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Biomedical subjects

S A Roberts

Publications and source records attributed to S A Roberts.

At least 19 recordsLinked to original sources
PubMed1997

Cytokeratins 20 and 7 in the differential diagnosis of metastatic carcinoma in cytologic specimens.

A series of 33 tumor cases (13 fine-needle aspirates and 20 effusion specimens) were evaluated for the expression of two cytokeratin (CK) subtypes; CK 20, expressed primarily in tumors of the GI tract, mucinous ovarian tumors and transitional cell carcinomas, and CK 7, found chiefly in non-GI tract adenocarcinomas, including breast and lung. CK 20 expression was demonstrated immunocytochemically in seven of seven metastatic colon and two of three metastatic transitional cell carcinomas tested. CK 20 was absent in all metastatic carcinomas of breast, ovary, lung, and uterus examined (23 cases). Anti-CK 7 stains were negative in four of six metastatic colonic carcinomas, with equivocal results in the remaining two cases. Metastatic lung, breast, and ovarian carcinomas were strongly positive for CK 7. This study demonstrates that the combined use of anti-CK 20 and anti-CK 7 antibodies is highly sensitive and specific for metastatic colonic adenocarcinoma in cytologic material and thus could play an important role in distinguishing this entity from other common primary carcinomas.

Antibodies, Monoclonal↗
PubMed1997

Differential survival of murine small and large intestinal crypts following ionizing radiation.

Radiation survival curves have been obtained for crypts in the small and large intestine of male BDF1 mice using the microcolony assay. Four regions of the small intestine and three regions of the large intestine were studied. One of the major objectives was to determine the optimal conditions for the microcolony assay in the large bowel. Various times post-irradiation were studied using different approaches and threshold criteria for surviving crypts. Small, but statistically significant, differences were observed along the length of the small intestine, but no differences were observed between different regions of the large intestine. There was a marked difference (p < 0.001) in the response in the large compared with the small intestine (D0 = 291 +/- 14 compared with 151 +/- 4 cGy respectively with corresponding extrapolation numbers of 18 +/- 4 and 377 +/- 65). The use of tritiated thymidine or vincristine helped in the identification of true survivors in the large bowel, but these approaches are not necessary in the small bowel. The longer the time after irradiation that the samples were fixed the easier it was to identify survivors in the colon. However, the longer the time the more animals died. The optimum compromise in these studies was to use partial-body irradiation (abdomen only) and to sample on the fifth day after irradiation. With these criteria the mid-colon survival curve had a D0 = 274 +/- 28 cGy and an extrapolation number of 22 +/- 10. The results can be considered in relation to published data on the levels of p53 and bcl-2 expression and apoptosis in murine small and large bowel.

Animals↗
PubMed1997

Accumulation of p53 in relation to long-term prognosis in colorectal carcinoma.

OBJECTIVE: To evaluate the prognostic value of p53 in colorectal cancer. DESIGN: A retrospective study to investigate the correlation between p53 in tumour tissue and the course of patients' disease. PATIENTS: One hundred and two patients who underwent radical surgery for colorectal cancer and were followed up for a minimum of 5 years, or until death, were included in this study. METHODS: The p53 expression in tumour tissue was studied by immunohistochemistry using CM1 polyclonal rabbit antibody and formalin-fixed, paraffin-embedded material. RESULTS: p53 accumulation was detected in 46% (47/102) of the tumours. There was no significant difference in long-term survival between the patients with p53 positive and negative tumours (P=0.86). Five-year survival rates were 55% for p53 positive tumours compared with 56% for patients with p53 negative tumours. However, patients with p53 overexpressing tumours showed a higher local recurrence rate than those having carcinomas with undetectable levels of p53, 23% versus 9% respectively; the 2-year actuarial rates of 26% and 9% were statistically different (P=0.015). CONCLUSION: The results suggest that in colorectal carcinoma accumulation of p53 is not associated with a difference in long-term prognosis. However, this phenomenon might be useful in the identification of patients with a high risk of local recurrence.

Adult↗
PubMed1996

The clinical significance of p53 accumulation in gastric carcinoma.

