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Biomedical subjects

S Frias

Publications and source records attributed to S Frias.

11 recordsLinked to original sources
PubMed2002

The clastogenic response of the 1q12 heterochromatic region to DNA cross-linking agents is independent of the Fanconi anaemia pathway.

Fanconi anaemia (FA) is a rare genetic syndrome of cancer susceptibility characterized by spontaneous and induced chromosome fragility, especially after treatment with cross-linking agents. Recent investigations showed interactions between FA proteins and chromatin remodelling factors. To investigate a potential uneven distribution of the FA pathway through the human genome depending on chromatin conformation, we have analysed chromosome breakage in the largest constitutively heterochromatic region in the human genome, the 1q12 band, in lymphocytes from FA patients, carriers and healthy controls after treatment with the cross-linking agents mitomycin-C (MMC) and diepoxybutane (DEB). As expected, a higher level of MMC-induced cytotoxicity and chromosome breakage was observed in cells from FA patients when compared with normal controls and carriers. However, the increase in 1q12 breakage after increasing concentrations of MMC was of a similar magnitude in FA patients, carriers and controls. Similarly, DEB induced a high level of overall genome chromosome fragility in cells from FA patients when compared with controls with no parallel increase in chromosome breaks specifically involving the heterochromatic band 1q12. We therefore conclude that, unlike the overall genome, the sensitivity of chromosome 1 constitutive heterochromatin to the chromosome breaking activity of cross-linking agents is independent of a functional FA pathway, indicating that the action of the FA pathway is unevenly distributed through the human genome.

Case-Control Studies↗
PubMed1999

Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport.

The fate of free cholesterol released after endocytosis of low-density lipoproteins remains obscure. Here we report that late endosomes have a pivotal role in intracellular cholesterol transport. We find that in the genetic disease Niemann-Pick type C (NPC), and in drug-treated cells that mimic NPC, cholesterol accumulates in late endosomes and sorting of the lysosomal enzyme receptor is impaired. Our results show that the characteristic network of lysobisphosphatidic acid-rich membranes contained within multivesicular late endosomes regulates cholesterol transport, presumably by acting as a collection and distribution device. The results also suggest that similar endosomal defects accompany the anti-phospholipid syndrome and NPC.

Animals↗
PubMed1997

Delayed repair of DNA damage by ionizing radiation in cells from patients with juvenile systemic lupus erythematosus and rheumatoid arthritis.

We used a single-cell alkaline gel electrophoresis (SCAGE) assay to study repair of primarily single-stranded DNA breaks after in vitro exposure to ionizing radiation in cells from children with systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis (JRA), systemic sclerosis (SSc) and dermatomyositis. Peripheral blood lymphocytes from patients with SLE, JRA and SSc had significantly greater DNA damage after irradiation with 1.5 Gy and 30 min incubation (i.e. repair time) than did those from controls, as assessed by the length of the migrating DNA comet. The mean comet tail lengths were: SLE, 42 microns; JRA, 40 microns; and SSc, 36 microns. Each of these was significantly different from controls, which had a mean comet tail length of 18 microns (P < 0.001, < 0.001 and < 0.05, respectively). Cells from patients with dermatomyositis had an average comet tail length of 22 microns and were not significantly different from controls. Understanding the etiology of the delay in DNA repair in these diseases may provide insight into disease pathogenesis.

Adolescent↗
PubMed1996

Effect of hydroxyurea and normal plasma on DNA synthesis in lymphocytes from Fanconi anemia patients.

Fanconi anemia (FA) is characterized at the cellular level by a high frequency of spontaneous chromosomal aberrations; crosslinking agents cause an abnormal increase in the frequency of chromosomal damage, and semiconservative DNA synthesis is severely inhibited. Deoxyribonucleotides are needed in both semiconservative and repair DNA synthesis. To investigate the involvement of deoxyribonucleotide pools in the inhibition of DNA synthesis in FA, we evaluated the effect on FA lymphocytes of hydroxyurea (HU), an inhibitor of ribonucleotide reductase which is known to alter the intracellular levels of deoxyribonucleotides. To achieve this goal, lymphocyte cultures of 4 FA patients and 4 normal individuals were used. Cultures were treated with HU and/or mitomycin C and normal human plasma. All cultures were processed to detect the number of DNA synthesizing nuclei by autoradiography. Scoring of 2000 nuclei for each kind of culture every 6 h in the last 24 h of incubation showed that, in long incubation periods, DNA synthesis in FA is largely inhibited by HU and this hypersensitivity may be partially decreased by addition of normal human plasma. It is known that recovery from damage induced by HU involves several enzymes such as flavin oxido-reductase, superoxide dismutase and catalase which are involved in the production or scavenging of O2 radicals; FA cells are deficient in the detoxification of oxygen and this could explain the response of FA cells to HU.

Cells, Cultured↗
PubMed1994

Tetrasomy 18p in two cases confirmation by in situ hybridization.

Two cases with an extra small metacentric chromosome are described. Classic cytogenetic analysis was insufficient for identification of the marker origin. High resolution banding and fluorescence in situ hybridization (FISH) using a chromosome specific painting probe indicated that both marker chromosomes originated from chromosome 18. The correlation between phenotype, cytogenetics and FISH results allowed us to conclude that the patients are tetrasomic for 18p. A comparison of the clinical features of our two patients with other twelve previously reported patients where tetrasomy 18p was confirmed, is also presented.

Aneuploidy↗
PubMed1991

Effect of mitomycin C and bromodeoxyuridine on Fanconi anemia lymphocytes.

The authors studied the effect of mitomycin C (MMC) and bromodeoxyuridine (BrdU) on the induction of chromosome aberrations on lymphocytes of four patients with Fanconi anemia (FA) and of one normal subject. A control culture and six experiments were designed to test the possible synergic effect of MMC and BrdU. Their results revealed no evidence of MMC-BrdU synergism on the induction of chromosome aberrations in FA lymphocytes. However, chromosomes showed more damage when FA cells were harvested 24 h after MMC stress than when cells were harvested shortly after treatment. This can be explained by a DNA repair defect or by a toxic effect of oxygenation of cells during the procedure.

Bromodeoxyuridine↗
PubMed1988

Mitomycin C effect on Robertsonian translocations.

Centromeric breaks and dissociation of Robertsonian translocations have been suggested to be the cause of a few cases of mosaicism. One possible explanation for dissociation could be that the point of reunion of the two acrocentrics would be a structurally fragile site. Mitomycin C (MMC) treatment of lymphocyte cultures from 6 patients having a Robertsonian translocation showed that in cases 1 and 2, who were already mosaics, MMC induced a statistically significant increase of the number of cells with the dissociated translocation. In the remaining cases a preferential centromeric break on the translocation was observed, indicating instability of the region. The relationship of monocentric and dicentric translocations, the viability of the cells resulting from the dissociation, and the clinical implications are discussed.

Cell Line↗
PubMed1984

Interstitial deletion of long arm of chromosome 13.

The case is presented of a patient with the karyotype 46,XX,del(13q)(pter----q22::q32----qter) confirmed by densitometry and a phenotype of mental and growth deficiency, hypotonia, hypertelorism, ptosis, broad nasal bridge, protruding upper incisors, short neck, dislocation of the hip, hypoplasia of the thumbs, fusion of fourth and fifth metacarpal bones and syndactyly of toes. The findings are compared with those of well documented cases with a similar deleted segment of the long arm of chromosome 13. Although it seems obvious that a clinical syndrome for the distal deletion 13q appears to exist more studies with banded chromosomes are needed.

Abnormalities, Multiple↗