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G D Wilson

Publications and source records attributed to G D Wilson.

At least 37 records · Page 2Linked to original sources
PubMed2001

Comparison of the BOD POD with the four-compartment model in adult females.

PURPOSE: This study was designed to compare the accuracy and bias in estimates of total body density (Db) by hydrostatic weighing (HW) and the BOD POD, and percent body fat (%fat) by the BOD POD with the four-compartment model (4C model) in 42 adult females. Furthermore, the role of the aqueous and mineral fractions in the estimation of body fat by the BOD POD was examined. METHODS: Total body water was determined by isotope dilution ((2)H(2)0) and bone mineral was determined by dual-energy x-ray absorptiometry. Db and %fat were determined by the BOD POD and HW. The 4C model of Baumgartner was used as the criterion measure of body fat. RESULTS: HW Db (1.0352 g x cm(-3)) was not statistically different (P = 0.35) from BOD POD Db (1.0349 g x cm(-3)). The regression between Db by HW and the BOD POD significantly deviated from the line of identity (Db by HW = 0.90 x Db by BOD POD + 0.099; R(2) = 0.94). BOD POD %fat (28.8%) was significantly lower (P < 0.01) than %fat by the 4C model (30.6%). The regression between %fat by the 4C model and the BOD POD significantly deviated from the line of identity (%fat by 4C model = 0.88 x %fat by BOD POD + 5.41%; R(2) = 0.92). BOD POD Db and %fat showed no bias across the range of fatness. Only the aqueous fraction of the fat-free mass (FFM) had a significant correlation with the difference in %fat between the 4C model and the BOD POD. CONCLUSION: These data indicate that the BOD POD underpredicted body fat as compared with the 4C model, and the aqueous fraction of the FFM had a significant effect on estimates of %fat by the BOD POD.

Absorptiometry, Photon↗
PubMed2000

Hypoxia-inducible expression of tumor-associated carbonic anhydrases.

The transcriptional complex hypoxia-inducible factor-1 (HIF-1) has emerged as an important mediator of gene expression patterns in tumors, although the range of responding genes is still incompletely defined. Here we show that the tumor-associated carbonic anhydrases (CAs) are tightly regulated by this system. Both CA9 and CA12 were strongly induced by hypoxia in a range of tumor cell lines. In renal carcinoma cells that are defective for the von Hippel-Lindau (VHL) tumor suppressor, up-regulation of these CAs is associated with loss of regulation by hypoxia, consistent with the critical function of pVHL in the regulation of HIF-1. Further studies of CA9 defined a HIF-1-dependent hypoxia response element in the minimal promoter and demonstrated that tight regulation by the HIF/pVHL system was reflected in the pattern of CA IX expression within tumors. Generalized up-regulation of CA IX in VHL-associated renal cell carcinoma contrasted with focal perinecrotic expression in a variety of non-VHL-associated tumors. In comparison with vascular endothelial growth factor mRNA, expression of CA IX demonstrated a similar, although more tightly circumscribed, pattern of expression around regions of necrosis and showed substantial although incomplete overlap with activation of the hypoxia marker pimonidazole. These studies define a new class of HIF-1-responsive gene, the activation of which has implications for the understanding of hypoxic tumor metabolism and which may provide endogenous markers for tumor hypoxia.

Blotting, Western↗
PubMed2000

An SNP map of human chromosome 22.

The human genome sequence will provide a reference for measuring DNA sequence variation in human populations. Sequence variants are responsible for the genetic component of individuality, including complex characteristics such as disease susceptibility and drug response. Most sequence variants are single nucleotide polymorphisms (SNPs), where two alternate bases occur at one position. Comparison of any two genomes reveals around 1 SNP per kilobase. A sufficiently dense map of SNPs would allow the detection of sequence variants responsible for particular characteristics on the basis that they are associated with a specific SNP allele. Here we have evaluated large-scale sequencing approaches to obtaining SNPs, and have constructed a map of 2,730 SNPs on human chromosome 22. Most of the SNPs are within 25 kilobases of a transcribed exon, and are valuable for association studies. We have scaled up the process, detecting over 65,000 SNPs in the genome as part of The SNP Consortium programme, which is on target to build a map of 1 SNP every 5 kilobases that is integrated with the human genome sequence and that is freely available in the public domain.