BACKGROUND: Alterations in the expression of p53 tumor suppressor protein is a frequent event in human cancer but the practical implications of this phenomenon are yet to be fully exploited. The objective of this study was to determine the value of p53 accumulation as a marker of tumor progression and prognosis of gastric carcinoma patients and to evaluate whether this parameter can be properly assessed prior to surgery. METHODS: The expression of p53 was studied immunohistochemically in 200 gastric carcinomas using paraffin embedded surgical specimens and endoscopic biopsies. The correlation between p53 expression in tumor tissue, selected clinicopathologic variables, and the course of the patients' disease were analyzed. RESULTS: Results showed that 42.5% of the gastric carcinomas expressed elevated levels of p53 protein. P53 accumulation positivity correlated with increasing tumor stage and size (P < 0.001 and P = 0.025, respectively). P53 positive tumors had a higher propensity for lymph node and distant metastases (P < 0.001). P53 accumulation was also more frequently detected in carcinoma from proximal rather than distal stomach (P = 0.027). In patients receiving potentially curative resection for advanced cancer, p53 accumulation was an independent parameter and the strongest for poor prognosis (RR = 3.7, P < 0.001). There was complete concordance between immunohistochemical detection of p53 in endoscopic and surgical material. CONCLUSIONS: A preoperative assessment of p53 expression in gastric carcinoma can be helpful to identify patients at high risk of metastatic spread to regional lymph nodes and independently to identify those with especially poor prognosis. When combined with routine procedures, this simple and inexpensive test might allow appropriate planning of better treatment strategies.

Adult↗
PubMed1996

RP 64477: a potent inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase with low systemic bioavailability.

RP 64477 (N-butyl-3-(p-decyloxybenzamido)-4-(methylthio)benzamide) has been shown to be a potent inhibitor of the cholesterol esterifying enzyme Acyl-coenzyme A:cholesterol O-acyltransferase (EC 2.3.1.26; ACAT) in intestinal, hepatic, adrenal, and arterial tissue preparations obtained from a range of animal species. Drug concentrations producing 50% inhibition of enzyme activity (IC50 values) ranged from 14-283 nM. Inhibition by RP 64477 in a rabbit intestinal enzyme preparation was shown to be non-competitive with respect to the substrate oleoyl-CoA. In whole cell assays using human intestinal (CaCo-2), hepatic HepG2) and monocytic (THP-1) cell lines, RP 64477 inhibited ACAT activity with IC50s of 113, 503, and 180 nM, respectively. RP 64477 (0.03% w/w by diet) reduced significantly cholesterol absorption in cholesterol/cholic acid-fed rats from 94+/- 8% to 65 +/- 4%. In cholesterol-fed rabbits, cholesterol absorption was reduced from 72 +/- 5% to 50 +/-5% and 44 +/- 5% at dose levels of 10 and 30 mg kg-1 b.i.d., respectively. Plasma cholesterol levels were reduced dose-dependently in both cholesterol/cholic-acid-fed rats and cholesterol-fed rabbits. Neither cholesterol absorption nor plasma cholesterol levels were reduced significantly in animals maintained on standard laboratory diets. Pharmacokinetic studies indicated that RP 64477 were very poorly absorbed following oral administration to rats. Plasma levels of drug were < 2 ng mL-1 following a dose of 2000 mg kg-1 p.o.. When radiolabelled RP 64477 was administered orally, limited absorption was indicated by the overwhelming elimination of radioactivity in the faces (96.4% of administered material) coupled with low renal clearance (0.6% of dose) and biliary excretion (0.05% of dose). In conclusion, this work shows that RP 64477 is a potent inhibitor of ACAT obtained from a range of animal species and man. Inhibition of cholesterol absorption and hypocholesterolaemic activity has been demonstrated in rats and rabbits maintained on diets supplemented with cholesterol. Pharmacokinetic studies indicate low systemic exposure to RP 64477 as a result of limited absorption of this drug.

Acyl Coenzyme A↗
PubMed1996

Changes in the cellularity of the cortex of human hairs as an indicator of radiation exposure.

Growing hair follicles with their rapid cell proliferation would be expected to be sensitive organs to cytotoxic agents such as radiation. Various abnormalities in the hair and hair follicles have been reported in the past. Changes in the number of cells in the newly forming hair cortex have been shown in the mouse to be one of the more sensitive assays for radiation effects, and this approach could provide a basis for a biological dosimeter. Here we show for the first time using hair cortex cell counts some preliminary data indicating that the number of cell nuclei in a unit of length (140 microns) of the cortex of human hairs from the chest and scalp of patients undergoing fractionated radiotherapy falls significantly (P = 0.005) by 5%-10% 3 days after the first dose in a fractionated sequence of irradiations. The first dose was delivered on a Friday, and no further exposures were delivered until after the hair sample was taken on the 3rd day (Monday). No significant effect of radiation dose could be detected over the available. limited range of doses studied (5-6.5 Gy with one exit dose sample at 2.6 Gy). Also, the width varies from hair to hair. If the width of the hair is taken into account and the cortical nuclei counts are normalised to the width of each hair, the effects seen at day 3 become slightly more significant (P = 0.002), and those at day 5 also become significant (P = 0.012). Samples taken on the 5th day after the first (Friday) exposure were also 2 days after the second exposure and 1 day after the third exposure. However, little expression of damage attributable to the 2nd and 3rd exposures was anticipated since their effects would take some time to be expressed in the cortical region examined, which is some distance from the proliferative region of the follicle.

