Background:
Until recently, the molecular mechanisms explaining increased incidence of ovarian and breast cancers in carriers of BRCA1 gene mutations had not been clearly understood. Of significance is the finding that BRCA1 negatively regulates aromatase expression in vitro. Our objective was to characterise aromatase gene (CYP19A1) and its promoter expression in breast adipose and ovarian tissue in BRCA1 mutation carriers and unaffected controls.
Methods:
We measured aromatase transcripts, total and promoter-specific (PII, PI.3, PI.4) in prophylactic oophorectomy or mastectomy, therapeutic mastectomy, ovarian and breast tissue from unaffected women.
Results:
We demonstrate that the lack of functional BRCA1 protein correlates to higher aromatase levels in 85% of BRCA1 mutation carriers. This increase is mediated by aberrant transcriptional regulation of aromatase; in breast adipose by increases in promoter II/I.3 and I.4-specific transcripts; and in the ovary with elevation in promoter I.3 and II-specific transcripts.
Conclusions:
Understanding the link between BRCA1 and aromatase is significant in terms of understanding why carcinogenesis is restricted to estrogen-producing tissues in BRCA1 mutation carriers.

source

• Share:
• Bookmark on Delicious
• Digg this
• Share on Reddit
• Share with Stumblers
• Tweet this

Background:
Non-muscle invasive bladder neoplasms with invasion of the lamina propria (stage T1) or high grade of dysplasia are at "high risk" of progression to life-threatening cancer. However, the individual course is difficult to predict. Chromosomal instability (CI) is associated with high tumor stage and grade, and possibly with the risk of progression.
Methods:
To investigate the relationship between CI and subsequent disease progression, we performed a case-control-study of 125 patients with "high-risk" non-muscle invasive bladder neoplasms, 67 with later disease progression, and 58 with no progression. Selection criteria were conservative (non-radical) resections and full prospective clinical follow-up (> 5 years). We investigated primary lesions in 59, and recurrent lesions in 66 cases.
We used Affymetrix GeneChip(R) Mapping 10K and 50K SNP microarrays to evaluate genome wide chromosomal imbalance (loss-of-heterozygosity and DNA copy number changes) in 48 representative tumors. DNA copy number changes of 15 key instability regions were further investigated using QPCR in 101 tumors (including 25 tumors also analysed on 50K SNP microarrays).
Results:
Chromosomal instability did not predict any higher risk of subsequent progression. Stage T1 and high-grade tumors had generally more unstable genomes than tumors of lower stage and grade (mostly non-primary tumors following a "high-risk" tumor). However, about 25% of the "high-risk" tumors had very few alterations. This was independent of subsequent progression. Recurrent lesions represent underlying field disease. A separate analysis of these lesions did neither reflect any difference in the risk of progression. Of specific chromosomal alterations, a possible association between loss of chromosome 8p11 and the risk of progression was found. However, the predictive value was limited by the heterogeneity of the changes.
Conclusions:
Chromosomal instability (CI) was associated with "high risk" tumors (stage T1 or high-grade), but did not predict subsequent progression. Recurrences after "high-risk" tumors had fewer chromosomal alterations, but there was no association with the risk of progression in this group either. Thus, the prediction of progression of "high risk" non-muscle invasive bladder tumors using chromosomal changes is difficult. Loss of chromosome 8p11 may play a role in the progression process. About 25% of the "high risk" tumors were chromosomal stable.

source

• Share:
• Bookmark on Delicious
• Digg this
• Share on Reddit
• Share with Stumblers
• Tweet this

Background:
SELDI-TOF-MS (Surface Enhanced Laser Desorption/Ionization-Time of Flight-Mass Spectrometry) has become an attractive approach for cancer biomarker discovery due to its ability to resolve low mass proteins and high-throughput capability. However, the analytes from mass spectrometry are described only by their mass-to-charge ratio (m/z) values without further identification and annotation. To discover potential biomarkers for early diagnosis of osteosarcoma, we designed an integrative workflow combining data sets from both SELDI-TOF-MS and gene microarray analysis.
Methods:
After extracting the information for potential biomarkers from SELDI data and microarray analysis, their associations were further inferred by link-test to identify biomarkers that could likely be used for diagnosis. Immuno-blot analysis was then performed to examine whether the expression of the putative biomarkers were indeed altered in serum from patients with osteosarcoma.
Results:
Six differentially expressed protein peaks with strong statistical significances were detected by SELDI-TOF-MS. Four of the proteins were up-regulated and two of them were down-regulated. Microarray analysis showed that, compared with an osteoblastic cell line, the expression of 653 genes was changed more than 2 folds in three osteosarcoma cell lines. While expression of 310 genes was increased, expression of the other 343 genes was decreased. The two sets of biomarkers candidates were combined by the link-test statistics, indicating that 13 genes were potential biomarkers for early diagnosis of osteosarcoma. Among these genes, cytochrome c1 (CYC-1) was selected for further experimental validation.
Conclusions:
Link-test on datasets from both SELDI-TOF-MS and microarray high-throughput analysis can accelerate the identification of tumor biomarkers. The result confirmed that CYC-1 may be a promising biomarker for early diagnosis of osteosarcoma.

source

• Share:
• Bookmark on Delicious
• Digg this
• Share on Reddit
• Share with Stumblers
• Tweet this

Background:
Bone marrow transplantation (BMT) is often used in the treatment of various diseases. Before BMT, patients are submitted to a conditioning regimen (CR), which consists of the administration of high doses of chemotherapy. The action of many cytostatic drugs may produce excessive reactive oxygen species, which together with inadequate antioxidant protection can lead to oxidative stress, which in turn has been implicated in the etiology of various diseases. The objective of this study was to look for evidence of oxidative stress and also analyze -aminolevulinato dehydratase (ALA-D) activity as a possible marker of oxidative stress in autologous and allogeneic BMT patients.
Methods:
Lipid peroxidation, vitamin C, thiol groups levels and catalase, superoxide dismutase and ALA-D activity were determined in 37 healthy controls, 13 patients undergoing autologous peripheral blood stem cells transplantation and 24 patients undergoing allogeneic BMT.
Results:
We found that patients presented signs of oxidative stress before they were submitted to BMT, during CR and up to 20 days after BMT. There was a decrease in enzymatic and non enzymatic antioxidant defenses and in ALA-D activity and an increase in lipoperoxidation in the blood of both patient groups.
Conclusion:
This study showed oxidative stress in autologous and allogeneic BMT patients. Moreover, blood ALA-D activity seemed to be an additional biomarker of oxidative stress in BMT patients.

source

• Share:
• Bookmark on Delicious
• Digg this
• Share on Reddit
• Share with Stumblers
• Tweet this