Silvia Ursino

Università di Pisa, Pisa, Tuscany, Italy

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Publications (20)59.62 Total impact

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    ABSTRACT: Background: Conflicting data are reported on the association between mild thyroid failure and lipid profile, primarily regarding serum triglyceride values and patients with slightly elevated thyrotropin (TSH, <10 mIU/L). In this study, we assessed the possible influence of gender and age on this relationship. Methods: The study included 2308 consecutive patients who were seen for suspected or diagnosed thyroid disease (1874 women, 434 men, mean age 47.5±14.1 and 46.9±14.0 years, respectively) and on whom studies of thyroid status and lipoprotein profile were conducted after an overnight fast. Patients with uncontrolled diabetes mellitus and those taking lipid-lowering drugs were excluded. Results: There were 628 patients receiving L-thyroxine who had a diagnosis of hypothyroidism: 200 were hyperthyroid, and 120 were still hypothyroid. Overall, 648 patients were hypothyroid, and 290 were hyperthyroid. No gender difference in the frequency of TSH values in the ranges studied (i.e., TSH frequency distribution) was observed. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDLc) values (p<0.0003 and p<0.003, respectively) as well as the LDL/high-density lipoprotein cholesterol (HDLc) ratio (p<0.03) were elevated not only in unselected women with TSH values in the 4th TSH group (>10 mIU/L) but also in those of the 3rd group (3.6-10.0 mIU/L) who were older than 50 years (TC and LDLc p=0.01, LDL/HDLc ratio p=0.02 vs. euthyroid women). Among unselected men, only those of the 4th TSH group had elevated triglyceride (p<0.0001) but not cholesterol values. However, men of the 3rd and 4th TSH group who were older than 65 years had significantly higher TC, LDLc, and LDL/HDLc values as well (p=0.03, p=0.02 and p=0.01, respectively vs. euthyroid men). In the final model of stepwise regression for predicting each lipid parameter variation on the basis of age, TSH, free thyroxine (FT4), and body mass index (BMI) analysis, age had the highest standardized coefficient (0.36 and 0.37, respectively), followed by TSH (0.20 and 0.11, respectively) and FT4 (-0.11 and -0.09, respectively) when looking at TC and LDLc; whereas BMI had the highest standardized coefficient (0.28), followed by age (0.15) and TSH (0.11) when looking at triglyceride variation. Conclusions: This study confirms a gender differentiation in the relationship between hypothyroidism and the lipid profile, which is substantially influenced by age, especially in patients with mild thyroid impairment (TSH<10 mIU/L).
    Thyroid: official journal of the American Thyroid Association 10/2012; · 2.60 Impact Factor
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    ABSTRACT: Introduction:Human leukocyte antigen-G (HLA-G), a nonclassical major histocompatibility complex class I antigen, plays a pivotal role in immune tolerance and a paradoxical role in cancers.Aims:Our aims were to evaluate plasma soluble HLA-G (sHLA-G) concentrations and the 14-bp insertion/deletion polymorphism of the HLA-G gene in patients with papillary thyroid carcinoma (PTC) or Hashimoto's thyroiditis (HT) and to assess the possible association of these parameters with PTC aggressiveness.Methods:Samples for the analysis of sHLA-G and +14/-14-bp HLA-G polymorphism were obtained from 121 patients with HT and 183 with PTC; 245 gender- and age-matched healthy subjects served as controls. PTC histopathological aggressiveness was defined according to the last American Thyroid Association guidelines.Results:Positive serum antithyroid antibody titers were observed in 22% of PTC patients and lymphocyte infiltration of thyroid parenchyma at histological examination in 21%, whereas both circulating and histological autoimmunity was detectable in 12% of PTC patients. No differences in the +14/-14-bp polymorphism frequencies were observed between the study groups. The prevalence of detectable sHLA-G was lower in healthy controls (52%) as compared with both HT (57%) and PTC (62%) patients. By stratifying the study groups according to sHLA-G level of positive subjects, significantly higher plasma sHLA-G values in PTC (42.9 ± 3.3 ng/ml; P = 0.002) and HT patients (49.1 ± 2.6 ng/ml; P < 0.002) as compared with healthy controls (8.5 ± 1.8 ng/ml) were obtained. Moreover, PTC patients with detectable plasma sHLA-G levels showed a higher aggressive behavior (P < 0.04) than those without.Conclusions:Although confirming the frequent association between PTC and chronic autoimmune thyroiditis, these data suggest that elevated circulating sHLA-G levels, besides an important signal of alterations of immune homeostasis, may be considered a potential, novel marker of PTC histopathological aggressiveness at diagnosis. Additional studies are needed to confirm the actual role and clinical relevance of the HLA-G complex in PTC development and progression.
