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Biomedical subjects

A Vega

Publications and source records attributed to A Vega.

At least 19 recordsLinked to original sources
PubMed2002

Analysis of BRCA1 and BRCA2 in breast and breast/ovarian cancer families shows population substructure in the Iberian peninsula.

An estimated 5-10% of all breast and ovarian cancers are due to an inherited predisposition, representing a rather large number of patients. In Spain 1/13-1/14 women will be diagnosed with breast cancer during their lifetime. Two major breast cancer genes, BRCA1 and BRCA2, have been identified. To date, several hundred pathogenic mutations in these two genes have been published or reported to the Breast Cancer Information Core, BIC database (http://www.nhgri.nih.gov/Intramural_research_Lab transfer/Bic/index.html). In the present study, 30 Spanish breast and breast/ovarian cancer families (29 from Galicia, NW Spain, and 1 from Catalonia, NE Spain) were screened for mutations in the BRCA1 and BRCA2 genes. The analysis of these genes was carried out by SSCP for shorter exons and direct sequencing in the case of longer ones. Mutations were found in 8 of the 30 families studied (26.66%). It is important to note that all mutations were detected within the BRCA1 gene: 330 A>G, 910_913delGTTC, 2121 C>T, 3958_3962delCTCAGinsAGGC, and 5530 T>A. The BRCA1 330 A>G mutation was found in four unrelated families and accounted for 50% of all identified mutations.

Adult↗
PubMed2001

Rare HRAS1 alleles are a risk factor for the development of brain tumors.

BACKGROUND: The highly polymorphic HRAS1 minisatellite locus, located 1 kilobase downstream from the H-ras1 gene, has been associated with increased susceptibility to a variety of cancers. Microsatellite instability (MI), another molecular abnormality observed in human neoplasms, most likely reflects an increased mutation rate and also is thought to underlie cancer predisposition. The purpose of this study was to investigate the association between rare HRAS1 alleles and brain tumors and to correlate the HRAS1 allelotype with MI and clinicopathologic features. METHODS: Ninety-four patients with primary brain tumors (52 gliomas, 32 meningiomas, and 10 schwannomas) and 109 healthy control individuals were studied. The size of HRAS1 alleles was determined by fluorescent detection in an automated DNA sequencer. The interspersion pattern was assessed by the minisatellite variant repeat-polymerase chain reaction technique. RESULTS: Twenty of 94 (21.28%) patients with brain tumors had at least one rare allele, compared with 13 of 109 (11.92%) in the control population (Fisher exact test; P = 0.0329). The presence of rare alleles was associated with an increased risk of brain tumors (odds ratio, 1.99; 95% confidence interval, 0.93-4.27). The overrepresentation of rare alleles in tumor patients mainly reflects the higher frequency observed in the glioma group (P = 0.0086). The authors did not detect association between the presence of rare HRAS1 alleles and MI in their series. No significant difference in the distribution of these alleles was found when tumors were compared according to other clinicopathologic variables. CONCLUSIONS: The presence of rare HRAS1 alleles is associated with an increased risk for the development of glial neoplasms (OR = 2.72; 95% CI, 1.17-6.32). The lack of association between rare HRAS1 polymorphisms and MI suggests that these two genetic factors are not likely to be expression of the same underlying defect.

Alleles↗
PubMed2001

The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript.

In a BRCA1 screening in familial breast cancer carried out in different centres in Spain, France, and United Kingdom, a missense mutation 330A>G which results in a Arg to Gly change at codon 71 (R71G) was independently identified in 6 families, all of them with Spanish ancestors. This residue coincides with the -2 position of the exon 5 donor splice site. We further investigated the effect of this base substitution on the splicing of BRCA1 mRNA. The sequence analysis of the cDNA indicated that 22 bp of exon 5 were deleted, creating with the first bases of exon 6 a termination codon at position 64, which results in a truncated protein. The BRCA1 haplotype of the R71G carrier patients and Spanish controls was analysed by use of six microsatellites located within or near BRCA1. Our results are consistent with the possibility that these families shared a common ancestry with BRCA1 R71G being a founder mutation of Spanish origin.

Age of Onset↗
PubMed2001

Mutation analysis of the adenomatous polyposis coli (APC) gene in northwest Spanish patients with familial adenomatous polyposis (FAP) and sporadic colorectal cancer.