Cell Line↗
PubMed2000

Cell production rates in human tissues and tumours and their significance. Part 1: an introduction to the techniques of measurement and their limitations.

In the past two decades, the technology of laser cytometry and use of the halogenated thymidine (HP) analogues bromodeoxyuridine and iododeoxyuridine as proliferation labels, have allowed us to quantify the rate of cell turnover in tissues and tumours, in clinical samples as in laboratory models. The principal studies have used injection of bromo- or iododeoxyuridine to measure cell production rates in vivo. Flow cytometry (FCM) has been used to estimate the S phase labelling index (LI) and the S phase duration (Ts) and calculate the cell production rate, represented by the potential doubling time (Tpot). This has allowed calculation of time-dependent indices of proliferation from single biopsies of HP pulse labelled human tissues and tumours. In the first part of this two-part review, we describe the technique and its limitations as a biological assay. The second part summarizes the knowledge gained about cell production rates and the relevance that this information may have to future investigative, prognostic and treatment strategies.

Bromodeoxyuridine↗
PubMed2000

Cell production rates in human tissues and tumours and their significance. Part II: clinical data.

This paper reviews the available data for cell production rates of human tissues and tumours, measured in vivo using halogenated pyrimidine labelling and laser cytometry. The technique has now been widely evaluated, and we draw general inferences from the proliferative data over a broad range of tumour and tissue types. Estimates of the S-phase duration, the time taken for DNA synthesis in cycling cells, are consistent over a narrow range with a median value of around 10 hours, notwithstanding the constraints of the experimental and statistical technique, in normal tissues and tumours. This suggests that Ts values may be a species-specific constant. The more easily measured labelled S-phase fraction, or labelling index, shows much greater intra and intertumour variation within any one tumour class. It may thus be a surrogate for time dependent measurements to a first order approximation. The cell production rate, described by the potential doubling time (Tpot), is remarkably rapid in most tumours, a median value of the order of 5 days, and much faster than clinical volume doubling times for most lesions. The rapid cell production rates in normal tissues and tumours highlight the importance of cell loss in the growth and modelling of biological structures. Cell production rate measurements do not adequately describe the biological aggressiveness of tumours. They may be used to refine adjuvant strategies for radiotherapy and chemotherapy in experimental research. Dynamic halogenated pyrimidine labelling has provided unique and valuable insights into the living biology of human tissues and tumours.

Adenocarcinoma↗
PubMed2000

Aberrant expression of cyclin A in head and neck cancer.

Cyclin A expression was studied in a series of 65 squamous cell carcinomas of the head and neck (HNSCC) and compared with known markers of proliferation, iododeoxyuridine (IdUrd) and Ki-67, to assess whether aberrant expression was prevalent. Patients had previously been administered IdUrd to study cell kinetics in relation to outcome of radiotherapy. The data showed that all three parameters were highly correlated although the absolute values were different. The median labelling indices (LI) for IdUrd, cyclin A and Ki-67 were 10.7, 17.1 and 30.8% respectively, reflecting the known pattern of differential cell cycle expression. However, there were a significant number of cases in which an unexpected relationship between cyclin A and either IdUrd or Ki-67 was present. Some of these were attributable to overexpression but others indicated underexpression. Although the greater variability and range of cyclin A expression, coupled with its more closely associated role in cell cycle regulation, might suggest that it may be a more informative marker for cell proliferation than Ki-67, the aberrant expression seen in over one third of cases would indicate that caution should be exercised in interpreting cyclin A as a surrogate marker of proliferation in HNSCC.

