Professional competence of doctors in the United Kingdom.
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Clinical Competence↗
Biomedical subjects
M Talbot
Publications and source records attributed to M Talbot.
Chemical camouflage of antigenic determinants: stealth erythrocytes.
In a number of clinical circumstances it would be desirable to artificially conceal cellular antigenic determinants to permit survival of heterologous donor cells. A case in point is the problem encountered in transfusions of patients with rare blood types or chronically transfused patients who become allosensitized to minor blood group determinants. We have tested the possibility that chemical modification of the red blood cell (RBC) membrane might serve to occlude antigenic determinants, thereby minimizing transfusion reactions. To this end, we have covalently bound methoxy(polyethylene glycol) (mPEG) to the surface of mammalian RBC via cyanuric chloride coupling. Human RBC treated with this technique lose ABO blood group reactivity as assessed by solution-phase antisera agglutination. In accord with this, we also find a profound decrease in anti-blood group antibody binding. Furthermore, whereas human monocytes avidly phagocytose untreated sheep RBC, mPEG-derivatized sheep RBC are ineffectively phagocytosed. Surprisingly, human and mouse RBC appear unaffected by this covalent modification of the cell membrane. Thus, mPEG-treated RBC are morphologically normal, have normal osmotic fragility, and mPEG-derivatized murine RBC have normal in vivo survival, even following repeated infusions. Finally, in preliminary experiments, mPEG-modified sheep RBC intraperitoneally transfused into mice show significantly improved (up to 360-fold) survival when compared with untreated sheep RBC. We speculate that similar chemical camouflage of intact cells may have significant clinical applications in both transfusion (e.g., allosensitization and autoimmune hemolytic disease) and transplantation (e.g., endothelial cells and pancreatic beta cells) medicine.
Animals↗
Development of medullary thyroid carcinoma in transgenic mice expressing the RET protooncogene altered by a multiple endocrine neoplasia type 2A mutation.
Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome that comprises three clinical subtypes: MEN type 2A (MEN-2A), MEN type 2B (MEN-2B), and familial medullary thyroid carcinoma (FMTC). Medullary thyroid carcinoma (MTC), a malignant tumor arising from calcitonin-secreting thyroid C cells, is the cardinal disease feature of this syndrome, and mortality in affected MEN-2 patients is mainly caused by this malignancy. Germ-line mutations of the RET protooncogene, which encodes a receptor tyrosine kinase, are responsible for these three neoplastic-prone disorders. MEN2 mutations convert the RET protooncogene in a dominantly acting oncogene as a consequence of the ligand-independent activation of the tyrosine kinase. The majority of MEN2A and FMTC mutations are located in the extracellular domain and cause the replacement of one of five juxtamembrane cysteines by a different amino acid. To examine whether expression of a MEN2A allele of RET results in transformation of C cells, we have used the transgenic approach. Expression of the RET gene altered by a MEN2A mutation was targeted in C cells by placing the transgene under the control of the calcitonin gene-related peptide/calcitonin promoter. Animals of three independent transgenic mouse lines, which expressed the transgene in the thyroid, displayed overt bilateral C cell hyperplasia as early as 3 weeks of age and subsequently developed multifocal and bilateral MTC. Moreover, these tumors were morphologically and biologically similar to human MTC which afflicts MEN2 individuals. These findings provide evidence that the MEN2A mutant form of RET is oncogenic in parafollicular C cells and suggest that these transgenic mice should prove a valuable animal model for hereditary MTC.
Animals↗
Targeted oncogenesis in the thyroid of transgenic mice.
We have developed mouse models for tumors affecting the epithelial cellular compartment of the thyroid which has been targeted using the bovine thyroglobulin (bTg) promoter. Transgenic mice expressing the human activated c-Ha-Ras gene developed papillary thyroid carcinomas demonstrating the oncogenic potential of activated Ras gene in the thyroid gland. Transgenic mice express the mutant form of the alpha subunit of the adenylate cyclase-coupled G alpha s with mutations at codon 201 (R201H). The expression of this mutant transgene is not by itself sufficient to produce benign tumors or even hyperplasia, but the transgenic mice have inherited a predisposition to develop thyroid adenomas.
