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Biomedical subjects

G Brun

Publications and source records attributed to G Brun.

At least 19 recordsLinked to original sources
PubMed1992

V-src-induced-transcription of the avian clusterin gene.

We have isolated the avian gene T64 corresponding to the mammalian clusterin, on the basis of high accumulation of its template mRNA in cells infected with oncogenic retroviruses. Since the clusterin was shown to have a protective effect against the immune system, its induction by oncogenic viruses is of major biological importance. The unique, short 5 kb-long T64 genomic locus is inactive in normal quail embryo fibroblasts in primary culture whereas it shows a high transcriptional activity after transformation by the Rous sarcoma virus. The 963 bp-long 5' flanking region is sufficient to drive the transcription of the chloramphenicol acetyltransferase reporter gene in a thermodependent manner when a thermosensitive version of pp60v-src is used. Deletion and point mutation analyses of the promoter show that the v-src response requires at least two separate elements: PUR and AP-1, located respectively at positions -167 to -152 and -25 to -19 relative to the single transcription initiation site. In addition, the binding of specific nuclear factors to these responsive elements correlates with the T64 promoter activation.

Animals↗
PubMed1992

The long repetitive polypurine/polypyrimidine sequence (TTCCC)48 forms DNA triplex with PU-PU-PY base triplets in vivo.

Polypurine/polypyrimidine repetitive sequences occur with high frequency in eucaryotic genomes, particularly around transcription units. Since such sequences are known to adopt triple stranded-structures under appropriate conditions in vitro, it is of major interest to know if they occur in vivo, and thus if they can have some biological importance by inducing structural constraints in the genomic DNA. To this end, we have isolated a (TTCCC)48 sequence, present in the promoter of an avian gene, and tested its ability to form PU-PY-PY and PU-PU-PY triple helices in vitro, through the oligonucleotide gel shift technique and single strand-specific nuclease footprinting. We have then developed an oligonucleotide protection assay, which can be adapted to in vivo investigations. This strategy leads us to conclude that in vivo conditions allow preponderant formation of triplex of the PU-PU-PY class.

Animals↗
PubMed1992

Substances in human urine that strongly inhibit bacterial mutagenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and related heterocyclic amines.

Extracts of human urine were shown to contain substances that strongly inhibited the liver S9-mediated mutagenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in Salmonella typhimurium TA98 strain in a liquid incubation assay. The inhibitory effect was unrelated to cytotoxicity and was similar with urine extracts from smokers and non-smokers. Under similar assay conditions, the mutagenicity of the related amino-imidazoazaarenes, 2-amino-3-methyl-imidazo[4,5-f]quinoline, 2-amino-3,8-dimethylimidazo[4,5-f]-quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline was also found to be strongly inhibited by urine extracts. Decreased or enhanced mutagenicity was seen with 2-acetyl-aminofluorene and 2-aminoanthracene depending on the type of assay, and the time of incubation in liquid medium. A weak inhibition of the mutagenicity of 2-nitrofluorene, a direct-acting mutagen, was observed only after a short incubation time. Mutagenicity of 4-nitroquinoline N-oxide was not altered by the presence of urine extracts at concentrations shown to be inhibitory for the mutagenicity of heterocyclic aromatic amines. Our data suggest that the inhibitory substances in urine act through their capacity to non covalently bind the parent heterocyclic and aromatic amines, thus affecting their availability in aqueous medium for diffusion into liver microsomes where metabolic activation takes place.

Amines↗
PubMed1992

Immunohistochemical detection of pulmonary cytochrome P450IA and metabolic activities associated with P450IA1 and P450IA2 isozymes in lung cancer patients.