Adult↗
PubMed2000

An analysis of p16 tumour suppressor gene expression in acral lentiginous melanoma.

Acral lentiginous melanoma is a particularly aggressive melanocytic lesion but, due to its comparative rarity, biological investigations into the behaviour of this subtype of melanoma are lacking. The activity of the recently described p16 tumour suppressor gene, thought to be the 'familial melanoma gene', was studied in 24 patients with subungual melanoma and 44 patients with plantar melanoma. Lower levels of p16 oncoprotein were demonstrated than that found in other histogenetic types of melanoma. Stratification of patients of all disease stages revealed a poorer survival in patients with low p16 expression (log rank test, chi(2)= 3.9, P = 0. 05). These data suggest that p16 inactivation may play an important role in the development and progression of acral lentiginous melanomas. However, the level of p16 expression was not prognostic since survival analysis on stratification of stage I patients according to p16 level did not reach statistical significance for both survival and disease free interval.

Aged↗
PubMed2000

Aggressive basal cell carcinoma in young patients: fact or fiction?

It has been suggested that basal cell carcinomas (BCC) arising in younger patients may be of a more aggressive phenotype than those that present in the older population. The purpose of this study was to investigate this hypothesis by comparing the histological types of BCC in a large cohort of young and old patients.A total of 271 histological specimens and clinical records were evaluated. A consecutive series of 120 patients under 50 years old were compared with a consecutive series of 151 patients over 50 years of age. Tumours were classified according to the accepted definition of aggressive (morphoeic, infiltrative and micronodular) and less aggressive (nodular and superficial) histological growth patterns. Aggressive growth types were found in 35% of patients over 50 and 33% of patients under 50. There was a higher rate of incomplete excision in younger patients but this did not reach significance (16% compared to 9%, P = 0.1). This study found that BCC arising in young patients are not histologically different to those found in the older population. Clinically observed aggressive behaviour of BCC in young patients may result from inadequate surgical excision due to cosmesis and diagnostic doubt.

Adolescent↗
PubMed2000

Regulation of FOS by different compartmental stresses induced by low levels of ionizing radiation.

We irradiated different cellular compartments and measured changes in expression of the FOS gene at the mRNA and protein levels. [(3)H]Thymidine and tritiated water were used to irradiate the nucleus and the whole cell, respectively. (125)I-Concanavalin A binding was used to irradiate the cell membrane differentially. Changes in FOS mRNA and protein levels were measured using semi-quantitative RT-PCR and SDS-PAGE Western blotting, respectively. Irradiation of the nucleus or the whole cell at a dose rate of 0.075 Gy/h caused no change in the level of FOS mRNA expression, but modestly (1.5-fold) induced FOS protein after 0.5 h. Irradiation of the nucleus at a dose rate of 0.43 Gy/h induced FOS mRNA by 1.5-fold after 0.5 h, but there was no significant effect after whole-cell irradiation. FOS protein was transiently induced 2.5-fold above control levels 0.5 h after a 0. 43-Gy/h exposure of the nucleus or the whole cell. Irradiation of the cell membrane at a dose rate of 1.8 Gy/h for up to 2 h caused no change in the levels of expression of FOS mRNA or protein, but a dose rate of 6.8 Gy/h transiently increased the level of FOS mRNA 3-fold after 0.5 h. These data demonstrate the complexity of the cellular response to radiation-induced damage at low doses. The lack of quantitative agreement between the transcript and protein levels for FOS suggests a role for post-transcriptional regulation.

Cell Membrane↗
PubMed1999

Tumour cell kinetics as a prognostic factor in squamous cell carcinoma of the cervix treated with radiotherapy.

