Biomedical subjects

P Ghiorzo

Publications and source records attributed to P Ghiorzo.

8 recordsLinked to original sources

PubMed2004

INK4/ARF germline alterations in pancreatic cancer patients.

BACKGROUND: Roughly 40% of germinal mutations in melanoma families (MF) affect p16(INK4a) and p14(ARF). We investigated the association between INK4/ARF alterations and the occurrence of pancreatic cancer in MF and in sporadic pancreatic cancer (SPC) patients. PATIENTS AND METHODS: Forty-nine MF, 66 SPC cases and 54 controls were enrolled. The INK4/ARF locus was screened. RESULTS: As compared with the general population, the risk of pancreatic cancer (PC) was increased 9.4-fold [95% confidence interval (CI) 2.7-33.4] and 2.2-fold (95% CI 0.8-5.7) in G101W-positive and -negative MF, respectively, while mean ages at onset were 61 and 77 years, respectively. A 1.7 (95% CI 1.06-2.79) increased risk of cancer at any site was observed among first-degree relatives of SPC cases as compared with controls. The G101W founder mutation was detected in 4% of SPC cases but the rate increased to 13% when tumor clustering in either branch of families was taken into account. One G101W-positive PC patient with a melanoma in a first-degree relative harbored a germline deletion of the second allele, including exon 1B. CONCLUSIONS: The presence of a deletion including exon 1B in two PC patients points to the involvement of p14(ARF) in the development of PC and may suggest that the increased risk of PC in MF is caused by impairment of both loci.

Adenocarcinoma↗

PubMed2003

Anti-inflammatory effects of leflunomide on cultured synovial macrophages from patients with rheumatoid arthritis.

BACKGROUND: Leflunomide and its active metabolite A77 1726 reversibly inhibits the enzyme dihydro-orotate dehydrogenase, the rate limiting step in de novo synthesis of pyrimidines and progression of the cell cycle in different cell lines, mainly activated T lymphocytes. OBJECTIVE: To analyse in vitro the possible anti-inflammatory effects exerted by A77 1726, on cultured macrophages, obtained from the synovial tissues of patients with rheumatoid arthritis (RA). METHODS: The effects of different doses of A77 1726 on intracytoplasmic expression and extracellular concentration of inflammatory cytokines (tumour necrosis factor alpha (TNFalpha), interleukin (IL) 1beta, IL6), as well as the influence on production and expression of intercellular adhesion molecule-1 (ICAM-1) and cyclo-oxygenase 2 (COX-2) by primary cultures of synovial macrophages from patients with RA, were evaluated by immunocytochemistry and western blot analysis. The observations were made at four and 24 hours. RESULTS: A progressive and significant time and dose dependent decrease of the number of positive macrophages for intracellular TNFalpha and IL1beta, treated with different doses of A77 1726, was found in comparison with untreated cells. The extracellular concentration of TNFalpha was found to be significantly decreased in media containing cultured macrophages at 24 hours for all tested doses of A77 1726. At 24 hours, a significant time and dose dependent decrease of ICAM-1 and COX-2 expression by cultured macrophages after A77 1726 treatment was found. CONCLUSIONS: In conclusion, the mechanism of antiproliferative activity exerted by leflunomide on activated T lymphocytes seems to be the same mechanism (alteration of the cell cycle progression) which interferes with the functions of other activated cells-namely, the monocytes/macrophages, which are strongly involved in the inflammatory reaction in RA synovial tissue. The positive clinical results seem to confirm that leflunomide exerts an anti-inflammatory action on phagocytic cells in short and long term treatment of RA.

Aniline Compounds↗

PubMed2000

Reply to fusaro

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Journal Article↗

PubMed2000

Mutation screening of the CDKN2A promoter in melanoma families.

Germline mutations of CDKN2A, at 9p21, are responsible for predisposition to melanoma in some families. However, evidence of linkage to 9p21 has been demonstrated in a significant proportion of kindreds with no detectable mutations in CDKN2A. It is possible that mutations in noncoding regions may be responsible for predisposition to melanoma in these families. We have analyzed approximately 1 kb of the CDKN2A promoter upstream of the start codon in an attempt to identify causal mutations in 107 melanoma families. Four sequence variants were detected. Two of these (A-191G and A-493T) did not segregate with disease and were present in a control population at a comparable frequency, indicating that they are unlikely to predispose to melanoma. The A-493T variant appeared to be in linkage disequilibrium with the previously described CDKN2A polymorphism Ala148Thr. The variant G-735A was detected in the control population, but segregation of this variant with melanoma within families could not be discounted. The fourth variant (G-34T), located in the 5' UTR, creates an aberrant initiation codon. This variant appeared to segregate with melanoma and was not detected in a control population. G-34T has recently been identified in a subset of Canadian melanoma families and was concluded to be associated with predisposition to melanoma. The creation of an aberrant initiation site in the 5' UTR may have an important role in carcinogenesis in a small percentage of families; however, mutations in the CDKN2A promoter appear to have a limited role in predisposition to melanoma.

