Biomedical subjects

Mehdi Nosrati

Publications and source records attributed to Mehdi Nosrati.

9 recordsLinked to original sources

PubMed2006

Prognostic significance of nuclear receptor coactivator-3 overexpression in primary cutaneous melanoma.

PURPOSE: To assess the prognostic significance of nuclear receptor coactivator-3 (NCOA3) overexpression in primary cutaneous melanoma. PATIENTS AND METHODS: NCOA3 expression was assessed using immunohistochemical analysis of a melanoma tissue microarray (TMA) containing primary melanomas from 343 patients with defined histology and follow-up. The impact of the presence or absence of various prognostic factors on relapse-free survival (RFS) and disease-specific survival (DSS) of melanoma patients was assessed using Cox regression and Kaplan-Meier analysis. The impact of presence or absence of various factors on sentinel lymph node (SLN) metastasis was assessed using logistic regression analysis. RESULTS: Increasing degree of NCOA3 expression was significantly predictive of SLN metastasis (P = .013) and the mean number of SLN metastases (P = .031). Kaplan-Meier analysis demonstrated a significant association between NCOA3 overexpression and reduced RFS (P = .021) and DSS (P = .030). Logistic regression analysis revealed increasing degree of NCOA3 expression to be an independent predictor of SLN status (P = .017). Multivariate Cox regression analysis showed the independent impact of NCOA3 expression on RFS (P = .0095) and DSS (P = .021). NCOA3 was the most powerful factor predicting DSS, outperforming tumor thickness and ulceration. CONCLUSION: These results identify NCOA3 as a novel, independent marker of melanoma outcome, with a significant impact on SLN metastasis, RFS, and DSS.

Biomarkers, Tumor↗

PubMed2006

Genes and pathways downstream of telomerase in melanoma metastasis.

Recent studies have demonstrated a role for telomerase in driving tumor progression, but its mechanism of action remains unclear. Here we show that stable, ribozyme-mediated suppression of mouse telomerase RNA reduced telomerase RNA expression, telomerase activity, and telomere length, which significantly reduced tumor invasion and metastatic potential. Our studies reveal that previously unidentified effects of telomerase may mediate its tumor-promoting effects. First, reducing telomerase activity induced a more dendritic morphology, accompanied by increased melanin content and increased expression of tyrosinase, a key enzyme in melanin biosynthesis. Second, gene expression profiling revealed that telomerase targeting down-regulated expression of several glycolytic pathway genes, with a corresponding decrease in glucose consumption and lactate production. Thus, telomerase activity controls the glycolytic pathway, potentially altering the energy state of tumor cells and thereby modulating tyrosinase activity and melanin production. These studies have important implications for understanding the mechanisms by which telomerase promotes tumor invasion and metastasis.

Animals↗

PubMed2005

The gene expression signatures of melanoma progression.

Because of the paucity of available tissue, little information has previously been available regarding the gene expression profiles of primary melanomas. To understand the molecular basis of melanoma progression, we compared the gene expression profiles of a series of nevi, primary melanomas, and melanoma metastases. We found that metastatic melanomas exhibit two dichotomous patterns of gene expression, which unexpectedly reflect gene expression differences already apparent in comparing laser-capture microdissected radial and vertical phases of a large primary melanoma. Unsupervised hierarchical clustering accurately separated nevi and primary melanomas. Multiclass significance analysis of microarrays comparing normal skin, nevi, primary melanomas, and the two types of metastatic melanoma identified 2,602 transcripts that significantly correlated with sample class. These results suggest that melanoma pathogenesis can be understood as a series of distinct molecular events. The gene expression signatures identified here provide the basis for developing new diagnostics and targeting therapies for patients with malignant melanoma.

Biopsy↗

PubMed2005

The role of microsatellites as a prognostic factor in primary malignant melanoma.