Cell Count↗
PubMed1996

Dose-rate sparing for micronucleus induction in lymphocytes of controls and ataxia-telangiectasia heterozygotes exposed to 60Co gamma-irradiation in vitro.

We investigated the reproducibility of the cytochalasin B micronucleus (MN) assay in irradiated human lymphocytes to assess its suitability in predicting cancer predisposition and response to radiotherapy by virtue of defects in the processing of clastogenic lesions. G0 lymphocytes were exposed to 3.0 Gy 60Co gamma-rays at high (HDR) or low dose-rate (LDR). Six healthy donors were assayed three times each in nine experiments and compared with six ataxia-telangiectasia (A-T) heterozygotes. In controls, significant interexperiment variability in MN yields was observed at HDR and LDR, also in dose-rate sparing (i.e. reduction in MN yield at LDR compared with HDR). Significant inter-individual variability was seen at HDR, but not at LDR or for sparing. Average sparing was 66.4 +/- 4.8%. In spite of the experimental variability, a significant difference between controls and A-T heterozygotes was detected at LDR, and 5/6 heterozygotes had sparing values below the control range. This gives encouragement for the use of this assay in predictive testing if sources of experimental variability can be identified so as to improve discrimination between individuals. HDR and to a lesser extent LDR irradiation induced significant mitotic inhibition, seen as a reduction in binucleate cells after cytocholasin treatment. A positive correlation between mitotic inhibition and MN frequency suggests that similar lesions may be involved in these effects.

Adult↗
PubMed1996

Chromosomal radiosensitivity in G2-phase lymphocytes as an indicator of cancer predisposition.

Sanford et al. (Int. J. Radiat. Biol. 55, 963-981, 1989) have reported that G2-phase cells from many heritable cancer-prone conditions exhibit higher yields of X-ray-induced chromosome damage than those found in the majority of healthy controls. We have applied their protocol to lymphocytes of a group of control and cancer-prone individuals to see if we could confirm these observations. For control donors we observed higher aberration yields, different kinetics and more interexperiment variability than found by Sanford et al. These differences could not be attributed to unavoidable minor variations in procedures (e.g. serum batches, glassware washing methods), but the difference in X-ray qualities used in the two laboratories may have made a small contribution to the discrepancies. We attribute some of our experimental variability to the fact that, to varying extents in different experiments, centrifugation of cells prior to irradiation can slow down the progression of cells into metaphase and that cells can continue to repair during the harvesting procedure (centrifugation and hypotonic treatment). We have applied the assay to cases of ataxia telangiectasia (AT, homozygotes and heterozygotes), xeroderma pigmentosum (homozygotes and heterozygotes), familial adenomatous polyposis and the syndromes Li-Fraumeni, basal cell nevus, Down's and Fanconi's but have been unable to discriminate between these groups and controls except for AT homozygotes. By including a control sample in parallel with samples from cancer-prone groups we found a significant difference in mean aberration yields between controls and AT homozygotes and heterozygotes, but not for the other groups. Since technical features could explain the discrepancies between our laboratories, we have devised our own G2-phase assay which appears to be giving promising results.

Adenomatous Polyposis Coli↗
PubMed1996

Gamma-ray-induced cell killing and chromosome abnormalities in the bone marrow of p53-deficient mice.

