E Abril

Hospital Universitario Virgen de las Nieves, Granata, Andalusia, Spain

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Publications (18)58.98 Total impact

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    ABSTRACT: Recently, several research groups have evaluated CAPN10 gene in polycystic ovarian syndrome (PCOS) patients and other phenotypes, including hirsutism or intermediate phenotypes of PCOS. Molecular genetic analysis of CAPN10 gene indicates that different alleles may play a role in PCOS susceptibility and could be associated with idiopathic hirsutism. However, these observations are not exempt from controversy, because independent studies cannot replicate these preliminary findings. We present a haplotype-phenotype correlation study of CAPN10 haplotypes in 148 women showing ecographically detected polycystic ovaries (PCO) combined with one or more of these clinical symptoms: amenorrhea or severe oligomenorrhea, hyperandrogenism, and anovulatory infertility, as well as 93 unrelated controls. We have reconstructed and analyzed 482 CAPN10 haplotypes in patients and controls. We detected the association of UCSNP-44 allele with PCO phenotype in the Spanish population (P = 0.02). In addition, we identified several CAPN10 alleles associated to phenotypic differences observed between PCO patients, such as the presence of hypercholesterolemia (haplotype 1121, P = 0.005), presence of hyperandrogenic features (P = 0.05), and familial cancer incidence (haplotype 1111, P = 0.0005). Our results confirm the association of UCSNP-44 allele with PCO phenotype in the Spanish population. Moreover, we have identified novel candidate risk alleles and genotypes, within CAPN10 gene, that could be associated with important phenotypic and prognosis differences observed in PCOS patients.
    Journal of Clinical Endocrinology &amp Metabolism 12/2003; 88(11):5529-36. · 6.43 Impact Factor
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    ABSTRACT: Polycystic ovary syndrome (PCOS) is characterized by chronic anovulation infertility, hyperandrogenemia, and frequently insulin resistance. This study investigated whether polymorphisms in the CAPN10 gene are related with PCOS etiology. The allelic frequencies and genotypes of CAPN10 polymorphisms UCSNP-44, 43, 19, and 63 were determined in 55 well characterized women with polycystic ovaries and 93 unrelated healthy controls using spectrofluorimetric analyses and real-time PCR. Our data indicate that CAPN10 UCSNP-44 allele is associated with PCOS in the Spanish population (P = 0.01). These results support a role of Calpain 10 gene in PCOS susceptibility in humans.
    Journal of Clinical Endocrinology &amp Metabolism 09/2002; 87(8):3971-6. · 6.43 Impact Factor
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    ABSTRACT: The inhibition of transcription factor functions was used to define their role in phorbol ester-induced cellular differentiation of a monocytic cell line, U937. We demonstrate a differential effect on cell adhesion and differentiation: antisense or competitive binding with double-stranded oligonucleotides antagonized the functions of AP-1, NF-kappaB, and PU.1 transcriptional factors. In the presence of phorbol 12-myristate 13-acetate (PMA), U937 cells attached to the plastic surface and cells were characterized by marked expression of beta2-integrin molecules on the cell surface. We show that the in vivo differentiation of U937 cells appears to occur normally in the absence of AP-1 activity. In contrast, the addition to the cell culture of phosphorothioate oligonucleotides that contained the NF-kappaB or PU.1 binding sites significantly inhibited U937 differentiation. The absence of NF-kappaB led to pleiotropic effects with a clear reduction in the expression of integrin and other lineage-specific myeloid antigens on the cell surface. In contrast, the absence of PU.1 had a more restricted effect on integrin expresion on the cell surface, probably as a result of blockage of CD18 gene expression.
    Experimental Hematology 03/1999; 27(2):353-64. · 2.91 Impact Factor
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    ABSTRACT: HC class I expression can be up-regulated by interferons (IFN) and other cytokines. Both IFNalpha and IFNgamma have been shown to exert their effects via a recently discovered signalling pathway by inducing tyrosine phosphorylation of their receptors. Receptors for interferons and other cytokines signal through the action of associated protein tyrosine kinases of the JAK family (Janus kinase) and latent cytoplasmic transcriptional activators from the STAT family (signal transducers and activators of transcription). Here we report a gastric adenocarcinoma cell line, AGS, that is defective in its response to either IFNalpha or IFNgamma. AGS cells display selective alterations only in MHC class I inducibility and not in constitutive MHC class I expression. In nuclear extracts of AGS cells, no binding activity to interferon-responsive elements (GAS/ISRE) was observed. We found that AGS cells showed an extremely low level of STAT1 expression, which may be responsible for the absence of biological response to IFN. Because STAT1-deficient cells are highly sensitive to infection by virus, the absence of these proteins may also contribute to the tumor phenotype, giving the tumor a selective advantage, by inhibiting cell growth suppression mediated by IFN and abetting escape from the T cell antitumor response.