    The Journal of Clinical Endocrinology and Metabolism 08/2012; · 6.31 Impact Factor
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    ABSTRACT: Background Conflicting data are reported on the association between mild thyroid failure and lipid profile, primarily regarding serum triglyceride values and patients with slightly elevated TSH (<10 mIU/l). In this study, we assessed the possible influence of gender and age on this relationship. Methods The study included 2308 consecutive patients who were seen for suspected or diagnosed thyroid disease (1874 F, 434 M, mean age 47.5±14.1 and 46.9±14.0 years, respectively) who had studies of thyroid status and lipoprotein profile after an overnight fast. Patients with uncontrolled diabetes mellitus and those taking lipid-lowering drugs were excluded. Results. 628 patients receiving L-thyroxin had already a diagnosis of hypothyroidism: 200 were hyperthyroid and 120 still hypothyroid. Overall, 648 patients resulted hypothyroid and 290 hyperthyroid. No gender difference in the frequency of TSH values in the ranges studied (i.e. TSH frequency distribution) was observed. Total cholesterol (TC) and LDL cholesterol (LDLc) values (p<0.0003 and p<0.003, respectively) as well as the LDL/HDLc ratio (p<0.03) were elevated in unselected women with TSH values in the 4th TSH group (>10 mIU/l) but also in those of the 3rd group (3.6<TSH<10.0 mIU/l) older than 50 years (TC and LDLc p=0.01, LDL/HDLc ratio p=0.02 Vs euthyroid women). Among unselected men only those of the 4th TSH group had elevated triglyceride (p<0.0001) but not cholesterol values. However, men of the 3rd and 4th TSH group older than 65 years had significantly higher TC, LDLc and LDL/HDLc values too (p=0.03, p=0.02 and p=0.01, respectively Vs euthyroid men). In the final model of stepwise regression for predicting each lipid parameter variation on the basis of age, TSH, FT4, and body mass index (BMI) analysis, age had the highest standardized coefficient (0.36 and 0.37, respectively), followed by TSH (0.20 and 0.11, respectively) and FT4 (-0.11 and -0.09, respectively) looking at TC and LDLc whereas, BMI had the highest standardized coefficient (0.28), followed by age (0.15) and TSH (0.11) looking at triglyceride variation. Conclusions This study confirms a gender differentiation in the relationship between hypothyroidism and lipid profile, which is substantially influenced by age, especially in patients with mild thyroid impairment (TSH<10 mIU/l).