OBJECTIVE: To determine the impact of microsatellites as a prognostic factor in primary cutaneous melanoma. DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. Patients A total of 504 patients with a history of primary melanoma observed for 2 years or having experienced a first relapse. MAIN OUTCOME MEASURES: Overall survival (OS) and relapse-free survival (RFS). RESULTS: Forty-five patients had evidence of microsatellites in their primary melanoma. Presence of microsatellites significantly correlated with the presence of several other histologic high-risk factors such as tumor thickness, ulceration, Clark level, vascular factors, and mitotic rate. Univariate analysis demonstrated decreased RFS and OS in patients with microsatellites. Presence of microsatellites was associated with increased locoregional metastasis but not distant metastasis. In multivariate analysis, with the inclusion of 6 other clinical and histologic factors, presence of microsatellites was a significant predictor of RFS but not OS. Patients with clinical macrosatellites had a trend toward worsening OS compared with those with microsatellites. CONCLUSIONS: The presence of microsatellites is intimately tied to other markers of melanoma aggressiveness. Microsatellites appear to predict locoregional relapse and RFS but neither distant metastasis nor OS. These results may have implications for patient care as well as the inclusion of microsatellites in stage III of the current classification.

Analysis of Variance↗

PubMed2004

Antitumor activity of systemically delivered ribozymes targeting murine telomerase RNA.

PURPOSE: To test ribozymes targeting mouse telomerase RNA (mTER) for suppression of the progression of B16-F10 murine melanoma metastases in vivo. EXPERIMENTAL DESIGN: Hammerhead ribozymes were designed to target mTER. The ribozyme sequences were cloned into a plasmid expression vector containing EBV genomic elements that substantially prolong expression of genes delivered in vivo. The activity of various antitelomerase ribozymes or control constructs was examined after i.v. injection of cationic liposome:DNA complexes containing control or ribozyme constructs. Expression of ribozymes and mTER at various time points were evaluated by quantitative real-time PCR. Telomerase activity was examined using the telomeric repeat amplification protocol. RESULTS: Systemic administration of cationic liposome:DNA complexes containing a plasmid-expressed ribozyme specifically targeting a cleavage site at mTER nucleotide 180 significantly reduced the metastatic progression of B16-F10 murine melanoma. The antitumor activity of the anti-TER 180 ribozyme in mice was abolished by a single inactivating base mutation in the ribozyme catalytic core. The EBV-based expression plasmid produced sustained levels of ribozyme expression for the full duration of the antitumor studies. In addition to antitumor activity, cationic liposome:DNA complex-based ribozyme treatment also produced reductions in both TER levels and telomerase enzymatic activity in tumor-bearing mice. CONCLUSIONS: Systemic, plasmid-based ribozymes specifically targeting TER can reduce both telomerase activity and metastatic progression in tumor-bearing hosts. The work reported here demonstrates the potential utility of plasmid-based anti-TER ribozymes in the therapy of melanoma metastasis.

Animals↗

PubMed2004

NF-kappa B in the vascular progression of melanoma.

PURPOSE: To examine a model of melanoma progression based on vascular factors and the role of NF-kappa B in the vascular progression of melanoma. PATIENTS AND METHODS: A data set of 526 patients from the University of California San Francisco Melanoma Center with 2 years of follow-up or first relapse was studied. The impact of the presence or absence of various prognostic factors on overall survival of melanoma patients was assessed using Cox regression and Kaplan-Meier analysis. A matched-pair analysis of NF-kappa B expression was performed in cases with vascular involvement and increased tumor vascularity versus matched controls lacking these factors. RESULTS: Cox regression analysis of factors evaluated by the American Joint Committee on Cancer Melanoma Staging Committee reproduced the powerful impact of tumor thickness and ulceration in this data set. With the inclusion of vascular factors such as tumor vascularity and vascular involvement, ulceration was no longer significant in predicting overall survival. By multivariate analysis, vascular involvement and tumor vascularity were the strongest predictors of melanoma outcome. Tumor vascularity seems to be a precursor of both vascular involvement and ulceration. A matched-pair tissue array analysis demonstrated the significant correlation between overexpression of NF-kappa B-p65 and the development of vascular factors. CONCLUSION: Vascular factors play an important role in the progression of malignant melanoma. Ulceration may be a surrogate marker for the interactions between melanoma and the tumor vasculature. NF-kappa B seems to play an important role in the development of these factors.

Biomarkers, Tumor↗

PubMed2002

Tumor vascularity in the prognostic assessment of primary cutaneous melanoma.