Adolescent↗

PubMed1999

Characterization of ligurian melanoma families and risk of occurrence of other neoplasia.

Germline mutations impairing the p16(INK4)-function have previously been demonstrated to be responsible for genetic predisposition in at least one half of melanoma-prone kindreds of North European origin. Familial melanoma kindreds have also been found to present an increased risk of pancreatic cancer and other cancers, but results relative to more common neoplasias incidence, in particular, are heterogeneous. We report here a clinical-epidemiological study, including the presence of additional neoplasias, in 14 apparently unrelated kindreds coming from a small geographic region of Northern Italy (Liguria), having therefore lived for generations in similar environmental conditions. We identified the common p16 missense mutation (Gly101Trp) reported in several previously studied kindreds, in 7 of 14 families, whereas the remaining 7 families had no detectable mutations in the coding region of p16 gene. Median age at diagnosis and other melanoma features were studied. When compared with the expected figures, based on regional incidence rates, a significant excess of pancreatic cancer, with 4 cases diagnosed, and of breast cancer, with 7 cases, was observed. The 7 families without apparent CDKN2A involvement were also negative for hot-spot exon 2 mutation of CDK4. Environmental factors do not appear to play a role in the excess of non-melanoma neoplasia in our families, as somewhat substantiated by the control group, composed of spouses and members of non-affected branches; they do not reveal any increased cancer incidence compared with the general population. Furthermore, given the proven significance of interaction between the melanoma susceptibility gene and the propensity to sunburns and other environmental risk factors, our results, obtained from a small but homogeneous sample, may have important implications for further risk assessment studies.

Adolescent↗

PubMed1997

c-Rel and p65 subunits bind to an upstream NF-kappaB site in human granulocyte macrophage-colony stimulating factor promoter involved in phorbol ester response in 5637 cells.

To further clarify the complex transcriptional regulation of the human GM-CSF gene, which was extensively investigated in activated T cells, we have studied the role of an upstream NF-kappaB like site in the 5637 non-lymphoid cell line, which derives from a bladder carcinoma and constitutively produces GM-CSF. This sequence, named the A element, has an active role on GM-CSF transcription and is responsive to the tumor promoter PMA in transient transfection experiments. We describe here a heterodimeric binding complex of NF-kappaB subunits (c-Rel and p65) which is identical to the one obtained using the HIV-LTR-kappaB site as recognition sequence and different from the one (c-Rel and p50) observed with nuclear extracts from Mo T-lymphoid HTLV-II infected cells.

Cell Nucleus↗

PubMed1996

An upstream positive regulatory element in human GM-CSF promoter is recognized by NF-kappa B/Rel family members.

To further extend the previous analysis of cis-acting elements and cognate trans-acting factors that contribute to GM-CSF transcriptional regulations, we have examined a promoter region between -1742 and -2010. DNase I footprinting assays showed four protected sequences named A, B, C and D. DNA transfections in the T-lymphoid Mo cell line, which constitutively expresses GM-CSF, indicated that the A element, located between -2002 and -1984, has a positive role on transcription. Further characterization by electrophoretic mobility shift assays in the presence of different competitor oligonucleotides showed that this element binds a factor of the NF-kappa B/Rel family.

Base Sequence↗

PubMed1996

MEL-P, a GM-CSF-producing human melanoma cell line.

A human melanoma cell line, MEL-P, expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and its specific receptor was newly established from a primary nodular lesion of a patient with a particularly unfavourable prognosis. Cytogenetic, immunophenotypic, cytokine and intercellular adhesion molecule (ICAM)-1 production analyses confirmed that this cell line was similar to the fresh melanoma cells from which it had been established. MEL-P constitutes a valuable model for the study of multistep tumour progression and the role of biologically active GM-CSF production in human malignant melanoma. Our results show a decreasing expression of HLA class I molecules during in vitro culture, when GM-CSF secretion attains the highest levels, and a constantly high production of ICAM-1. The inhibitory effect of GM-CSF antisense treatment on cellular growth might suggest the presence of an autocrine mechanism. On the whole, these data are consistent with the possible involvement of high GM-CSF production in the metastatic competence of melanoma cells through the autocrine mechanism of growth and/or the activation of other migration-related molecules by its local production in metastatic invasion.

Adult↗