Germline mutations in the tumor-suppresor APC gene are associated with hereditary familial adenomatous polyposis (FAP) and somatic mutations are common in sporadic colorectal cancer. In this study, we report the identification of three novel germline mutations: 1682-1683insA, 3252-3253insAT, 3544A>T and a new somatic mutation 4130-4131delTT, all giving rise to truncated APC proteins. The majority of the mutations we found originate a truncated APC protein and cause the FAP phenotype. However, special attention must be given to the missense mutations Asp1822Val and Ser2621Cys since their segregation with the FAP phenotype is questionable. In our FAP families we did not find any genetical alterations at codon 1309, being this mutation the most frequent reported in APC. Differences in the recurrence of pathological mutations in APC could exist among populations. However, epidemiological studies must be performed to confirm this hypothesis.

Adenomatous Polyposis Coli↗
PubMed2001

Length variability and interspersion patterns of the HRAS1 minisatellite: a new approach for the reconstruction of human population relationships.

During recent years the HRAS1 minisatellite has been analysed by several authors because of its putative association with cancer susceptibility. The aim of this report is to test the usefulness of this minisatellite in investigating human population relationships. We have studied 370 chromosomes from two well-differentiated populations: Galicia (North-west Iberia) and South-east Africa, as well as available data on allele length gene frequencies. The fragment analysis results show a strong tendency to differentiate between non-African and African populations. In spite of the usefulness of fragment analysis, the minisatellite variant repeat (MVR) approach of the HRAS1 minisatellite appears to be a more powerful method for use in human population studies, due to the high level of diversity of its interspersion pattern structures. In addition, this approach has allowed us to define some new structural characteristics of this minisatellite. Four different major groups of human HRAS1 minisatellite alleles could be distinguished following a structural criterion based on the MVR code. Furthermore, the characterisation of the HRAS1 minisatellite in chimpanzees revealed clear differences when compared to humans, not only with respect to the allele size but also to the internal structure.

Africa, Southern↗
PubMed2001

Identification of Mycobacterium marinum in sea-urchin granulomas.

BACKGROUND: Sea-urchin granuloma is a chronic granulomatous reaction arising after injury with sea-urchin spines. Classified as an allergic foreign-body type of granuloma, it is believed to be a delayed-type reaction to an as yet unidentified antigen. In a clinicopathological study, 50 biopsy specimens from 35 patients diagnosed as having sea-urchin granuloma caused by Paracentrotus lividus, we found different inflammatory patterns that in some cases suggested a mycobacterial infection. OBJECTIVES: To investigate and identify mycobacterial DNA in formalin-fixed and paraffin-embedded skin biopsy specimens diagnosed as sea-urchin granulomas. METHODS: A search combining polymerase chain reaction amplification using Mycobacterium genus-specific primers, and subsequent restriction enzyme analysis enabling identification to the species level, was performed in 41 samples. RESULTS: Amplification of a 924-bp DNA fragment encoding mycobacterial 16S rRNA gene was positive in eight biopsy specimens from seven patients (21%). M. marinum-specific restriction patterns were identified in three samples. CONCLUSIONS: Although further controlled studies are necessary, from these data it would appear that mycobacteria may play a pathogenic role in some cases of sea-urchin granuloma.

Adolescent↗
PubMed2000

Synthesis and biological evaluation of 2,5-dihydropyrazol.

A novel series of 2,5-dihydropyrazolo[4,3-c]quinolin-3-ones has been prepared. These compounds showed good PDE 4 inhibitory activity and weak affinity for rolipram's binding site. They also exhibited a good anti-inflammatory profile without emetic side effects.

Animals↗
PubMed2000

A conformation change in the carboxyl terminus of Alzheimer's Abeta (1-40) accompanies the transition from dimer to fibril as revealed by fluorescence quenching analysis.

Alzheimer's disease is characterized by the presence of insoluble, fibrous deposits composed principally of amyloid beta (Abeta) peptide. A number of studies have provided information on the fibril structure and on the factors affecting fiber formation, but the details of the fibril structure are not known. We used fluorescence quenching to investigate the solvent accessibility and surface charge of the soluble Abeta(1-40) dimer and amyloid fibrils. Analogs of Abeta(1-40) containing a single tryptophan were synthesized by substituting residues at positions 4, 10, 34, and 40 with tryptophan. Quenching measurements in the dimeric state indicate that the amino-terminal analogs (AbetaF4W and AbetaY10W) are accessible to polar quenchers, and the more carboxyl-terminal analog AbetaV34W is less accessible. AbetaV40W, on the other hand, exhibits a low degree of quenching, indicating that this residue is highly shielded from the solvent in the dimeric state. Correcting for the effect of reduced translational and rotational diffusion, fibril formation was associated with a selective increase in solvent exposure of residues 34 and 40, suggesting that a conformation change may take place in the carboxyl-terminal region coincident with the dimer to fibril transition.