Resistance to the lethal effects of ionizing radiation has been demonstrated in a wide variety of cell types with defects in the p53 gene (thymocytes, splenic B and T cells, in vitro hemopoietic colony-forming cells and intestinal cells of the mouse, embryo cells of the rat, and human Burkitt's lymphoma cells). In contrast, Slichenmeyer et al. (Cancer Res. 53, 4164-4167, 1993) found no evidence of resistance in fibroblasts derived from p53 null mice. The aim of our study was to compare the radiation response of hemopoietic colony-forming cells (in vitro CFC) and of fibroblastoid colony-forming cells or units (CFU-F) within the same tissue (marrow) in p53 null mice (-/-), heterozygotes (+/-) and wild-type animals (+/+). We have also tested the hypothesis that, in proliferating cells, radiation-induced cell killing is mediated through chromosome damage by examining the relationship between these end points in hemopoietic cells of the three mouse types. Both in vitro CFC and CFU-F of -/- mice were resistant to cell killing compared with +/+ and +/- mice whose cellular sensitivities were indistinguishable. The resistance was characterized by a broader "shoulder" on the cell survival curve, i.e. a higher extrapolation number but similar D0 values using the multitarget model or a lower alpha coefficient using the linear-quadratic model. The frequency of chromosomally abnormal marrow cells after irradiation was similar for the three genotypes. However, marrow cells with aberrations carried more aberrations in -/- mice than in +/+ or +/- mice such that the total number of aberrations per 100 cells was higher in -/- mice. Since there were no differences in the yields of aberrations between genotypes in spleen lymphocytes or in CFU-F (both noncycling at the time of irradiation) and less mitotic inhibition in -/- marrow cells than in +/+ or +/- cells, the chromosomal radiosensitivity of -/- marrow hemopoietic cells might be related to reduced cell cycle delay allowing insufficient time for repair, but other explanations have been considered. We postulate that the radiation resistance of both hemopoietic CFC and CFU-F in -/- mice is a consequence of the failure of DNA/chromosome damage to trigger apoptosis or permanent cell cycle arrest to the same extent as in the +/+ or +/- mice: hence the lack of correlation between chromosome damage and cell death in the three mouse types.

Analysis of Variance↗
PubMed1995

The New York High-Risk Project. Psychoses and cluster A personality disorders in offspring of schizophrenic parents at 23 years of follow-up.

BACKGROUND: We herein present lifetime prevalence rates of psychoses and DSM-III-R cluster A personality disorders in sample A of the New York High-Risk Project, a prospective study following offspring of parents with schizophrenia (HRSz subjects) and affective illness (HRAff subjects) and of psychiatrically normal parents (NC subjects) from midchildhood to adulthood. METHODS: We interviewed the offspring in adulthood with the Schedule for Affective Disorders and Schizophrenia, Lifetime Version, for Axis I disorders and the Personality Disorder Examination for Axis II disorders. RESULTS: Lifetime prevalence rates (+/- SE) of schizophrenia and unspecified psychosis were 11.1% +/- 4.3% and 5.6% +/- 3.1%, respectively, in the HRSz group and 0% in the HRAff and NC groups. Rates of schizoaffective disorder subclassified as mainly schizophrenic, however, were highest in the HRAff group. Rates of psychotic affective disorders did not differ between the HRSz and other groups. Age-corrected morbidity risks were similar to lifetime prevalence rates. Rates of the three cluster A personality disorders did not differ among the groups, but the combined rate was greater in the HRSz and HRAff groups than in the NC group. CONCLUSIONS: Our data strongly support a specific familial liability to narrowly defined schizophrenia that is not shared by families of probands with affective disorder. Schizoaffective disorder and cluster A personality disorders, however, occur in families of both schizophrenic probands and probands with affective disorder. Psychotic affective disorders, which are not increased in HRSz subjects, do not appear to be an expression of the liability to schizophrenia.

Adolescent↗
PubMed1995

Apoptosis, intrinsic radiosensitivity and prediction of radiotherapy response in cervical carcinoma.

Apoptosis is an important mechanism of cell death in tumours and it is seen both prior to and following radiotherapy. In this study patients with proven carcinoma of the cervix had measurement made of the percentage of apoptotic cells (apoptotic index or AI) in pre-therapy biopsies. Measurements of intrinsic radiosensitivity (SF2), already shown to be a predictor of outcome, had previously been made on the same pre-therapy biopsies. Mitotic index (MI) and Ki-67 antigen staining were also recorded as markers for proliferation. Patients were divided into those with an AI above or below the median and in general increasing apoptosis was associated with poor prognosis. The 5-year survival rate for tumours with an AI below the median was 79% and was significantly greater than the rate of 47% for those with an AI above the median (p = 0.003). There was also a significantly increased 5-year local recurrence-free rate for patients with an AI below the median compared with those with an AI above the median (79 versus 61%, p = 0.012). In addition, AI and SF2 acted as independent prognostic indicators. Patients with both an SF2 and AI value above the median did badly (25% 5-year survival, 46% local control) compared with those with an SF2 and AI below the median (80% 5-year survival, 100% local control). Apoptosis showed correlation with MI (n = 66, r = 0.34, p = 0.002) and cell staining for the Ki-67 antigen (n = 57, r = 0.25, p = 0.03), but neither MI nor Ki-67 were related to patient outcome. This suggests that while apoptosis may be a reflection of tumour proliferation this cannot in itself explain the ability of apoptosis to predict clinical outcome for this series of patients. The study raises the possibility of AI and SF2 being used together as predictors of tumour response to radiotherapy.