Adenylyl Cyclases↗
Chromosome 11q13 gene amplifications in oral and oropharyngeal carcinomas: no correlation with subclinical lymph node invasion and disease recurrence.
Gene amplifications in the q13 band of chromosome 11 are among the most frequent genetic alterations in head and neck squamous cell carcinomas. Previous studies have suggested that such amplification is a marker of aggressive tumor evolution. Their potential for predicting subclinical lymph node invasion or disease recurrence was investigated in a prospective series of 50 oral and oropharyngeal carcinomas. Cell DNA content was also measured in 32 tumors of this series. Gene amplifications affecting the 11q13 band were detected in 11 of 50 (20%) patients, a relatively low frequency in comparison with data reported previously for other carcinomas of the upper aerodigestive tract, especially hypopharyngeal carcinomas. These gene amplifications were preferentially associated with aneuploidy. Cervical lymph nodes of 26 clinically N0 (Tumor-Node-Metastasis staging) patients were surgically explored. The frequency of 11q13 amplifications was very similar in the presence or in the absence of histological invasion, 3 of 15 (20%) and 2 of 11 (18%), respectively. Thus, 11q13 amplifications do not appear to be a reliable marker for prediction of subclinical lymph-node invasion in oral and oropharyngeal carcinomas. The detection of 11q13 amplifications was also not associated with a higher risk of disease recurrence. These data suggest that not only the prevalence but also the prognostic significance of 11q13 amplifications varies between tumors at different sites in the upper aerodigestive tract.
Adult↗
Analysis of p53 serum antibodies in patients with head and neck squamous cell carcinoma.
BACKGROUND: Mutation of the p53 tumor suppressor gene (also known as TP53) often leads to the synthesis of p53 protein that has a longer than normal half-life. Mutant p53 protein that accumulates in tumor cell nuclei can be detected by means of immunohistochemical staining techniques. Serum antibodies directed against p53 protein (p53-Abs) have been detected in some cancer patients. PURPOSE: We assayed serum samples from 80 patients with head and neck squamous cell carcinoma (HNSCC) for the presence of p53-Abs, and we evaluated potential associations between the presence of these antibodies and other histopathologic and clinical features. METHODS: Serum was collected from each patient at the time of diagnosis. In addition, tumor biopsy specimens were obtained before the initiation of treatment. An enzyme-linked immunosorbent assay was used to detect p53-Abs. The accumulation of p53 protein in tumor cell nuclei was assessed immunohistochemically by use of the anti-p53 monoclonal antibody DO7. Patient treatment consisted of radiotherapy alone, primary chemotherapy followed by radiotherapy, or surgery and postoperative radiotherapy. Relapse-free and overall survival from the beginning of treatment were estimated by use of the Kaplan-Meier method; survival comparisons were made by use of the logrank statistic. Univariate and multivariate analyses were conducted to identify factors associated with survival. Reported P values are two-sided. RESULTS: Fifteen (18.8%) of the 80 patients had p53-Abs. Tumor cell nuclei in 43 (58.9%) of 73 assessable biopsy specimens exhibited strong p53 immunostaining. Patient treatment method and the accumulation of p53 protein in tumor cell nuclei were not associated with increased risks of relapse or death. In univariate analyses, advanced tumor stage (> T1 [TNM classification]) and the presence of p53-Abs were significantly associated with an increased risk of death (P for trend = .007 and P = .002, respectively), whereas advanced tumor stage, substantial regional lymph node involvement (> N1), and the presence of p53-Abs were associated with an increased risk of relapse (P for trend = .002, P = .02, and P < .0001, respectively). In multivariate analyses, advanced tumor stage and the presence of p53-Abs were significantly associated with increased risks of relapse (p for trend = .04 and P = .003, respectively) and death (P for trend = .04 and P = .03, respectively). At 2 years of follow-up, the overall survival proportion was 63% (95% confidence interval [CI] = 47%-80%) when no p53-Abs were detected compared with 29% (95% CI = 4%-54%) when p53-Abs were detected. Relapse-free survival at 2 years was 62% (95% CI = 49%-76%) if no p53-Abs were detected compared with 13% (95% CI = 0%-31%) if p53-Abs were detected. CONCLUSIONS AND IMPLICATIONS: The proportion of patients with HNSCC who have serum p53-Abs is smaller than that of patients exhibiting tumor cell accumulation of p53 protein. The presence of p53-Abs is significantly associated with increased risks of relapse and death.