    Cancer Immunology and Immunotherapy 11/1998; 47(2):113-20. · 3.64 Impact Factor
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    ABSTRACT: We studied the incidence of microsatellite instability (MI) in lesions defined as cervical intraepithelial neoplasia (CIN). The human papillomavirus (HPV) status of the tissues was also determined. DNA from tissue samples and autologous lymphocytes were studied for five loci located within or adjacent to the DNA mismatch repair genes. Replicate errors were detected in 7 out of 47 (14.8%) samples of cervical tissue from 24 women. Our results indicate that the defect in DNA repair-associated genes does not appear to be necessary for the selection of clones which progress from dysplasia to carcinoma. Although HPV DNA of highly oncogenic types (16/18) was detected in most cervical lesions and may be an important factor for MI, we also detected MI in two loci in HPV-negative normal tissue, indicating that further events can also be involved in mismatch repair defects.
    Journal of experimental & clinical cancer research: CR 10/1998; 17(3):361-6. · 1.50 Impact Factor
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    ABSTRACT: A new HLA-class-I altered phenotype is described in melanoma. This phenotype is the result of a combination of HLA-B-locus down-regulation and HLA-haplotype loss. The alteration was found in 2 melanoma cell lines generated from 2 patients; one was derived from an in vivo lesion (FM37) and the other was obtained after in vitro immunoselection (R22.2). The R22.2 cell line was isolated from FM55P, a cell line derived from a primary melanoma, after in vitro treatment with a heterologous HLA-A2-restricted cytotoxic-T-lymphocyte (CTL) clone. Two additional cell lines from patient 55 were obtained from 2 s.c. metastases (FM55M1 and FM55M2). Iso-electric focusing and flow-cytometric studies showed a significant reduction in the expression of both HLA-B alleles in all cell lines studied. The expression of HLA-B-locus products recovered completely after IFN-gamma treatment of FM55P, M1 and M2. In contrast, FM37 and R22.2 tumour cells showed an additional HLA defect: the absence of one HLA haplotype. Simple tandem-repeat polymorphism markers spanning chromosome 6 showed that DNA from the 2 samples (FM37 and R22.2) showed loss of heterozygosity (LOH). In both cases, homozygosity was observed on 6p, which maps the HLA region, the final consequence being a tumour cell that expressed a single HLA-class-I allele (HLA-A3 and HLA-A1 respectively). FM37 cells may thus reflect the in vivo counterpart of resistance to lysis by HLA-A2-restricted tumour-infiltrating lymphocytes.
    International Journal of Cancer 02/1998; 75(2):317-23. · 6.20 Impact Factor
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    ABSTRACT: A new HLA-class-I altered phenotype is described in melanoma. This phenotype is the result of a combination of HLA-B-locus down-regulation and HLA-haplotype loss. The alteration was found in 2 melanoma cell lines generated from 2 patients; one was derived from an in vivo lesion (FM37) and the other was obtained after in vitro immunoselection (R22.2). The R22.2 cell line was isolated from FM55P, a cell line derived from a primary melanoma, after in vitro treatment with a heterologous HLA-A2-restricted cytotoxic-T-lymphocyte (CTL) clone. Two additional cell lines from patient 55 were obtained from 2 s.c. metastases (FM55M1 and FM55M2). Iso-electric focusing and flow-cytometric studies showed a significant reduction in the expression of both HLA-B alleles in all cell lines studied. The expression of HLA-B-locus products recovered completely after IFN-γ treatment of FM55P, M1 and M2. In contrast, FM37 and R22.2 tumour cells showed an additional HLA defect: the absence of one HLA haplotype. Simple tandem-repeat polymorphism markers spanning chromosome 6 showed that DNA from the 2 samples (FM37 and R22.2) showed loss of heterozygosity (LOH). In both cases, homozygosity was observed on 6p, which maps the HLA region, the final consequence being a tumour cell that expressed a single HLA-class-I allele (HLA-A3 and HLA-A1 respectively). FM37 cells may thus reflect the in vivo counterpart of resistance to lysis by HLA-A2-restricted tumour-infiltrating lymphocytes. Int. J. Cancer 75:317–323, 1998. © 1998 Wiley-Liss, Inc.
    International Journal of Cancer 01/1998; 75(2):317 - 323. · 6.20 Impact Factor
