whether the association between GSTM1 null/GSTTI null and survival in ovarian cancer is mediated by the influence of these genes on p53 expression. In 81 women with pure invasive ovarian cancer, GSTM1 null and GSTT1 null genotypes were identified using polymerase chain reaction and p53 expression was assessed using immunohistochemistry. The association of these factors with survival was examined using Cox's proportional hazards regression models. Performance status (P < 0.001), operative stage (P = 0.004), residual disease (P = 0.001), histologic subtype (P = 0.05), tumor grade (P = 0.007), and the combined GSTMI null/GSTTl null genotype (P = 0.023) were all individually associated with survival. p53 expression was not associated with survival (P = 0.45). In a multivariate analysis, the effects of GSTM1 null/GSTT1 null on survival were lost when residual disease and tumor grade were included. The effects of p53 expression on survival were unchanged when residual disease, tumor grade, operative stage, and performance score were included. GSTM1 null/GSTT1null did not influence the effects of p53 expression on survival and vice versa. The GSTM1 null/GSTT1 null genotype was associated with response to primary chemotherapy (P = 0.007) but p53 expression was not. We conclude that the association of GSTM1 null/GSTTl null with survival appears to be mediated through different mechanisms to p53 expression in ovarian cancer and in addition, may be a better predictor of outcome.
    International Journal of Gynecological Cancer 01/2001; 11(2):107-12. · 1.94 Impact Factor
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    ABSTRACT: We describe the use of our selected ion flow tube mass spectrometric technique (SIFT-MS) for the analysis of the headspace above urine. Ammonia, nitric oxide, acetone, ethanol and methanol are identified as the dominant species. As expected, the ammonia is increased in the headspace by making the urine alkaline and the nitric oxide is increased by making the urine acidic. Nitric oxide is abnormally high in the headspace of acidified bacterially infected urine and nitrous acid is also detected. The potential clinical implications of analyses of urine by SIFT-MS are alluded to.
    Rapid Communications in Mass Spectrometry 02/1999; 13(8):724-9. · 2.51 Impact Factor
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    ABSTRACT: We have used selected ion flow tube mass spectrometry (SIFT-MS) to determine the concentration of formaldehyde in the headspace of urine from patients suffering from bladder and prostate cancer and from several healthy subjects as controls. We address the potential problems associated with the use of ion chemistry to quantify formaldehyde in the presence of the relatively large number densities of water molecules and show that formaldehyde can be quantified in urine headspace using analysis by SIFT-MS. These studies show that formaldehyde is clearly elevated in the headspace of the urine from the cancer patients as compared with urine from the healthy controls. Thus, with further improvements in the methodology and the sensitivity of our SIFT-MS technique, formaldehyde quantification in urine headspace using this new analytical method could be a valuable non-invasive indicator of the presence of early-stage tumours in the body.
    Rapid Communications in Mass Spectrometry 02/1999; 13(14):1354-9. · 2.51 Impact Factor
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    ABSTRACT: We describe the use of our selected ion Bow tube mass spectrometric technique (SIFT-MS) for the analysis of the headspace above urine. Ammonia, nitric oxide, acetone, ethanol and methanol are identified as the dominant species. As expected, the ammonia is increased in the headspace by making the urine alkaline and the nitric oxide is increased by making the urine acidic. Nitric oxide is abnormally high in the headspace of acidified bacterially infected urine and nitrous acid is also detected. The potential clinical implications of analyses of urine by SIFT-MS are alluded to. Copyright (C) 1999 John Wiley & Sons, Ltd.
    RAPID COMMUNICATIONS IN MASS SPECTROMETRY. 13(8):724-729.
  • [show abstract] [hide abstract]
    ABSTRACT: We describe the use of our selected ion Bow tube mass spectrometric technique (SIFT-MS) for the analysis of the headspace above urine. Ammonia, nitric oxide, acetone, ethanol and methanol are identified as the dominant species. As expected, the ammonia is increased in the headspace by making the urine alkaline and the nitric oxide is increased by making the urine acidic. Nitric oxide is abnormally high in the headspace of acidified bacterially infected urine and nitrous acid is also detected. The potential clinical implications of analyses of urine by SIFT-MS are alluded to. Copyright (C) 1999 John Wiley & Sons, Ltd.
    Rapid Communications in Mass Spectrometry. 13(8):724-729.