The main polycyclic aromatic hydrocarbon-inducible cytochrome P450 was studied in lung tissue from 57 lung cancer patients by immunohistochemistry, using a monoclonal antibody (1-7-1) that recognizes P450IA1 and P450IA2 isozymes. The intensity of immunostaining was compared with the pulmonary activity of a P450IA1-dependent enzyme, aryl hydrocarbon hydroxylase (AHH), and with P450IA2-related metabolic activity estimated from the ratio of caffeine metabolites in urine. Immunostaining was not observed in peripheral lung tissue of nonsmokers or ex-smokers but was seen in the bronchiolar and alveolar epithelium of all patients who were smokers and had a peripheral carcinoma (16/16) and of 60% (10/17) of those who had a bronchial carcinoma. AHH activity was positively related to the intensity of immunostaining, and an almost 2-fold increase due to smoking was detected in the ratios of caffeine metabolites. These results demonstrate that tobacco smoke induces P450IA1 in the lung and probably P450IA2 in the liver, and suggest a role for certain metabolic phenotypes of P450IA1 in peripheral pulmonary carcinoma.

Adenocarcinoma↗
PubMed1991

Overexpression of c-jun, junB, or junD affects cell growth differently.

The coding sequences of murine c-jun, junB, or junD, which code for proteins with practically identical dimerization and DNA binding properties, were introduced into a nondefective retroviral vector, and the phenotype of primary avian fibroblasts chronically infected with each of these viruses was studied. Cells expressing c-jun grew in low-serum medium and developed into colonies in agar, two properties characteristic of in vitro transformation. Cells expressing junB grew in agar, with a reduced efficiency as compared to c-jun, but did not grow in low-serum medium. Finally, no effect of junD expression on cell growth was observed. These different phenotypes suggest that these three closely related transcription factors play distinct roles during normal cell growth. Analysis of c-jun deletion mutants and of c-jun/junB and c-jun/junD chimeric genes showed that the N-terminal portion (amino acids 2-168) of the c-Jun protein that is involved in transcriptional activation is required for efficient transformation. On the contrary, cells expressing a truncated mouse c-Jun lacking this N-terminal domain grew slower than normal embryo fibroblasts. The reduced growth rate may be related to the finding that expression of the intact or the truncated mouse c-jun repressed the endogenous avian c-Jun homologue, suggesting that functional c-Jun product is required for normal cell growth.

Amino Acid Sequence↗
PubMed1991

Genotoxicity of ochratoxin A and structurally related compounds in Escherichia coli strains: studies on their mode of action.

Ochratoxin A, ochratoxin alpha (its major metabolite in rodents) and seven structurally related substances were assayed for SOS DNA repair inducing activity in Escherichia coli PQ37 strain. At a concentration range of 0.1-4 mM, ochratoxin A, chloroxine, 5-chloro-8-quinolinol, 4-chloro-meta-cresol and chloroxylenol were found to induce SOS-DNA repair in the absence of an exogenous metabolic activation system. Ochratoxin B, ochratoxin alpha, 5-chlorosalicylic acid and citrinin were inactive, but all except ochratoxin alpha were cytotoxic. Thus, the presence of a chlorine at C-5 in ochratoxin A and in other analogues appears to be one determinant of their genotoxicity. In order to ascertain whether this reactivity involves a bacterial glutathione conjugation reaction, we investigated the modifying effect on the genotoxicity of ochratoxin A of amino oxyacetic acid, an inhibitor of cysteine conjugate beta-lyase. Amino oxyacetic acid decreased the cytotoxicity of ochratoxin A but did not alter its genotoxic activity, suggesting the formation of a cytotoxic thiol-containing derivative. The way in which ochratoxin A and some of its active analogues induce SOS DNA repair activity was further investigated in E. coli PQ37 and in three derived strains (PQ300, OG100 and OG400, containing deletions within the oxy R regulon). The response in PQ37 strain was measured in the absence and presence of Trolox C, a hydrosoluble form of vitamin E. Trolox C completely quenched the genotoxicity of ochratoxin A, which was no greater in mutated than in wild type strains. These results implicate an ochratoxin A-derived free radical rather than reduced oxygen species as genotoxic intermediate(s) in bacteria.

Aminooxyacetic Acid↗
PubMed1991

[Endometrial resection for metrorrhagia: 45 cases].