Aged↗
Thyroid pathologies in transgenic mice expressing a human activated Ras gene driven by a thyroglobulin promoter.
Four transgenic mice carrying the human activated c-Ha-Ras gene, the expression of which was driven into the thyroid gland by a bovine thyroglobulin promoter, have been produced. The M1 and M2 mice developed papillary thyroid carcinomas and the M2 mouse also developed a lung carcinoma, however none of them transmitted the transgene. Both the M3 and the M4 mice gave rise to transgenic lines. M3 progeny mice develop a goitre with morphological aspects of hyperplasia as well as a thymus hyperplasia. M4 developed a papillary thyroid carcinoma and a lung carcinoma. Lung tumors but not thyroid tumors were observed in M4 adult transgenic progeny. In this M4 line, thyroid dysgenesis leading to growth retardation and premature death was observed upon serial backcross that enhanced the DBA/2J genetic background. The development of thyroid tumors in M1, M2, M4 transgenic mice demonstrates the oncogenic potential of activated Ras gene in the thyroid gland. The M4 line raises interesting questions relative to the interference between the Ras-mediated signal transduction pathway and thyroid morphogenesis.
Animals↗
Evaluation of the significance of polyamines and their oxidases in the aetiology of human cervical carcinoma.
The risk of cancer of the cervix is linked with sexual behaviour. Although infectious agents such as human papillomaviruses (HPVs) are implicated, these alone may be insufficient to induce the disease. We have investigated the potential role of oxidation products of the polyamines spermine and spermidine and the diamine putrescine in seminal plasma (SP) as co-factors in the development of cervical cancer. These amines are oxidised by polyamine oxidase (PAO) and diamine oxidase (DAO) to generate oxygen radicals and hydrogen peroxide, reactive aldehydes and acrolein, which are likely to exert local mutagenic, cytotoxic and immunosuppressive effects in vivo. Using a chemiluminescence assay, we determined the levels of these amines in 187 samples of SP. Spermine plus spermidine, as substrates for PAO, were present in a range equivalent to 0-4.8 mg ml-1 spermine. Putrescine, as a substrate for DAO, was detectable in only 4 of 40 samples assayed (range 0-168 micrograms ml-1) and constitutes a minor component of the oxidisable content of SP. Cervical mucus (126 samples) was assayed for the presence of PAO and DAO. Both enzymes were present in 14.3% of the samples, PAO only in 21.4%, DAO only in 15.1% and neither enzyme in 49.2%. PAO levels ranged from 0 to 0.828 pmol peroxide generated min-1 mg-1 mucus and DAO levels ranged from 0 to 7.0 pmol peroxide generated min-1 mg-1 mucus. These results suggest that sexual activity in the absence of physical barrier contraception may lead to the generation of mutagenic and immunosuppressive polyamine oxidation products within the female genital tract. We thus propose that women with high levels of PAO and/or DAO in their cervical mucus may be at increased risk of cervical cancer, especially if the male partner's SP shows high polyamine levels. HPV infection may synergise with the effects of polyamine oxidation by suppressing apoptosis in keratinocytes carrying potentially oncogenic mutations, leading to the survival and proliferation of transformed cells in the cervix.
Adolescent↗
Oncogenic potential of guanine nucleotide stimulatory factor alpha subunit in thyroid glands of transgenic mice.
