Biomedical subjects

Lydia Puricelli

Publications and source records attributed to Lydia Puricelli.

10 recordsLinked to original sources

PubMed2007

Alteration of serum and tumoral neural cell adhesion molecule (NCAM) isoforms in patients with brain tumors.

The neural cell adhesion molecule (NCAM) is involved in the intercellular junctions of neurons and glial cells. We investigated its relevance as a biomarker in gliomas which main characteristic is their high invasiveness. We studied by Western blot the pattern of serum NCAM bands in patients with gliomas (n = 34), with brain metastasis of different primary cancers (n = 27) and with benign brain tumors (n = 22)] compared with healthy controls (n = 69). For densitometric analysis NCAM bands > or = 130 kDa (HMW) and <130 kDa (LMW) were clustered. We observed that glioma patients presented higher NCAM HMW and lower NCAM LMW levels than control subjects (P < 0.01). A similar pattern was found in patients with brain metastasis or brain benign tumors, suggesting that the pattern of serum NCAM bands would be useful to detect brain tumor pathology. On the other hand, serum NCAM expression was not associated with the main clinicopathological features of gliomas, including overall survival. Interestingly, we found that 9/12 patients with glioma showed a significant decrease in NCAM HMW/LMW ratio between 1-3 months after successful tumor removal. Thus, serum NCAM could be a useful marker for monitoring treatment.NCAM expression was also analyzed at tissular level in 59 glioma sections from paraffined tumors. We observed that NCAM immunostaining was inversely correlated with the histological grade of malignancy, remaining this association in a multivariate analysis. Besides, loss of NCAM staining was significantly associated with bad prognosis in an univariate analysis.

Adult↗

PubMed2006

Regulation of galectin-1 expression by transforming growth factor beta1 in metastatic mammary adenocarcinoma cells: implications for tumor-immune escape.

Tumors escape from immune surveillance by producing immunosuppressive cytokines and proapototic factors, including TGF-beta and galectin-1 (Gal-1). Since immunosuppressive mechanisms might act in concert to confer tumor-immune privilege, we investigated the potential cross talk between TGF-beta and Gal-1 in highly metastatic mammary adenocarcinoma (LM3) cells. While Gal-1 treatment was not capable of regulating TGF-beta synthesis, a pronounced and dose-dependent increase in Gal-1 expression was observed when tumor cells were treated with TGF-beta(1. )This effect was also observed in the murine lung adenocarcinoma LP07 and in the human breast adenocarcinoma MCF-7 cell lines. TGF-beta1-mediated upregulation of Gal-1 expression was specifically mediated by TbetaRI and TbetaRII, since it was abrogated when LM3 cells were infected with retroviral vectors expressing the dominant negative forms of these receptors. In addition, gal-1 gene sequence analysis revealed the presence of three putative binding sites for Smad4 and Smad3 transcription factors, consistent with the ability of TGF-beta(1) to trigger a Smad-dependent signaling pathway in these cells. Thus, TGF-beta(1) may trigger a Smad-dependent pathway to control Gal-1 expression, suggesting that distinct mechanisms might cooperate in tilting the balance toward an immunosuppressive environment at the tumor site.

Adenocarcinoma↗

PubMed2004

Meridianins, a new family of protein kinase inhibitors isolated from the ascidian Aplidium meridianum.

Meridianins are brominated 3-(2-aminopyrimidine)-indoles which are purified from Aplidium meridianum, an Ascidian from the South Atlantic (South Georgia Islands). We here show that meridianins inhibit various protein kinases such as cyclin-dependent kinases, glycogen synthase kinase-3, cyclic nucleotide-dependent kinases and casein kinase 1. Meridianins prevent cell proliferation and induce apoptosis, a demonstration of their ability to enter cells and to interfere with the activity of kinases important for cell division and cell death. These results suggest that meridianins constitute a promising scaffold from which more potent and selective protein kinase inhibitors could be designed.

Aminopyridines↗

PubMed2004

Neural cell adhesion molecule in human serum. Increased levels in dementia of the Alzheimer type.

Memory impairment is a process associated with alterations in neuronal plasticity, synapses formation, and stabilization. As the neural cell adhesion molecule (NCAM) plays a key role in synaptic bond stabilization, we analyzed the usefulness of soluble NCAM isoforms in the diagnosis of patients with dementia of the Alzheimer type (DAT). NCAM was measured in the sera of 70 control subjects and 43 DAT patients (with different severity of cognitive impairment, GDS), employing Western blot and densitometric quantification. LMW-NCAM bands (100-130 kDa) decreased significantly with age independently of sex. DAT patients presented values of LMW-NCAM and HMW-NCAM significantly higher than healthy controls of similar age (higher than 130 kDa). Only LMW-NCAM was associated with GDS. Our results suggest that NCAM could be involved in the pathogenesis of DAT disorder and that serum NCAM levels could be useful as differential diagnostic markers of the disease.