Treatment of metrorrhagia has recently been modified because of the use of the hysteroscope which allows two methods to be used: diathermy and endometrial ablation or laser destruction of the endometrium. This retrospective study of ablation of the endometrium was carried out on 45 cases: the patients had excessive bleeding or menorrhagia that had been developing and in an average about 18 months. The mean age of the patients was 48 years with a deviation of 7 years. More than half the women were overweight, a quarter weighing more than 80 kgs with a height of 1 metre 60. A third of the cases had pathology associated with the condition. In 24 cases endometrial resection was carried out by itself but in 21 cases endometrial resection was accompanied with removal of polyps or of submucous myomata. The results were: There was no anaesthetic complication or accident; The operation was complicated only once by perforation of a cornu; Bleeding stopped completely in 94% of cases with an average duration of follow-up of 7 1/2 months; Control hysterosalpingography showed synechiae in 70% of the cases; The histology showed a preponderance of mucosal hyperplasia and of small fibroids. The authors point out: that it is important to learn carefully the operative technique to lessen the risks of complications, but the clinical results compare with the best in the literature but with the price to pay of a high incidence of synechiae. The following questions will have to be answered in the future: What is the risk of cancer after endometrial ablation? Is it possible to avoid synechiae so that the whole cavity of the uterus can be assessed later? What is the role of medical as opposed to surgical treatment in heavy bleeding at the time of the menopause?

Adult↗
PubMed1990

Down regulation by p60v-src of genes specifically expressed and developmentally regulated in postmitotic quail neuroretina cells.

The avian neuroretina (NR) is composed of photoreceptors and different neurons that are derived from proliferating precursor cells. Neuronal differentiation takes place after terminal mitosis. We have previously shown that differentiating NR cells can be induced to proliferate by infection with Rous sarcoma virus (RSV) and that cell multiplication requires expression of a functional v-src gene. We speculated that the quiescence of NR cells could be determined by specific genes. Cell proliferation could then result from the negative regulation of these genes by the v-src protein. By differential hybridization of a cDNA library, we isolated eight clones corresponding to genes expressed in postmitotic NR cells from 13-day-old quail embryos, transcriptional levels of which are significantly reduced in NR cells induced to proliferate by tsNY68, an RSV mutant with temperature-sensitive mitogenic activity. Partial sequencing analysis indicated that one RNA encoded the calmodulin gene, whereas the other seven showed no similarity to known sequences. By using v-src mutants that induce NR cell proliferation in the absence of transformation, we showed that transcription of six genes was negatively regulated by the v-src protein and that of four genes was correlated with NR cell quiescence. We also report that a subset of genes are specifically transcribed in neural cells and developmentally regulated in the NR. These results indicate that the v-src protein regulates expression of genes likely to play a role in the control of neural cell growth or differentiation.

Animals↗
PubMed1990

Overexpression of avian or mouse c-jun in primary chick embryo fibroblasts confers a partially transformed phenotype.

The coding sequences of avian (quail) or murine c-jun proto-oncogenes were introduced into a non-defective retroviral vector derived from Rous sarcoma virus (RSV) in which c-jun replaces v-src. Primary avian fibroblasts chronically infected with either one of these viruses exhibit some phenotypic traits characteristic of RSV-transformed cells, including sustained growth in low serum medium and ability to develop colonies from single cells in agar, even though they are still of normal morphology and contact inhibited. This altered growth control correlates with enhanced AP1-specific DNA binding activity as well as with higher levels of c-Jun products. Unexpectedly, repression of the endogenous c-Jun product is observed in cells overexpressing murine c-Jun. Cells expressing the avian and the murine c-Jun products display qualitatively similar phenotypes; nevertheless, for every transformed trait considered, the murine c-jun seemed more potent than its quail homologue. These data suggest that the avian or murine c-jun proto-oncogenes may trigger a subset of the 'transforming functions' normally induced by v-src, and which are more specifically related to growth in low serum and in the absence of solid support.

Amino Acid Sequence↗
PubMed1989

Levels of mutagens in the urine of smokers of black and blond tobacco correlate with their risk of bladder cancer.

