Biomedical subjects

Patricia Castro

Publications and source records attributed to Patricia Castro.

6 recordsLinked to original sources

PubMed2005

Influence of interleukin-10 genetic polymorphism on survival rates in melanoma patients with advanced disease.

Individual ability to produce interleukin-10 (IL-10) may be of relevance in the development and evolution of cutaneous melanoma, probably due to its immunosuppressor and anti-angiogenic properties. Single nucleotide polymorphisms at positions -1082 (G/A), -819 (C/T) and -592 (C/A) in the IL-10 gene promoter were analysed in 100 healthy individuals and 98 melanoma patients using fluorogenic hybridization-specific probes in a 'real-time' thermocycler. Polymorphic frequencies were correlated with various prognostic factors and overall survival. The frequency of IL-10 polymorphic variants was similar in patients and controls. However, high producer genotypes at the -1082 position were over-represented in males with an older age at diagnosis. The analysis of the promoter genotypes in patients stratified according to clinical prognostic factors did not show any associations, although a trend (not statistically significant) towards a prolonged survival in patients genotyped as high IL-10 producers was observed. In addition, the low producer -1082AA genotype was significantly associated with decreased survival in patients with advanced disease. Similarly, the presence of this genotype shortened the overall survival in males after recurrence or metastasis development. In conclusion, the frequency of genetic variants in the IL-10 gene promoter was not associated with melanoma appearance, but conditioned the age at diagnosis in males and the overall survival in patients with advanced disease.

Adult↗

PubMed2004

The expression of Sprouty1, an inhibitor of fibroblast growth factor signal transduction, is decreased in human prostate cancer.

A considerable body of evidence indicates that alterations of fibroblast growth factors (FGFs) and their receptors contribute to prostate cancer progression. Recently, a new family of regulators of FGF activity has been identified. The Sprouty gene family negatively regulates FGF signaling in a variety of systems and could potentially limit the biological activity of FGFs in prostate cancer. Immunohistochemical analysis of normal and neoplastic prostate tissues using tissue microarrays revealed that Sprouty1 protein is down-regulated in approximately 40% of prostate cancers when compared with matched normal prostate. By quantitative real-time PCR analysis, we found that Sprouty1 mRNA levels were significantly decreased in prostate cancers in vivo in comparison with normal prostate. In prostate cancer cell lines, there is loss of the normal up-regulation of Sprouty1 mRNA and protein in response to FGFs. The decrease in Sprouty1 expression in the human prostate cancer, despite elevated levels of FGF ligands and FGF receptors, implies a loss of an important growth regulatory mechanism in prostate cancers that may potentiate the effects of increased FGF and FGF receptor expression in prostate cancer.

Cell Line, Tumor↗

PubMed2004

Interleukin-8 expression is increased in senescent prostatic epithelial cells and promotes the development of benign prostatic hyperplasia.

BACKGROUND: Benign prostatic hyperplasia (BPH) is an extremely common disease of older men characterized by increased growth of prostatic epithelial and stromal cells. Previously we showed that senescent epithelial cells accumulate in the prostate of aging men and secrete interleukin-1 alpha (IL-1 alpha). IL-8 is also present at increased levels in BPH tissues and induces expression of FGF2, a potent stromal growth factor. Therefore, we sought to determine if IL-8 is also expressed at increased levels by senescent epithelial cells and if this secreted IL-8 plays a role in the pathogenesis of BPH. METHODS: Expression of IL-8 in human BPH tissue and primary cultures of prostatic epithelial cells was analyzed using an enzyme-linked immunoabsorption assay (ELISA). Tissue senescence was assessed by a quantitative assay for senescence-associated beta galactosidase (SA-beta gal). Proliferation of primary and immortalized prostatic epithelial cells in response to IL-8 was determined by counting of cells at intervals after addition of IL-8. RESULTS: Expression of IL-8 is significantly increased in vitro when cultured prostatic epithelial cells undergo senescence. Quantitative assay of BPH tissue extracts revealed that tissue IL-8 levels are correlated with both SA-beta gal activity and prostate weight. IL-8 promotes proliferation of primary and immortalized prostatic epithelial cells in culture. CONCLUSIONS: Senescence of prostatic epithelial cells results in increased expression of IL-8, which can promote proliferation of non-senescent epithelial and stromal cells by direct and indirect mechanisms, and in this manner contributes to the increased tissue growth seen in BPH.

Cellular Senescence↗

PubMed2003

Cellular senescence in the pathogenesis of benign prostatic hyperplasia.