Adult↗

PubMed2004

Prognostic value of Mdm2, p53 and p16 in patients with astrocytomas.

Surgical cure of gliomas infiltrating into the brain is practically impossible and their clinical course is primarily determined by the biological behavior of the tumor cell. The purpose of this study was to analyze retrospectively prognostic input of p53, Mouse double minute-2 (Mdm2) and p16 in 103 uniformly treated patients with astrocytic tumors. The expression of these molecules was measured by immunohistochemical procedure. Prognostic evaluation was performed with the multivariate proportional hazards model. The follow-up period lasted 19 (5-122) months for the survivors. We observed that 66% of gliomas showed mutated p53, while only 17% overexpressed Mdm2, the p53-regulatory molecule. Besides, almost 50% of gliomas lost p16 immunopositivity. Only p53 labeling showed a positive correlation with the grade of malignancy, according with the WHO classification. The association between mutated p53 and histological grade remained when prognostic variables were considered in a multivariate analysis. No association between p53 status and overall survival was found. On the other hand, Mdm2 overexpression and, unexpectedly, p16 immunopositivity were associated with a shorter survival in an univariate analysis. However, Cox-regression analysis showed that only Mdm2 in female patients was an independent prognostic factor, associated with shorter survival. In conclusion, our results suggest that Mdm2 could be a relevant marker in determining the evolution of glioma patients and could provide a more objective way to classify astrocytomas.

Adolescent↗

PubMed2004

Prognostic value of cell cycle regulator molecules in surgically resected stage I and II breast cancer.

Success in breast cancer treatment depends greatly upon early detection, and in the employment of prognostic markers able to anticipate the evolution of the disease, allowing a more rational management of the patient. A fundamental cause of cancer is the alteration of the genetic material, which may modify the expression of proteins that play key roles in cell cycle progression. The aim of this study was to analyze the expression of cyclins D1, E, and B1 and of the CDKIs p16 and p21 in a population of uniformly treated patients with stage I or II breast tumors (n=56) compared with patients with benign breast pathology (n=23). Malignant breast tumors showed higher cyclin E and lower p21 expression than benign breast pathology (NS), determined by immunohistochemistry (IHC). In breast cancer patients, overexpression of cyclins D1 and E was associated with the presence of ER and stage respectively independently of other prognostic variables (multivariate analysis). Kaplan-Meier curves demonstrated that only overexpression of cyclin E was associated with a longer recurrence-free survival. Cox analysis showed that neither cyclins nor CDKIs were independent prognostic markers. We demonstrated that several regulators of cell cycle progression were altered in a large number of breast tumor cases, however, these abnormalities were not indicators of a worse outcome in breast cancer patients of stages I and II.

Adult↗

PubMed2003

Plasma MMP-9 (92 kDa-MMP) activity is useful in the follow-up and in the assessment of prognosis in breast cancer patients.

Previously we determined that plasma MMP-9 activity was significantly elevated in breast cancer patients compared to benign mammary pathologies and healthy controls. Now we analyzed its potential usefulness in the follow-up and in the prognosis of these patients. MMP-9 activity was measured by gelatin quantitative zymography in the euglobulin plasma fraction of 46 breast cancer patients in a 38-month follow-up study. Blood samples were obtained before surgery (S1), 1 month after (S2) and every 3 months. The relapse-free survival (RFS) and overall survival (OS) analysis was performed along 56 months in 113 patients using the Kaplan-Meier curves and Cox analysis. In 63% of the S2 analyzed, MMP-9 decreased after surgery. In 44 patients evaluated during the adjuvant period who developed a complete response, MMP-9 decreased compared to their S1, whereas 2 patients showed an enhancement in correlation with lack of response. Further analysis indicated that in all patients who never showed evidence of recurrence, plasma MMP-9 activity remained low, but it increased 1 to 8 months preceding the clinical detection of progression in those patients who relapsed. Kaplan-Meier curves indicated that high levels of plasma MMP-9 activity at the moment of breast cancer diagnosis were associated with a worse OS rate. Cox analysis showed it was not associated with tumor stage or patient's age. Our results, which show a good correlation between plasma MMP-9 activity and the clinical status of each patient, suggest its usefulness as a marker both in the follow-up and in the prognosis of breast cancer patients.

Adult↗

PubMed2002

Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells.