Levels of urinary mutagens, thioethers, N-nitrosamino acids, nitrate, nicotine, cotinine and creatinine were measured in 21 non-smokers, 26 smokers of blond tobacco, 9 smokers of black tobacco and 5 smokers of both types of tobacco, all eating a similar diet. Results were expressed either per 24 h urine or per mmol creatinine. The sum of urinary nicotine and cotinine levels (N + C) was used as a measure of exposure to the number of cigarettes smoked. Statistically significant positive dose-effect relationships were obtained between the urinary N + C levels and (i) the number of revertants (Salmonella typhimurium TA98, with a metabolic activation system); (ii) the concentration of thioethers; (iii) the levels of N-nitrosoproline or the sum of all nitrosamino acids excreted and (iv) the amount of urinary nitrate. No such correlation was found between N + C levels and induction potency in the SOS chromotest. A linear dose-effect relationship between urinary mutagenicity (i.e. log revertants of S. typhimurium TA98) and N + C levels or number of cigarettes per day was established for smokers of blond tobacco. After adjustment for N + C levels, the urine of smokers of black tobacco contained twice as much mutagenic material as did the urine of blond tobacco smokers (P = 0.02). For other exposure markers, no statistically significant difference was found between the two types of smokers. Epidemiological studies have shown that the risk of urinary bladder cancer is 2.5 times higher in smokers of black tobacco than in blond tobacco. Therefore, our findings on urinary mutagenicity provide experimental evidence that the type of tobacco is the factor responsible for the observed difference in risk and that smoking of black as compared to blond tobacco results in a higher exposure of the urinary bladder to genotoxic hence potentially carcinogenic substances.

Cotinine↗
PubMed1989

[Another case of Sertoli-Leydig cell ovarian tumor (arrhenoblastoma). Review of the literature].

In reporting another case of Sertoli-Leydig cell tumor (SLCT) treated by conservative management, the principal characteristics of these tumors are reviewed and a general review is made: SLCT (arrhenoblastomas) are rare endocrine tumors (1 p. cent of tumors of the ovary). They most frequently occur in young women, are unilateral in 98 p cent of cases, and are manifest after a long period by endocrine signs (75 p. cent of cases) whose most frequent combination is: amenorrhea-hirsutism-hoarse voice. They are classified in four histological types which have different prognoses. Their potential development varies and is variously assessed: these are tumors with a low incidence of malignancy (mean 18 p. cent). Under certain conditions, this permits the institution of conservative therapy conserving future fertility. Malignant types of tumors are treated in the same way as other malignant ovarian tumors: surgery is the main tool; radiotherapy is often insufficient and chemotherapy often provides remission more frequently than cure (80 p. cent 5 year survival).

Adult↗
PubMed1989

Expression of a novel gene encoding a 51.5 kD precursor protein is induced by different retroviral oncogenes in quail neuroretinal cells.

A cDNA clone, named T64, was isolated from a library of quail neuroretinal cells transformed by a thermosensitive v-src mutant of Rous sarcoma virus. it corresponds to the most abundant mRNA with thermodependent expression in these cells. T64 accumulation also correlated with pp60v-src activity in other cell types transformed by RSV, such as fibroblasts and myoblasts, but was independent of the proliferative state of the cells, indicating that T64 is rather implicated in the process of morphological transformation. Nuclear run on experiments showed that the accumulation of T64 mRNA in transformed neuroretinal cells is the consequence of an increased transcription rate. Enhancement of T64 expression on QNR cells was also achieved by infection with avian retroviruses harboring other oncogenes with protein kinase activity such as v-fps and v-mil. The 1.6 kb T64 mRNA was detected in vivo in a few quail tissues at levels 50-200-fold lower than in RSV-infected cells. DNA sequencing of the T64 cDNA revealed an open reading frame encoding a 449 amino acids protein with a typical N-terminal signal peptide and with significant amino acid sequence homology with a rat-secreted protein.

Amino Acid Sequence↗
PubMed1988

[Uterine rupture after tubal reimplantation].

The authors report a case of rupture of the right cornu of the uterus in the ninth month of pregnancy in a woman who had had her right tube implanted into her uterus. This complication is considered, in the discussion, to be rare. It is very difficult to prevent it happening during pregnancy. It would seem that a prophylactic caesarean operation should be carried out if the insertion of the placenta is in the area of the implantation.

Adult↗