PubMed Health⌕ Search

Biomedical subjects

S Diaz-Cano

Publications and source records attributed to S Diaz-Cano.

10 recordsLinked to original sources
PubMed2003

Activating point mutations in cyclin-dependent kinase 4 are not seen in sporadic pituitary adenomas, insulinomas or Leydig cell tumours.

Cell cycle dysregulation is one of the defining features of cancer. Cyclin-dependent kinase 4 (CDK4), together with its regulatory subunit cyclin D, governs cell cycle progression through the G1 phase. Cyclin-dependent kinase inhibitors, including p16(INK4A) (encoded by CDKN2A), in turn regulate CDK4. In particular, dysregulation of the p16/CDK4/cyclin D complex has been established in a variety of types of human tumours. Dominant activating mutations affecting codon 24 of the CDK4 gene (replacement of Arg24 by Cys or His) render CDK4 insensitive to p16(INK4) inhibition and are responsible for melanoma susceptibility in some kindreds. However, 'knock-in' mice homozygous for the CDK4(R24C) mutation were noted to develop multiple neoplasia, most commonly including endocrine tumours: pituitary adenomas, insulinomas and Leydig cell testicular tumours. We therefore speculated that sporadic human endocrine tumours might also harbour such mutations. The aim of the current study was to analyze the CDK4 gene for the two characterized activating mutations, R24C and R24H, in sporadic human pituitary adenomas, insulinomas and Leydig cell tumours. We used DNA extracted from 61 pituitary adenomas, and paired tumorous and neighboring normal genomic DNA extracted from 14 insulinoma and 6 Leydig cell tumour samples. Genomic DNA from patients with familial melanoma harbouring the R24C or the R24H mutations served as positive controls. All samples were subjected to PCR, mutation-specific restriction digests and/or sequencing. Both methodologies failed to detect mutations at these two sites in any of the sporadic endocrine tumours including pituitary adenomas, benign or malignant insulinomas or Leydig cell tumours, while the positive controls showed the expected heterozygote patterns. Protein expression of CDK4 was demonstrated by immunohistochemistry and Western blotting in pituitary and pancreatic samples. These data suggest that the changes in the regulatory 'hot-spot' on the CDK4 gene, causing various endocrine tumours in CDK4(R24C/R24C )mice, are not a major factor in sporadic pituitary, insulin beta-cell or Leydig cell tumorigenesis.

Adolescent↗
PubMed2001

Expression of galectins-1 and -3 correlates with defective mononuclear cell apoptosis in patients with juvenile idiopathic arthritis.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is characterized by hyperplasia of synovial cells and accumulation of mononuclear inflammatory infiltrates, which are locally maintained through a balance between cell proliferation and apoptosis. Although defective clearance of activated T cells in RA joints has been explained by alterations of the Fas-Fas ligand system, this has not been confirmed in synovial tissue of patients with JIA. We evaluated the relation between expression of galectin-1 (Gal-1) and galectin-3 (Gal-3) (beta-galactoside-binding proteins with pro- and anti-apoptotic properties, respectively) and the apoptosis and proliferation rates of infiltrative lymphocytes in synovial tissue of patients with JIA. METHODS: Using slide cytometry and in situ end labeling we observed dysregulated apoptosis of infiltrating mononuclear cells within the synovial tissue of patients with JIA. RESULTS: Patients with pauciarticular JIA showed minimal apoptosis, high Bcl-2 expression, and high or normal proliferation rates, while patients with polyarticular disease showed the lowest apoptotic indexes, accompanied by low Bcl-2 expression and low proliferation rates. We found that Gal-1 expression is downregulated and Gal-3 expression is upregulated in synovial tissue from patients with JIA. CONCLUSION: In patients with polyarticular JIA, accumulation of inflammatory cells is mainly due to downregulated apoptosis, whereas in patients with pauciarticular disease the process results from increased proliferation. Defective mononuclear apoptosis in synovial inflammatory infiltrates from patients with JIA could be explained in part by decreased Gal-1 and increased Gal-3 expression.

Antigens, Differentiation↗
PubMed2000

E-cadherin and adenomatous polyposis coli mutations are synergistic in intestinal tumor initiation in mice.

BACKGROUND & AIMS: Inactivation of the adenomatous polyposis coli (APC) gene is observed at early stages of intestinal tumor formation, whereas loss of E-cadherin is usually associated with tumor progression. Because both proteins compete for the binding to beta-catenin, an essential component of the Wnt signaling pathway, reduction of E-cadherin levels in an Apc mouse model could influence both tumor initiation and progression. In addition, loss or haploinsufficiency of E-cadherin may affect tumorigenesis by altering its cell-adhesive and associated functions. METHODS: Apc1638N mice were bred with animals carrying a targeted E-cadherin knockout mutation. RESULTS: Double heterozygous animals showed a significant 9-fold and 5-fold increase of intestinal and gastric tumor numbers, respectively, compared with Apc1638N animals. The intestinal tumors of both groups showed no significant differences in grading and staging. Loss of heterozygosity analysis at the Apc and E-cadherin loci in both intestinal and gastric Apc(+/1638N)/E-cad(+/-) tumors revealed loss of the wild-type Apc allele in most cases, whereas the wild-type E-cadherin allele was always retained. This was supported by a positive, although reduced, staining for E-cadherin of intestinal tumor sections. CONCLUSIONS: Introduction of the E-cadherin mutation in Apc1638N animals enhances Apc-driven tumor initiation without clearly affecting tumor progression.