PURPOSE: The vascular supply of the primary tumor is recognized to play an important role in the progression of a number of solid tumors. However, the role of tumor vascularity in the prognostic assessment of melanoma remains unclear. The purpose of this study was to determine the prognostic impact of patterns of vascularity on the outcome associated with cutaneous melanoma. PATIENTS AND METHODS: Tumor vascularity was documented prospectively using routine histopathologic analysis of 417 primary cutaneous melanomas from the University of California at San Francisco Melanoma Center database. Four patterns of tumor vascularity were recorded: absent, sparse, moderate, and prominent. RESULTS: Increasing tumor vascularity significantly increased the risk of relapse and death associated with melanoma, corresponding to reduced relapse-free and overall survival. By multivariate analysis, tumor vascularity was the most important determinant of overall survival, surpassing tumor thickness. Increasing tumor vascularity was associated with increased incidence of ulceration in the primary tumor. CONCLUSION: Tumor vascularity is an important prognostic factor in melanoma, rivaling tumor thickness. Increasing tumor vascularity is highly correlated with ulceration, possibly helping to explain the biologic basis of this known prognostic factor.

Adolescent↗

PubMed2002

Identification of gene function and functional pathways by systemic plasmid-based ribozyme targeting in adult mice.

To date, functional genomic studies have been confined to either cell-based assays or germline mutations, using transgenic or knockout animals. However, these approaches are often unable either to recapitulate complex biologic phenotypes, such as tumor metastasis, or to identify the specific genes and functional pathways that produce serious diseases in adult animals. Although the transcription factor NF-kappaB transactivates many metastasis-related genes in cells, the precise genes and functional-pathways through which NF-kappaB regulates metastasis in tumor-bearing hosts are poorly understood. Here, we show that the systemic delivery of plasmid-based ribozymes targeting NF-kappaB in adult, tumor-bearing mice suppressed NF-kappaB expression in metastatic melanoma cells, as well as in normal cell types, and significantly reduced metastatic spread. Plasmid-based ribozymes suppressed target-gene expression with sequence specificity not achievable by using synthetic oligonucleotide-based approaches. NF-kappaB seemed to regulate tumor metastasis through invasion-related, rather than angiogenesis-, cell-cycle- or apoptosis-related pathways in tumor-bearing mice. Furthermore, ribozymes targeting either of the NF-kappaB-regulated genes, integrin beta(3) or PECAM-1 (a ligand-receptor pair linked to cell adhesion), reduced tumor metastasis at a level comparable to NF-kappaB. These studies demonstrate the utility of gene targeting by means of systemic, plasmid-based ribozymes to dissect out the functional genomics of complex biologic phenotypes, including tumor metastasis.

Aging↗

PubMed2002

Altered clinical course of malignant melanoma in HIV-positive patients.

OBJECTIVE: To determine whether the natural history of melanoma is different in patients who test positive for human immunodeficiency virus (HIV) compared with matched control subjects. DESIGN: Retrospective cohort analysis. SETTING: Ambulatory care at 2 university-affiliated medical centers. PATIENTS: Each HIV-positive melanoma patient (n = 17) was randomly matched with 2 HIV-negative patients (HIV status unknown, but without risk factors for HIV) based on the melanoma subtype, tumor thickness, Clark level, tumor location, and sex and age of the patient. MAIN OUTCOME MEASURES: Disease-free survival and overall survival of HIV-positive and HIV-negative melanoma patients were compared using a matched-pairs analysis. CD4 cell counts were recorded at the time of melanoma diagnosis and disease recurrence. RESULTS: Melanoma patients who were HIV positive had a significantly shorter disease-free survival (P =.03) and overall survival (P =.045) compared with HIV-negative melanoma patients by matched-pairs analysis. There was an inverse relationship between CD4 cell counts and time to first melanoma recurrence. CONCLUSIONS: The natural history of malignant melanoma in HIV-positive patients is more aggressive compared with matched HIV-negative melanoma patients. Altered immune response and comorbid disease may play a role in the poor clinical outcome of HIV-positive patients. These findings have important implications in the management of melanoma in the setting of HIV disease.

Adult↗