Search

Background: Epithelial ovarian cancer (EOC) patients with BRCA mutations have better prognosis than nonhereditary cases matched for histology and stage and age at diagnosis, especially Ashkenazi Jews (AJ)., Materials and Methods: We retrospectively reviewed data on 700 highly ethnically heterogeneous patients diagnosed with stage Ic-IV EOC and evaluated for BRCA status between 1995 and 2009 in American, Israeli, and Italian medical centers., Results: The ethnicities of the 190 patients (median age 55.5 years, range 31-83 years) were AJ, Jewish non-Ashkenazi, Caucasian, African-American, Hispanic, or unknown. Ninety were BRCA1/2 carriers (71 BRCA1 and 19BRCA2). The most common mutations in AJ and non-AJ origins were 185delAG and 6174delT. Non-Jewish Caucasians exhibited the widest variation (>20 mutation subtypes). BRCA carriers had significantly prolonged median overall survival (93.6 months) compared with noncarriers (66.6 months; 95% confidence interval 44.5-91.7, P = 0.0081). There was no difference in progression-free survival., Conclusions: Our data demonstrate a wide variety of BRCA mutations in a highly ethnically diverse EOC population, and confirm that EOC BRCA mutation carriers have better prognosis with longer median survival than patients with nonhereditary disease. The contribution of unclassified BRCA variants to cancer etiology remains undetermined.

Elevated plasminogen activator inhibitor-1 (PAI-1) plasma levels, responsible for reduced fibrinolysis, are associated with animal and human obesity and with increased cardiovascular disease. The expression of PAI-1 has been found recently in animal and human adipose tissue. Factors and mechanisms regulating such an expression remain to be elucidated. In omental and/or subcutaneous biopsies from obese non-diabetic patients, incubated in Medium 199, we have confirmed that human adipose tissue expresses PAI-1 protein and mRNA; furthermore we have demonstrated that such an expression is clearly evident also in collagenase isolated human adipocytes and that it is stimulated by incubation itself and enhanced by exogenous human tumor necrosis factor-alpha (h-TNF-alpha). Since human adipose tissue produces TNF-alpha, to further characterize the relationship of PAI-1 to TNF-alpha, human fat biopsies were also incubated with Pentoxifylline (PTX) or Genistein, both known to inhibit endogenous TNF-alpha through different mechanisms. PTX caused a dose-dependent decrease of basal PAI-1 protein release, reaching 80% maximal inhibitory effect at 10(-3)M, the same inhibitory effect caused by Genistein at 100 microg/ml. This was associated to a marked inhibition of PAI-1 mRNA and of endogenous TNF-alpha production. Furthermore, when human fat biopsies were incubated in the presence of polyclonal rabbit neutralizing anti-human TNF-alpha antibody (at a concentration able to inhibit 100 UI/ml human TNF-alpha activity), a modest but significant decrease of the incubation induced expression of PAI-1 mRNA was observed (19.8+/-19.0% decrease, P = 0.04, n = 7). In conclusion, the results of this study demonstrate that PAI-I expression is present in human isolated adipocytes and that it is enhanced in human adipose tissue in vitro by exogenous TNF-alpha. Furthermore our data support the possibility of a main role of endogenous TNF-alpha on human adipose tissue PAI-1 expression. This cytokine, produced by human adipose tissue and causing insulin resistance, may be a link in the clinical relationship between insulin-resistance syndrome and increased PAI-1 plasma levels.

GABA (gamma-amino-butyric acid) receptors are a family of proteins involved in the GABAergic neurotransmission of the mammalian central nervous system (CNS). They have physiological importance and clinical relevance in several diseases. We report the identification, cloning, and fine mapping of the human cDNA for GABAB receptor. A 4.2-Kb cDNA containing an open reading frame for a predicted protein of 960 aa was isolated from a fetal brain cDNA library. It had a strong identity (91.5%) with the rat GABAB receptor (rGB1A) nucleotide sequence, that corresponded to 98.6% identity at the amino acid level. Expression of the GABAB at the transcription level was detected by Northern analysis in all brain areas examined. The GABAB receptor has been mapped to human chromosome 6p21.3 within the HLA class I region close to the HLA-F gene. Susceptibility loci for multiple sclerosis, epilepsy, and schizophrenia have been suggested to map in this region.

Six cases of mediastinal large B-cell lymphoma (MLCL) with sclerosis were analyzed for the presence and patterns of c-myc and bcl-2 loci rearrangements, and for the presence of Epstein-Barr virus DNA sequences by Southern blot hybridization, c-myc gene alterations were found in three of six cases. Two cases showed the presence of mutations or small rearrangements at the 3' end of the first exon. The c-myc gene abnormalities found in these two cases are similar to those observed in the translocation 8;14 of the endemic Burkitt's lymphomas or in its variants t(2;8) and t(8;22). A third case showed a major rearrangement of c-myc gene, with truncation within its first intron, similar to those observed in sporadic Burkitt's and in acquired immunodeficiency-associated lymphomas. None of the cases displayed bcl-2 gene rearrangements or contained viral sequences. Our data suggest a possible role for a translocation-mediated c-myc activation in the pathogenesis of MLCL. Conversely, bcl-2 gene and Epstein-Barr virus do not appear to be involved in the pathogenesis of these peculiar lymphomas. The association between c-myc structural modifications and MLCL also seems to be of relevance in light of the peculiar tendency of this tumor to involve unusual extranodal site (eg, kidney), reminiscent of the spreading attitude of Burkitt's limphomas.