Adenomatous Polyposis Coli Protein↗
PubMed2000

Prominent expression of mRNA for proinflammatory cytokines in synovium in patients with juvenile rheumatoid arthritis or chronic Lyme arthritis.

OBJECTIVE: To examine the cytokine profiles in synovium of patients with juvenile rheumatoid arthritis (JRA) or Lyme arthritis, 2 chronic inflammatory arthritides that affect children. METHODS: We used in situ hybridization with specific riboprobes to determine the expression of mRNA for proinflammatory or antiinflammatory cytokines in synovial samples from 5 patients with early, untreated JRA, 15 patients with late, treated JRA, and 9 patients with chronic Lyme arthritis. For comparison, synovia were examined from 6 patients with rheumatoid or psoriatic arthritis, and from 9 patients with various orthopedic conditions. RESULTS: Among the children with early, untreated JRA, a median of 3 to 8% of inflammatory cells in synovial samples expressed mRNA for the proinflammatory cytokines interleukin 1beta (IL-1beta), tumor necrosis factor-alpha(TNF-alpha), or interferon-gamma (IFN-gamma). Although a median of 3.9% of the cells expressed mRNA for the antiinflammatory cytokine IL-10, none had IL-4 mRNA. Most of the patients with late, treated JRA, chronic Lyme arthritis, rheumatoid, or psoriatic arthritis had mRNA for each of these proinflammatory cytokines in about 1% of the cells, whereas mRNA for the antiinflammatory cytokines was less frequent. The inflammatory cell density was much less in the synovium of patients with various orthopedic conditions, but about 1% of the infiltrating cells expressed mRNA for at least one of the proinflammatory cytokines. CONCLUSION: Patients with early or late JRA or chronic Lyme arthritis have expression of mRNA in synovial tissue primarily for proinflammatory cytokines, with less expression of antiinflammatory cytokines.

Adult↗
PubMed1997

Aggressive fibromatosis (desmoid tumor) is a monoclonal disorder.

Aggressive fibromatosis (also called deep fibromatosis or desmoid tumor) is a proliferation of cytologically benign-appearing fibrocytes, often resulting in significant functional loss. The nature of the lesion is controversial: some evidence suggests that it is a reactive process, whereas other evidence supports a neoplastic etiology. The pattern of X chromosome inactivation, using a technique based on polymerase chain reaction (PCR) amplification of a hypervariable CAG repeat region flanking Hhal restriction sites of the human androgen receptor gene, was determined in four cases in which cryopreserved tumor and adjacent normal tissue were available. All four tumors demonstrated a monoclonal pattern, while the adjacent normal tissues demonstrated a polyclonal pattern. This demonstrates that aggressive fibromatosis is proliferation of cells derived from a single clone with a growth advantage, and thus is likely a neoplastic process.

Arm↗
PubMed1997

Increased beta-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors).

Sporadic aggressive fibromatosis (also called desmoid tumor) is a monoclonal proliferation of spindle (fibrocyte-like) cells that is locally invasive but does not metastasize. A similarity to abdominal fibromatoses (desmoids) in familial adenomatous polyposis and a cytogenetic study showing partial deletion of 5q in a subset of aggressive fibromatoses suggests that the adenomatous polyposis coli (APC) gene plays a role in its pathogenesis. APC helps regulate the cellular level of beta-catenin, which is a downstream mediator in Wnt (Wingless) signaling. beta-Catenin has a nuclear function (binds transcription factors) and a cell membrane function (is a component of epithelial cell adherens junctions). Six cases of aggressive fibromatosis of the extremities from patients without familial adenomatous polyposis, or a family history of colon cancer, were studied. Immunohistochemistry, using carboxy and amino terminus antibodies to APC, and DNA sequencing showed that three of the six contained an APC-truncating mutation, whereas normal tissues did not contain a mutation. Western blot and Northern dot blot showed that all six tumors had a higher level of beta-catenin protein than surrounding normal tissues, despite containing similar levels of beta-catenin mRNA. Immunohistochemistry localized beta-catenin throughout the cell in tumor tissues, although it localized more to the periphery in cells from normal tissues. Reverse transcription polymerase chain reaction showed that the tumors expressed N-cadherin but not E-cadherin (a pattern of expression of proteins making up adherens junctions similar to fibrocytes), suggesting that the specific adherens junctions present in epithelial cells are not necessary for beta-catenin function. Increased beta-catenin may cause the growth advantage of cells in this tumor through a nuclear mechanism. The increased protein level, relative to the RNA level, suggests that beta-catenin is degraded at a lower rate compared with normal tissues. In some cases, this is caused by a somatic mutation resulting in a truncated APC protein.

Adenomatous Polyposis Coli Protein↗