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    ABSTRACT: The MAGE-1 gene, expressed in some tumors of different histological origins, codes for a tumor antigen recognized by cytotoxic T lymphocytes. The gene is not expressed in normal tissues with the exception of testes. The present study was designed to investigate the relationship between methylation of the MAGE-1 promoter and inactivation of the MAGE-1 gene. We examined the extent to which MAGE-1 B'B promoter sequences are methylated in tumor-cell lines, in order to determine whether methylation correlates with MAGE-1 expression. Using methylation-sensitive restriction analysis followed by polymerase chain reaction (PCR), we found an inverse correlation between methylation of the MAGE-1 B'B region and MAGE-1 expression. An unmethylated state was identified in DNA from sperm and some tumor-cell lines of different origins. In contrast, a hypermethylation state was found in leukocytes and other MAGE-1 non-expressing cells. Furthermore, treatment with 5-aza-2'-deoxycytidine, a demethylating agent, induced MAGE-1 expression in tumor-cell lines in which we found no direct relation between transcriptional activity of the B'B region and MAGE-1 expression. Binding of the nuclear factors to the B'-methylated probe was strongly inhibited, indicating that methylation of cytosine interferes directly in the binding of transcriptional factors.
    International Journal of Cancer 12/1996; 68(4):464-70. · 6.20 Impact Factor
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    ABSTRACT: Alpha/beta and gamma type interferons (IFN), act through distinct cell surface receptors and induce transcription of an overlapping sets of genes. MHC class I genes are inducible by both type of interferons. We have analyzed a gastric tumor cell line, AGS, which was completely defective in MHC class I response to interferon-alpha and gamma. Northern blot analysis demonstrated that the lack of IFN response was related with the absence of up-regulation of specific HLA class I mRNA. Electrophoretic mobility shift assays in various tumor cell lines after IFN-alpha and IFN-gamma treatment showed differential binding of the transcriptional factors to MHC class I regulatory elements. Comparison of kappa-B binding activity showed that IFN-alpha and IFN-gamma induced opposite changes in NF-kappa B binding activity in AGS cells, indicating that the absence of MHC class I response in AGS appears to be independent of kappa-B activity. In contrast, there were remarkable differences in the level of transcriptional factor binding to an interferon-responsive sequence element (IRSE), between AGS and other interferon-responsive tumor cell lines. This result suggests that the low level of transcriptional factor binding to IRSE in AGS cells was responsible of the lack of induction of MHC class I antigens. In this context, overlapping factors in the signal transduction pathway of both type I and II interferons may be involved in the non-responsiveness of this gastric carcinoma tumor cell line.
    Tissue Antigens 06/1996; 47(5):391-8. · 2.93 Impact Factor
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    ABSTRACT: α/β and γ type interferons (IFN), act through distinct cell surface receptors and induce transcription of an overlapping sets of genes. MHC class I genes are inducible by both type of interferons. We have analyzed a gastric tumor cell line, AGS, which was completely defective in MHC class I response to interferon-α and -γ. Northern blot analysis demonstrated that the lack of IFN response was related with the absence of up-regulation of specific HLA class I mRNA. Electrophoretic mobility shift assays in various tumor cell lines after IFN-α and IFN-γ treatment showed differential binding of the transcriptional factors to MHC class I regulatory elements. Comparison of k-B binding activity showed that IFN-α and IFN-γ induced opposite changes in NF-kB binding activity in AGS cells, indicating that the absence of MHC class I response in AGS appears to be independent of k-B activity. In contrast, there were remarkable differences in the level of transcriptional factor binding to an interferon-responsive sequence element (IRSE), between AGS and other interferon-responsive tumor cell lines. This result suggests that the low level of transcriptional factor binding to IRSE in AGS cells was responsible of the lack of induction of MHC class I antigens. In this context, overlapping factors in the signal transduction pathway of both type I and II interferons may be involved in the non-responsiveness of this gastric carcinoma tumor cell line.
    Tissue Antigens 01/1996; 47(5):391-398. · 2.93 Impact Factor