Heregulin (HRG) and type I receptor tyrosine kinase (RTK) expression was investigated in the highly invasive and metastatic LM3 cell line, our previously described model of metastasis for mammary cancer (Bal de Kier Joffe et al. [1986] Invasion Metastasis 6:302-12; Urtreger et al. [1997] Int J Oncol 11:489-96). Although LM3 cells do not express HRG, they exhibit high levels of ErbB-2 and ErbB-3 as well as moderate expression of ErbB-4. Addition of exogenous HRGbeta1 resulted in inhibition of both proliferation and migration of LM3 cells. HRGbeta1 was also able to decrease the activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9), 2 key enzymes in the invasion and metastatic cascade. HRGbeta1 treatment of LM3 cells induced tyrosine phosphorylation of ErbB-2, ErbB-3 and ErbB-4 as well as the formation of ErbB-2/ErbB-3 and ErbB-2/ErbB-4 heterodimers. Assessment of the signaling pathways involved in HRGbeta1 action indicated that the addition of HRGbeta1 to LM3 cells resulted in activation of phosphatidylinositol 3- kinase (PI-3K) and in strong induction of the association of the p85 subunit of PI-3K with ErbB-3. HRGbeta1 also caused the rapid activation of ERK1/ERK2 and Stat3 and Stat5 (signal transducers and activators of transcription [STAT]). This is the first demonstration of the ability of HRGbeta1 to activate STATs in mammary tumor cells. Blockage of PI-3K activity with its chemical inhibitor wortmannin, or of MEK1/ERKs activity with PD98059, resulted in suppression of the ability of HRGbeta1 to inhibit LM3 cell growth. Notwithstanding the suppression of these 2 signaling pathways, HRGbeta1 still proved capable of inhibiting uPA activity. Therefore, our results provide evidence that signaling pathways involved in HRGbeta1-induced proliferation appear to be distinct from those involved in HRGbeta1 regulation of uPA, a protease that plays a pivotal role in invasion and metastasis.

Animals↗

PubMed2002

CD44 expression in human gliomas.

BACKGROUND AND OBJECTIVES: Glioma invasiveness involves the attachment of tumor cells to the brain extracellular matrix, rich in hyaluronic acid (HA). CD44, the principal receptor for HA is found as a standard molecule (CD44s) or as variants (CD44v). We undertook a retrospective study to evaluate the expression pattern of CD44s, the isoforms CD44v3, v4/5 and v6 and to correlate their expression with clinical-anatomopathological parameters and survival rate. METHODS: The expression of these molecules was evaluated immunohistochemically in 84 gliomas. RESULTS: No expression of CD44v was detected in any tumors. CD44s staining of tumor cells was found in 70 of 84 (83.3%) of the gliomas. In 23 of 39 (59.0%) of the GBM more than the 70% of the cells were stained, while only 2 of 21 (9.5%) of LGA showed high expression. The association between CD44 and histological grade remained when the prognostic variables were considered in a multivariate analysis. Higher expression of CD44 was associated with worse overall survival rate; however, the Cox analysis indicated that survival was not associated with CD44. CONCLUSIONS: Our results suggest that overexpression of CD44s could be relevant in determining the highly invasive behaviour of gliomas, though it does not behave as an independent prognostic factor for survival.

Adolescent↗

PubMedDate not supplied

Expression of CD44s and CD44 splice variants in human melanoma.

The ability of tumor cells to adhere and detach from extracellular matrix and endothelial cells, is a crucial step in the metastatic process and may alter the clinical prognosis of some human tumors such as melanomas. CD44, the major cell surface receptor for hyaluronate, has been implicated in cell adhesion and in tumor progression. We studied the expression of standard CD44 molecule (CD44s) and its variants v3 and v6 in 57 human primary melanoma biopsies, without previous treatment. We analyzed the association between CD44 expression and the principal clinicopathological features, including survival. Fifty-six of 57 tumors expressed CD44s, associated to the cytoplasmic membrane. No expression of CD44v3 or CD44v6 was detected. No association between CD44s expression and prognostic factors such as tumor thickness, growth type, stage or anatomic site of the lesion was found. However, a positive correlation between CD44s expression and Clark level (Spearman, p<0.001) was found. While only 33.3% of melanomas Clark I + II showed high expression of CD44s (more than 50% of positive cells), 82.6% of melanomas Clark IV + V did so. Kaplan-Meier analysis revelead that patients whose melanomas had high expression of CD44s showed a reduced relapse free survival (RFS) rate, though without statistical significance. No difference between the level of CD44 expression and overall survival (OS) was found. We conclude that melanomas only expressed CD44s, and that its level was associated with Clark's stage. CD44s seems not to be useful as a tumor marker, because it does not predict either RFS or OS.

Adult↗