PURPOSE: Proliferative rate and DNA ploidy status were evaluated by flow cytometry in cervical cancer patients, prior to radiotherapy, to assess their importance as prognostic factors to predict survival rates. MATERIAL AND METHODS: Between 1987 and 1995, a total of 260 patients with squamous cell carcinoma (SCC) of the cervix, FIGO stages IB-IIIB were analysed. Tumour samples were incubated with bromodeoxyuridine (BrdUrd) in vitro to measure their total labelling index (totLI) and LI (totLI for diploid and anLI for aneuploid tumours). Proliferation was also assessed by S-phase fraction (SPF) analysis of the DNA profile. Patients had intracavitary therapy (three applications, each of 16 Gy to point A) and XRT of 40-50 Gy given over 4-5 weeks. RESULTS: The cervical tumours were characterized by a high proliferation rate which varied within each clinical stage of disease. The totLI ranged from 1.1 to 33.1% with median value of 9.6% whilst the LI ranged from 1.1 to 37.1% with a median value of 10.9%. Univariate analysis identified patient's age (cut-offpoint < or = 50&greater; years) and to a lesser extent proliferation (cut-off point, median totLI=9.6%) as significant prognostic factors for 5-year survival. The median survival time for younger patients ( < or = 50 years) with tumours of low proliferation (totLI < or = 9.6%) tumours was 17.5 months compared with 56 months in the faster proliferating tumours (P=0.0354). In the older patient sub-group, proliferation rate had no influence on survival. The median LI value was not a useful parameter in survival. Cox multivariate analysis showed that patient age ( < or = 50 years) and low proliferation of the tumour cells (totLI < or = 9.6) were unfavourable prognostic factors for cervical cancers treated with radiotherapy. DNA ploidy was not significant in this series. CONCLUSIONS: These data suggest that further improvements in therapy might be gained by selection of alternative treatments strategies such as neoadjuvant chemotherapy or radiation sensitizers in younger patients with more slowly proliferating tumours.

Adult↗
PubMed1999

The value of pretreatment cell kinetic parameters as predictors for radiotherapy outcome in head and neck cancer: a multicenter analysis.

PURPOSE: The aim of this study was to assess the potential of pre-treatment cell kinetic parameters to predict outcome in head and neck cancer patients treated by conventional radiotherapy. MATERIALS AND METHODS: Data from 11 different centers were pooled. Inclusion criteria were such that the patients received radiotherapy alone, and that the radiotherapy was given in an overall time of at least 6 weeks with a dose of at least 60 Gy. All patients received a tracer dose of either iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) intravenously prior to treatment and a tumor biopsy was taken several hours later. The cell kinetic parameters labeling index (LI), DNA synthesis time (Ts) and potential doubling time (Tpot) were subsequently calculated from flow cytometry data, obtained on the biopsies using antibodies against I/BrdUrd incorporated into DNA. Each center carried out their own flow cytometry analysis. RESULTS: From the 11 centers, a total of 476 patients conforming to the inclusion criteria were analyzed. Median values for overall time and total dose were 49 days and 69 Gy, respectively. Fifty one percent of patients had local recurrences and 53% patients had died, the majority from their disease. Median follow-up was 20 months; being 30 months for surviving patients. Multivariate analysis revealed that T-stage, maximum tumor diameter, differentiation grade, N-stage, tumor localization and overall time correlated with locoregional control, in decreasing order of significance. For the cell kinetic parameters, univariate analysis showed that only LI was significantly associated with local control (P=0.02), with higher values correlating with a worse outcome. Ts showed some evidence that patients with longer values did worse, but this was not significant (P=0.06). Tpot showed no trend (P=0.8). When assessing survival in a univariate analysis, neither LI nor Tpot associated with outcome (P=0.4, 0.4, respectively). Surprisingly, Ts did correlate with survival, with longer values being worse (P=0.02). In the multivariate analysis of local control, LI lost its significance (P=0.16). CONCLUSIONS: The only pretreatment kinetic parameter for which some evidence was found for an association with local control (the best end-point for testing the present hypothesis) was LI, not Tpot, and this evidence disappeared in a multivariate analysis. It therefore appears that pretreatment cell kinetic measurements carried out using flow cytometry, only provide a relatively weak predictor of outcome after radiotherapy in head and neck cancer.