Adult↗
PubMed1995

Serum tumour markers in carcinoma of the uterine cervix and outcome following radiotherapy.

A study was made of the prognostic value of measurements of pretreatment serum marker levels in patients with carcinoma of the uterine cervix undergoing radiotherapy. The markers studied were carcinoma antigen 125 (CA125), squamous cell carcinoma antigen (SCC) and tissue polypeptide antigen (TPA). The levels of all three markers increased with disease stage. In a univariate analysis stratifying patients according to either median values or cut-off levels representing the top of the normal range, pretreatment levels predicted patient survival (follow-up times 1-4 years). In a multivariate analysis, disease stage was the most important prognostic variable and, after allowing for stage, only CA125 was a significant independent predictor of treatment outcome. These data suggest that, in carcinoma of the cervix treated with radiotherapy, pretreatment measurements of CA125, but not SCC and TPA, may have a role to play in defining prognosis.

Antigens, Neoplasm↗
PubMed1995

Abnormal radiosensitivity of lymphocytes from breast cancer patients with excessive normal tissue damage after radiotherapy: chromosome aberrations after low dose-rate irradiation.

There is a need for a simple, rapid assay for predicting normal tissue reactions in radiotherapy patients to reduce morbidity in sensitive patients and to allow dose escalation in resistant cases. Towards this goal we have investigated the gamma-ray sensitivity of lymphocytes from 16 breast cancer patients who had shown an exaggerated acute or late radiation reaction ('overreaction') of normal tissues after radiotherapy, using chromosome damage (dicentrics) as the endpoint because of its close relationship with cell killing. The use of a low dose-rate (LDR; 0.31 cGy min-1) was found to be better than a high dose-rate (170 cGy min-1) in discriminating between over-reactors and controls, as predicted (and here confirmed) from previous studies on ataxia-telangiectasia (A-T) homozygotes and heterozygotes. Five of seven patients with excessive early skin reactions (e.g. erythema, moist desquamation) showed abnormal radiosensitivity, manifested either as aberration yields above the control range after LDR exposure or as less sparing than controls. The average LDR yield for early over-reactions was significantly higher than for controls (p = 0.009) and average sparing was less (p = 0.0002). Two of 10 patients with late complications (fibrosis, telangiectasia) had LDR yields above the control range, but the average yield for late over-reactors was not significantly above that of controls. Unexpectedly, two patients (one early, one late reaction) had LDR aberration yields below the control range. Quantitatively our results are consistent with the notion that over-reacting breast cancer patients are carriers of the A-T gene. Pilot studies on controls showed that the sparing effect of LDR irradiation was increased by lowering the dose-rate to 0.13 cGy min-1 and by using micronuclei rather than metaphase damage as the endpoint. These modifications to the protocol will be used in a large-scale prospective study.

Adult↗
PubMed1995

Deduction of the clonogen content of intestinal crypts: a direct comparison of two-dose and multiple-dose methodologies.

A microcolony assay was used in conjunction with fractionated gamma irradiation to determine the number of clonogens in murine intestinal crypts with varying doses of irradiation used in the determination. The experimental design allows direct comparison between two-dose methodologies, employing one and two (or two or four) equal dose fractions, and multiple-dose methodologies involving determination of the crypt survival curves for a number of fractionation regimens using equal doses per fraction. The two-dose methodology yielded estimates of clonogen number of between 3 and 4 at low delivered dose (single and double fractions each of 6.5-7.5 Gy), rising to around 40 at high biological doses (two and four fractions each of 5.75 or 6.5 Gy). The multifraction methodology yielded estimates of clonogen number which increased from 13 after a single fraction to values of 26 and 22 after three and four fractions. However, the latter values were reduced to 11 and 9, and showed little evidence of any dependence on fraction number, when data pertaining to high biologically effective doses were excluded. Hence it is concluded that the high values for clonogen number typically deduced from such multiple-dose protocols, compared with the generally lower (but dose-dependent) values obtained from two-dose protocols, may be explained at least partially by the higher biological doses generally employed in the multiple-dose protocols.

Animals↗