Transgenic mice have been used to address the issue of the oncogenic potential of mutant guanine nucleotide stimulatory factor (Gs) alpha subunit in the thyroid gland. The expression of the mutant Arg-201-->His Gs alpha subunit transgene has been directed to murine thyroid epithelial cells by bovine thyroglobulin promoter. The transgenic animals develop hyperfunctioning thyroid adenomas with increased intracellular cAMP levels and high uptake of [125I]iodine and produced elevated levels of circulating triiodothyronine and thyroxine. These animals demonstrate that the mutant form of Gs alpha subunit carries an oncogenic activity, thus supporting the model that deregulation of cAMP level alters growth control in thyroid epithelium. These animals represent models for humans with autonomously functioning thyroid nodules.
Animals↗
Correlation between p53 gene expression and tumor-cell proliferation in oropharyngeal cancer.
The aim of our study was to analyze the correlation between tumor-cell kinetics measured in vivo and p53 gene expression in a series of 49 oropharyngeal cancers. The duration of the S phase (TS), the labelling index (LI) and the potential doubling time (Tpot) were obtained by flow-cytometry measurements of a tumor biopsy obtained after i.v. injection of 200 mg bromodeoxyuridine into patients. An adjacent section of the same samples was studied by immunohistochemistry for the detection of p53 protein. Over-expression of the p53 protein, as defined by strong p53 immunostaining of tumor nuclei, was found in 23/49 of the samples. Aneuploid tumors showed a higher LI, a shorter Tpot and a higher proportion of p53 gene over-expression. A significant correlation was seen between p53 over-expression and short Tpots. Indeed 87.5% of the tumors with a very short Tpot (< or = 3 days) had p53 over-expression, as compared with 27% of tumors with a longer Tpot (> 3 days). Our data strongly suggest that over-expression of the p53 gene is associated with rapid tumor-cell proliferation in this type of cancer.
Aged↗
Canadian Forces physician assistants.
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Canada↗
Immunohistochemical study of adrenocortical carcinoma. Predictive value of the D11 monoclonal antibody.
BACKGROUND: The diagnosis of adrenocortical carcinoma (ACC) may be difficult with conventional light microscopy, especially when the tumor is nonfunctioning. Until now, no specific adrenocortical tumor marker was available. The current study was undertaken to investigate the interest of the D11 MoAb for the diagnosis and prognosis of ACC. METHODS: Eighteen adrenocortical carcinomas, 10 primary adrenomedullary tumors, 20 primary hepatocellular carcinomas, 50 primary renal cell carcinomas, 5 primary lung carcinomas, and 18 intraadrenal metastases were analyzed immunohistochemically with the D11 monoclonal antibody. ACC were also evaluated for the expression of other tumor markers, including neuron-specific enolase, chromogranin A, S-100, Leu-7, vimentin, KL1, AE1AE3, and epithelial membrane antigen. Relationships between clinical features and results of immunohistochemistry were also sought. RESULTS: Nuclear D11 staining appears to be highly specific for normal adrenocortical cells and related tumors. Nuclear D11 positivity was demonstrated in 44% of ACC and was restricted to well-differentiated tumors. No cytoplasmic or nuclear D11 staining was observed in adrenomedullary tumors. D11 reactivity confined to the cytoplasm was found in 5 of 18 adrenal metastases, in all 20 hepatocellular carcinomas tested, in 3 of 5 lung carcinomas, and in 1 of 50 primary renal cell carcinomas. Patients with nuclear D11 immunostaining were initially seen with metastases less often and survived longer than those with no nuclear D11 immunostaining (P < 0.05). CONCLUSIONS: Nuclear D11 immunoreactivity may help to differentiate ACC from intraadrenal metastases and adrenomedullary tumors. This also selects a group of ACC patients with a more favorable outcome.
Adolescent↗
The role of sulfhydryl groups and calcium in the mercuric chloride-induced inhibition of glutamate uptake in rat primary astrocyte cultures.