Analysis of Variance↗
PubMed1999

Modulation of the acoustic startle reflex by emotionally-toned film-clips.

It has been widely reported that the eyeblink component of the acoustic startle reflex can be modulated by emotionally-toned slide stimuli; pleasant slides reduce eyeblink amplitudes whereas unpleasant slides enhance them. The present study examines the modulation of the acoustic startle reflex by short (2-min) film-clips classified as pleasant, unpleasant or neutral, on the basis of subjective ratings. These film-clips were also evaluated with respect to their test-retest reliability in producing affective states as well as modulating startle reflexes. Overall, results showed significant reduction of startle during pleasant clips and augmentation during unpleasant clips. However, on first showing, one of the two unpleasant clips (a medical demonstration film depicting details of toe surgery) actually inhibited the startle reflex rather than augmented it. This is discussed in terms of the proposition that only stimuli which arouse fear can be guaranteed to augment startle; stimuli that are repulsive may produce perceptual and emotional 'blunting' that reduces startle amplitude.

Acoustic Stimulation↗
PubMed1999

Reproducibility of measurements of potential doubling time of tumour cells in the multicentre National Cancer Institute protocol T92-0045.

We compared the flow cytometric measurement and analysis of the potential doubling time (Tpot) between three centres involved in the National Cancer Institute (NCI) protocol T92-0045. The primary purpose was to understand and minimize the variation within the measurement. A total of 102 specimens were selected at random from patients entered into the trial. Samples were prepared, stained, run and analysed in each centre and a single set of data analysed by all three centres. Analysis of the disc data set revealed that the measurement of labelling index (LI) was robust and reproducible. The estimation of duration of S-phase (T(S)) was subject to errors of profile interpretation, particularly DNA ploidy status, and analysis. The LI dominated the variation in Tpot such that the level of final agreement, after removal of outliers and ploidy agreement, reached correlation coefficients of 0.9. The sample data showed poor agreement within each of the components of the measurement. There was some improvement when ploidy was in agreement, but correlation coefficients failed to exceed values of 0.5 for Tpot. The data suggest that observer-associated analysis of T(S) and tissue processing and tumour heterogeneity were the major causes of variability in the Tpot measurement. The first two aspects can be standardized and minimized, but heterogeneity will remain a problem with biopsy techniques.

Aneuploidy↗
PubMed1999

Measurement of c-myc oncogene expression provides an accurate prognostic marker for acral lentiginous melanoma.

Acral lentiginous melanoma is a particularly aggressive tumour with a worse prognosis than other varieties of primary cutaneous melanoma. In order to study the biology of this disease, the activity of the c-myc oncogene was studied in tumours from 45 patients using flow cytometry. High levels of oncoprotein were found in all tumours and exceeded that documented in other varieties of cutaneous melanoma. Survival analysis with stratification of patients according to oncogene activity provided a useful prognostic marker with shorter disease free interval (Log-Rank test, chi 2 = 16.7, P < 0.0001) and overall survival (Log-Rank test, chi 2 = 8.9, P = 0.002) in tumours with high oncoprotein levels. Multivariate analysis revealed c-myc oncogene expression to be more accurate in predicting clinical outcome than all existing clinicopathological parameters including the Breslow depth (Cox's proportional hazards model, P = 0.0011). This study provides biological evidence to explain the aggressive behaviour of acral melanoma and supports the application of oncogene measurement as an accurate prognostic marker.

Adult↗
PubMed1999

Is Dupuytren's disease caused by an imbalance between proliferation and cell death?