BACKGROUND: Senescent cells accumulate in tissues with age and show changes in protein expression that may influence the function of adjacent cells and contribute to the development of tissue pathologies associated with aging. Benign prostatic hyperplasia (BPH) is an extremely common disease of older men characterized by increased growth of prostatic epithelial and stromal cells. In BPH, there is an increased expression of Il-1alpha by prostatic epithelial cells that results in elevated expression of FGF7 by stromal cells, which in turn is strongly correlated with epithelial proliferation. METHODS: Human BPH tissue and primary cultures of prostatic epithelial cells were analyzed by histochemical and quantitative assays for senescence-associated beta galactosidase (SA-beta gal). Il-1alpha expression was localized by immunohistochemistry and Il-1alpha tissue content determined by enzyme-linked immunoabsorption assay. RESULTS: Expression of Il-1alpha is significantly increased in vitro when cultured prostatic epithelial cells undergo senescence. In BPH tissue a substantial population of epithelial cells express senescence-associated beta galactosidase (SA-beta gal), a marker of cellular senescence. By quantitative assay, SA-beta gal activity is correlated with both tissue levels of Il-1alpha and the severity of BPH. CONCLUSIONS: One mechanism driving BPH in older men is the accumulation of senescent epithelial cells expressing Il-1alpha, which in turn increases FGF7 secretion and proliferation of non-senescent epithelial cells. Thus there is a mechanistic linkage between cellular senescence and one of the most common pathologies of older men.

Cellular Senescence↗

PubMed2003

Interindividual variations in constitutive interleukin-10 messenger RNA and protein levels and their association with genetic polymorphisms.

BACKGROUND: Genetic variations in the interleukin (IL)-10 gene promoter have been associated with levels of induced production of IL-10, disease susceptibility, and allograft rejection. Small amounts of this cytokine are constitutively produced and are important in maintaining the physiologic function of the cytokine network. In this study, we evaluated the distribution of IL-10 basal levels and its genetic regulation in a healthy Spanish population. METHODS: Polymorphisms at the -1,082, -819, and -512 positions of the IL-10 promoter were analyzed by polymerase chain reaction amplification and hybridization with fluorescent-labeled allele-specific probes in 183 Spanish people. Levels of IL-10 messenger (m)RNA were tested by real-time reverse transcription-polymerase chain reaction in 123 healthy donors. Serum concentrations of IL-10 were measured by a highly sensitive ELISA, whereas protein amounts in lipopolysaccharide culture supernatants were quantified by an in-house ELISA. RESULTS: The frequency of IL-10 promoter alleles and haplotypes in our population showed remarkable differences from other Caucasian populations. Large interindividual variations were found in mRNA and protein constitutive levels of IL-10, which allowed its classification in low and intermediate/high producers. We found statistical differences in mRNA concentration between the polymorphic variant GCC/GCC and the low producer genotypes. The G allele at position -1082 was the most important genetic factor in the regulation of constitutive IL-10 mRNA levels. Similarly, we also found an association of this polymorphic position with serum concentration greater than 2 pg/mL. CONCLUSIONS: Constitutive levels of IL-10 (mRNA and serum protein) displayed remarkable interindividual variations, which are genetically controlled by polymorphic variants at the cytokine gene promoter.

Alleles↗

PubMed2002

A novel, evolutionarily conserved gene family with putative sequence-specific single-stranded DNA-binding activity.

Complete and partial deletions of chromosome 5q are recurrent cytogenetic anomalies associated with aggressive myeloid malignancies. Earlier, we identified an approximately 1.5-Mb region of loss at 5q13.3 between the loci D5S672 and D5S620 in primary leukemic blasts. A leukemic cell line, ML3, is diploid for all of chromosome 5, except for an inversion-coupled translocation within the D5S672-D5S620 interval. Here, we report the development of a bacterial artificial chromosome (BAC) contig to define the breakpoint and the identification of a novel gene SSBP2, the target of disruption in ML3 cells. A preliminary evaluation of SSBP2 as a tumor suppressor gene in primary leukemic blasts and cell lines suggests that the remaining allele does not undergo intragenic mutations. SSBP2 is one of three members of a closely related, evolutionarily conserved, and ubiquitously expressed gene family. SSBP3 is the human ortholog of a chicken gene, CSDP, that encodes a sequence-specific single-stranded DNA-binding protein. SSBP3 localizes to chromosome 1p31.3, and the third member, SSBP4, maps to chromosome 19p13.1. Chromosomal localization and the putative single-stranded DNA-binding activity suggest that all three members of this family are capable of potential tumor suppressor activity by gene dosage or other epigenetic mechanisms.

Amino Acid Sequence↗