Inhibition by mercuric chloride (MC) of the astrocytic uptake of the excitotoxic neurotransmitter L-glutamate (L-GLU) has been postulated to contribute to MC neurotoxicity. In the present study, we analyzed the ability of two sulfhydryl (SH)-protecting agents: a cell membrane non-penetrating compound-reduced glutathione (GSH), and the membrane permeable dithiothreitol (DTT), to reverse the inhibitory action of MC on the initial rate of uptake of radiolabelled GLU (100 microM) in primary cultures of rat astrocytes. MC at 5 microM concentration reduced the uptake to 46% of control when present in the incubation medium during the 5 min of actual uptake, and to 27% of control when astrocytes were preincubated for 30 min in HEPES buffer containing MC prior to GLU uptake measurements. GLU uptake inhibition caused by 30 min preincubation with MC was partly relieved by the addition of 1 mM DTT during the actual 5 min uptake period. However, this inhibition could not be reversed by 1 mM GSH. Accordingly, it is postulated that the inhibitory effect exerted by MC on GLU uptake is associated with vulnerable SH groups located within, but not on the surface of the cell membrane. Neither 5 microM N-ethylmaleimide (NEM) nor 5 microM or 25 microM iodoacetate (IA) affected GLU uptake, indicating steric hindrance of the access of these two sulfhydryl reagents to the SH groups critical for the uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Recombinant hirudin: a new prospect in thrombosis.
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Animals↗
Biology of recombinant hirudin (CGP 39393): a new prospect in the treatment of thrombosis.
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Animals↗
A training course for doctors' receptionists.
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England↗
Identification of a subset of normal B cells with a Burkitt's lymphoma (BL)-like phenotype.
Fresh biopsy cells from cases of Burkitt's lymphoma (BL) display a homogeneous cell surface phenotype. The cells were found to be reactive with the pan B cell marker B1, and consistently co-expressed the BL-associated glycolipid antigen, BLA, and the common acute lymphoblastic leukemia antigen, CALLA, but lacked the B cell "activation" antigens characteristically expressed on EB virus-transformed normal B cells. Microscopic and cell sorter analysis of cells isolated from a series of fresh normal tonsils have identified a subpopulation of normal B cells carrying the same cell surface markers. That BLA and CALLA could be co-expressed on individual B cells was demonstrated by two-color immunofluorescence (IF) of tonsils in suspension, and immunoperoxidase (IP) staining of serial tonsil sections. These BLA+, CALLA+, "activation" antigen- cells were further characterized as B1+, sIgM+, sIgD-, C3d/EB virus receptor+ and were susceptible to virus-induced transformation in vitro. IF studies on Percoll-fractionated tonsillar cell populations and direct examination of IP-stained tonsil semi-thin sections indicated that the BLA+, CALLA+ cells were localized in germinal centers. Their morphological characteristics matched those of BL cells, and their location within germinal centers was consistent both with the known phenotype of germinal center tonsillar B cells and with the description of BL as a proliferation of centroblasts. We suggest that this population of tonsillar germinal center B cells provides the normal counterpart of BL tumor cells.
Antibodies, Monoclonal↗
Acid secretory capacity and plasma gastrin concentration after administration of omeprazole to normal subjects.
In a randomized double-blind study, two groups of eight healthy volunteers received either placebo or omeprazole 40 mg o.m. for 14 days. Fasting plasma gastrin concentration and peak acid output in response to a maximal intravenous dose of pentagastrin were measured before, during and after the 14 days of treatment. Omeprazole caused a 68% (mean) decrease in the peak acid output when measured 24 hours after the last dose, with a simultaneous increase in the fasting plasma gastrin concentration. When measured 1, 2, 3 and 8 weeks after cessation of treatment, there was no significant difference in the peak acid output between the two groups. The study demonstrates that there is no increase in the acid production capacity after 2 weeks of treatment with omeprazole. Thus it would appear that the rise in the plasma gastrin concentration during short-term treatment with omeprazole does not induce parietal cell hypertrophy or hyperplasia.
Adult↗