Alzheimer Disease↗
PubMed2000

Rapid real-time fluorescent PCR gene dosage test for the diagnosis of DNA duplications and deletions.

BACKGROUND: Current methods to determine gene dosage are time-consuming and labor-intensive. We describe a new and rapid method to assess gene copy number for identification of DNA duplications or deletions occurring in Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), respectively. METHODS: We studied 16 patients with HNPP, 4 with CMT1A, and 49 control subjects. We used real-time PCR on the LightCycler system with use of a single capillary tube and no post-PCR handling. A polymorphic fragment of the PMP22 gene was amplified to determine gene dosage for heterozygous samples. The presence of two alleles was used to indicate that no deletion was present in HNPP samples. The ratio obtained between the areas under each allele melting curve of heterozygous CMT1A samples was used to determine whether the sequence was duplicated or normal. Homozygous samples required a competitive gene dosage test, where the ratio between the areas under the melting curves of the target DNA of samples and of the competitor molecule was used to determine whether the target sequence was duplicated, deleted, or normal. Samples from HNPP, CMT1A, and controls were analyzed. RESULTS: Area ratios were approximately 0.6, 1.0, and 2.0 for HNPP, control, and CMT1A samples, respectively. The results agreed with those obtained by Southern blotting and microsatellite analysis in the same samples. CONCLUSIONS: Direct and competitive real-time fluorescent PCR can differentiate one, two, or three copies of the target DNA. The method described is sensitive and accurate for detection of CMT1A duplications and HNPP deletions and is faster and easier than current methods.

Charcot-Marie-Tooth Disease↗
PubMed1998

Design, synthesis, and biological activities of new thieno[3,2-d] pyrimidines as selective type 4 phosphodiesterase inhibitors.

A common pharmacophore for compounds structurally related to nitraquazone has been derived. Using this pharmacophore, new structures have been designed, synthesized, and evaluated for their inhibitory potencies against cyclic adenosine 5'-monophosphate (cAMP) specific phosphodiesterase (PDE 4). From these compounds, 4-benzylamino-2-butylthieno[3,2-d]pyrimidine (4) was selected for optimization. The effects of changes to the lipophilic groups and the amino linkage on the PDE 4 activity have been investigated. As a result, some potent PDE 4 inhibitors, selective with respect to PDE 3, have been identified. A selected group of compounds have been further evaluated for their ability to displace [3H]rolipram from its binding site and also to potentiate isoprenaline-induced cAMP accumulation in isolated guinea pig eosinophils. Of these, 2-butyl-4-cyclohexylaminothieno[3,2-d]pyrimidine (33) has an interesting profile, with an important improvement in PDE 4/[3H]rolipram ratio with respect to reference drugs, and good activity in cAMP potentiation, consistent with efficient cell penetration.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1998

Minisatellite variant repeat (MVR) analysis of the HRAS1 minisatellite locus.

Two alternative electrophoretic strategies were used to study the internal variation of the HRAS1 minisatellite after minisatellite variant repeat mapping (MVR-PCR) was carried out. While the use of automated sequencers with fluorescent based technology is ideal for analyzing fragment size, and therefore, for analyzing the repeat number, the use of polyacrylamide gels and silver staining is more appropriate for the analysis of internal variation. Thirteen different fragments ranging from 27 to 80 repeats were found in a sample from 80 healthy Caucasian individuals. By using MVR mapping we were able to detect heterozygotes which appear as homozygotes when fragment length analysis was used. As a result of this, the 13 alleles, which we had detected, increased to 16 alleles when MVR sequences were analyzed. The extremely conservative arrays of repeats allow us to infer the theoretical origin of rare alleles from a major group of specific alleles. The HRAS1 minisatellite has been extensively studied due to its association with cancer. However, the methodology used up to now has limited the scope of previous research. Our approach permits the identification of alleles in a fast and reliable way using their MVR codes, thus allowing association studies with cancer.

3' Untranslated Regions↗