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    ABSTRACT: The MAGE-1 gene, expressed in some tumors of different histological origins, codes for a tumor antigen recognized by cytotoxic T lymphocytes. The gene is not expressed in normal tissues with the exception of testes. The present study was designed to investigate the relationship between methylation of the MAGE-1 promoter and inactivation of the MAGE-1 gene. We examined the extent to which MAGE-1 B′B promoter sequences are methylated in tumor-cell lines, in order to determine whether methylation correlates with MAGE-1 expression. Using methylation-sensitive restriction analysis followed by polymerase chain reaction (PCR), we found an inverse correlation between methylation of the MAGE-1 B′B region and MAGE-1 expression. An unmethylated state was identified in DNA from sperm and some tumor-cell lines of different origins. In contrast, a hypermethylation state was found in leukocytes and other MAGE-1 non-expressing cells. Furthermore, treatment with 5-aza-2′-deoxycytidine, a demethylating agent, induced MAGE-1 expression in tumor-cell lines in which we found no direct relation between transcriptional activity of the B′B region and MAGE-1 expression. Binding of the nuclear factors to the B′-methylated probe was strongly inhibited, indicating that methylation of cytosine interferes directly in the binding of transcriptional factors. © 1996 Wiley-Liss, Inc.
    International Journal of Cancer 01/1996; 68(4):464-470. · 6.20 Impact Factor
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    ABSTRACT: The MAGE-1 gene encodes an antigen recognized on melanoma cells by autologous cytotoxic T cells. This gene shows a wide range of expression in many human tumors but not in normal tissues except for testes. We used reverse transcription polymerase chain reaction assays to analyze the expression of the MAGE-1 gene in two variants of an erythroleukemic cell line, K562. Comparison of two variants of the K562 cell line in different stages of differentiation showed different patterns of expression of the MAGE-1 gene. The more undifferentiated cell line (K562A) expressed high levels of specific MAGE-1 mRNA, in contrast to K562B, which features of erythroid differentiation, without MAGE-1 expression. Interestingly, we could not modulate MAGE-1 gene expression when in vitro differentiation of K562A was induced with Ara-C. Finally, our data indicate that MAGE-1 expression is not necessary for the maintenance of the transformed phenotype.
    Immunobiology 12/1995; 194(4-5):449-56. · 2.81 Impact Factor
  • Hemoglobin 10/1995; 19(5):287-9. · 0.89 Impact Factor
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    ABSTRACT: The MAGE-1 gene encodes an antigen recognized on melanoma cells by autologous cytotoxic T cells. This gene shows a wide range of expression in many human tumors but not in normal tissues except for testes. We used reverse transcription polymerase chain reaction assays to analyze the expression of the MAGE-1 gene in two variants of an erythroleukemic cell line, K562. Comparison of two variants of the K562 cell line in different stages of differentiation showed different patterns of expression of the MAGE-1 gene. The more undifferentiated cell line (K562A) expressed high levels of specific MAGE-1 mRNA, in contrast to K562B, which features of erythroid differentiation, without MAGE-1 expression. Interestingly, we could not modulate MAGE-1 gene expression when in vitro differentiation of K562A was induced with Ara-C. Finally, our data indicate that MAGE-1 expression is not necessary for the maintenance of the transformed phenotype.
    Immunobiology 01/1995; 194(4):449-456. · 2.81 Impact Factor
  • Hemoglobin 01/1995; 19(5):287-289. · 0.89 Impact Factor
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    ABSTRACT: Heterozygous beta-thalassemia manifests hematologically with microcytosis, reduced red blood cell hemoglobin concentration and high hemoglobin A2 levels. Almost all molecular alterations are due to point mutations. We attempt to determinate the frequency of that mutations in the Oriental Andalusia Area, and its relationship with the hematological phenotype. We have studied 45 heterozygous patients. DNA samples were amplified by PCR, using the printers CD7 and HI1. A 16 Kb fragment corresponding to beta globin gene was obtained and analyzed by Dot Blot assay and hybridized with allelic specific oligonucleotide (ASO) probes to detect the 6 more frequent mutations found in the South of Spain. Codon 39 nonsense mutation (31.1%) was the most frequent finding followed by IVS-1 NT 110 (26.7%). The relationship between hematological parameters and molecular mutations concluded that IVS-I NT 6 mutation developed a minimal anemia. From the practical point of view, this study indicates that we were able to detect more than 90% of heterozygous beta-tal. with 5 out of 6 ASO probes used in this work. Thus, our data also provides a further implication in prenatal diagnosis.
    Sangre 09/1994; 39(4):253-6.
  • Human Immunology. 02/1994; 39(2):129.
  • Human Immunology - HUM IMMUNOL. 01/1994; 39(2):129-129.

Publication Stats

239 Citations
58.98 Total Impact Points

Institutions

  • 1995–1999
    • Hospital Universitario Virgen de las Nieves
      • Department of Pathology
      Granata, Andalusia, Spain
  • 1996
    • University of Granada
      • Departamento de Análisis Matemático
      Granada, Andalusia, Spain