Dupuytren's contracture shares certain properties with malignant tumours, characterized by proliferation and lack of apoptosis, which may be induced by the c-myc oncogene. Because of these similarities, the relationship between the c-myc oncogene expression, bcl-2 oncogene (anti-apoptotic gene) and proliferation was investigated in Dupuytren's disease. Proliferation was assessed by immunohistochemical staining of the mib-1 antibody. Results were compared with those from fibrosarcoma specimens, representing a related malignant tumour. Non-diseased fascia from Dupuytren patients and flexor retinaculum from patients undergoing carpal tunnel release without Dupuytren's disease were used as controls. Expression of c-myc was elevated in primary Dupuytren's disease and fibrosarcoma specimens, whilst recurrent Dupuytren's disease, non-diseased Dupuytren fascia and flexor retinaculum exhibited significantly lower levels. Neither bcl-2 nor mib-1 were detected in Dupuytren's disease, non-diseased fascia or flexor retinaculum, in contrast to fibrosarcoma. The imbalance between proliferation and apoptosis, producing malignant growth was thus confirmed for fibrosarcoma, but not for Dupuytren's disease.

Adult↗
PubMed1999

Efficient in vivo targeting of malignant melanoma by single-chain Fv antibody fragments.

Single-chain antibody fragments (scFvs) have superior pharmacokinetic and biodistribution characteristics compared with larger antibody fragments when used for radioimaging of human tumours. An scFv specific for malignant melanoma (B4 scFv) was tested in a mouse xenograft model for human melanoma and compared with the monoclonal antibody (MAb) LHM2. LHM2 is specific for the high molecular weight proteoglycan melanoma-associated antigen (HMW-MAA), while B4 scFv binds a novel melanoma-specific antigen. The B4 scFv was cleared rapidly from the circulation (t(1/2)alpha = 7 min) compared with LHM2 MAb (t(1/2)alpha = 37 min). However, the B4 scFv had an unusually long t(1/2)beta (437 min compared with 384 min for LHM2 MAb). Biodistribution studies showed that B4 accumulated specifically in the tumour grafts. Although non-specific accumulation in the liver, lung, spleen and blood was lower than with LHM2, non-specific accumulation of B4 in the kidney was higher. Despite this, the overall targeting efficiency in this study, as determined by tumour:normal tissue ratios, showed that B4 was superior to whole antibody. Immunoscintigraphy images showed good correlation with the biodistribution data for B4 and LHM2. This study represents the first use of an anti-melanoma scFv in vivo.

Animals↗
PubMed1999

c-myc, p53, and Bcl-2 expression and clinical outcome in uveal melanoma.

AIMS: Overexpression of c-myc protein has independent prognostic significance in a variety of primary and metastatic cutaneous melanomas which suggests a possible role for this gene in melanomagenesis. We have therefore examined the importance of this oncogene in uveal melanoma and studied the coexpression of two other gene products, Bcl-2 and p53, which might contribute to its effect. METHODS: The percentage of cells positive for nuclear c-myc expression was estimated by flow cytometric analysis of nuclei extracted from paraffin blocks. The expression of Bcl-2 and p53 protein was assessed by immunohistochemistry. A total of 71 tumours were studied and the results compared with survival with a mean follow up period of 6 years. RESULTS: c-myc was expressed in > 50% of the cells by 70% of the tumours, and was independently associated with improved survival in a Cox multiple regression-model. Although Bcl-2 was expressed by the majority of the cells in 67% tumours, it was without effect on prognosis. None of the cases studied showed convincing positivity for p53. Analysis of coexpression showed that the best survival was seen in c-myc+/Bcl-2+ tumours and the worst in c-myc-/Bcl-2-tumours. CONCLUSION: The finding of improved rather than reduced survival in c-myc positive tumours is at variance with skin melanoma. There was no evidence to suggest that c-myc was modulated by upregulation of Bcl-2 or p53 inactivation/mutation. Although Bcl-2 is unlikely to have any effect on tumour growth or metastasis, it could contribute to the general lack of susceptibility to apoptosis in these tumours.

Adolescent↗