    Thyroid: official journal of the American Thyroid Association 08/2012; · 2.60 Impact Factor
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    ABSTRACT: Targeting the epidermal growth factor receptor has played a central role in advanced non-small cell lung cancer research, treatment, and patient outcomes over the last several years; however, a number of questions about this approach remain to be addressed. Through the Istituto Toscano Tumori and the Italian Association of Women Against Lung Cancer Project, we collected 411 lung adenocarcinomas from several clinical centers in Tuscany. Mutations were assessed by sequencing exons 18-21 of the epidermal growth factor receptor gene, and by restriction fragment length polymorphism analysis of codons 12 and 13 of the K-RAS gene. Epidermal growth factor receptor mutations (12.6%) were more frequently observed in females (p<0.0001), in non-smokers (p=0.005), and in the presence of bronchioloalveolar features (p=0.0004). K-RAS mutations (17.9%) were more frequent in males (p=0.0007) and were associated with smoking habits (p=0.005). Epidermal growth factor receptor and K-RAS mutations were mutually exclusive (p=0.001). We focused on 21 female patients with advanced/metastatic lung adenocarcinoma who received gefitinib 250 mg/day (expanded access) or erlotinib 150 mg/die as second/third-line therapy; partial response was associated with classic epidermal growth factor receptor mutations (p=0.006) and with a non-smoking history (p=0.02). None of the female patients with partial response and/or stable disease showed K-RAS alterations. Although the data obtained in our study have yet to be analyzed and confirmed with a larger number of patients treated with tyrosine kinase inhibitors, they should provide useful information for targeted therapy, in particular for non-smoking female lung cancer patients.
    Oncology Reports 10/2009; 22(4):683-91. · 2.30 Impact Factor
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    ABSTRACT: Interferon (IFN) therapy may induce a generalized activation of the immune system, hence triggering or exacerbating autoimmune disease. Apoptosis contributes to the development of hypothyroidism in autoimmune thyroiditis. IFN can affect all phases of the cell cycle and may induce apoptosis in several cell lines from varied histologies. To date, no data exist on the possible effect of type I IFN(s) on FAS/FASL system and cell apoptosis of human thyroid follicles. Therefore, we evaluated the effect of both IFN-alpha and -beta on apoptosis in primary human thyrocyte cultures and the potential role of the FAS/FASL pathway. Thyrocytes were cultured in monolayers and FAS, FASL, and Bcl-2 mRNA expression was determined by reverse transcriptase polymerase chain reaction after exposure to 10 mIU/mL bovine thyroid-stimulating hormone alone or in combination with increasing doses of IFN-alpha or -beta for 24, 48, and 72 hours. The percentage of apoptotic hypodiploid cells was evaluated by flow cytometry. Thyroid-stimulating hormone significantly decreased FAS and increased Bcl-2 mRNA expression while reducing the percentage of hypodiploid cells. The concomitant addition of either IFN-alpha or -beta reduced cell viability and increased the number of hypodiloid cells, but only IFN-beta modulated the expression of FAS and Bcl-2 mRNA expression in a proapoptotic sense. Both type I IFN(s) increase apoptosis in primary thyrocyte cultures, but only IFN-beta modulates FAS and Bcl-2 gene expression toward a proapoptotic pathway. Because apoptosis plays an important role in thyroid homeostasis and disease, this mechanism may contribute to the development and progression of type I IFN(s) therapy-associated thyroid disease.
    Thyroid: official journal of the American Thyroid Association 03/2009; 19(2):149-55. · 2.60 Impact Factor
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    ABSTRACT: Mutations of the p53 gene represent the most common genetic alterations in human cancer. Several reports have focused on p53 polymorphisms as risk factors in lung cancer, in particular at codon 72 of exon 4, encoding either an arginine (Arg72R) or a proline (Pro72P) amino acid. Polymorphisms at codon 72 of the p53 gene were determined using a PCR-RFLP-based method. We analysed the relationship of this polymorphism to patient survival in 121 non-small cell lung cancer (NSCLC) cases. Interestingly, the 72P homozygous NSCLC patients often presented high-grade tumours and had significantly poorer survival rates than patients with R72 homozygotes or heterozygotes. Our results may help clarify discrepancies in the literature concerning the prognostic role of p53 codon 72 variants.
    Oncology Reports 04/2008; 19(3):771-3. · 2.30 Impact Factor
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    ABSTRACT: A total of 42 polymorphisms have been identified in the TP53 gene. The polymorphic site of p53 at codon 72 in exon 4 and p53PIN3, a 16 bp insertion/duplication in intron 3, are the most studied. We tested p53PIN3 and the combined effect of the p53 codon72 and PIN3 polymorphisms on prognosis in 101 NSCLC cases. This study provides support for the prognostic effects of the multi-variant alleles from p53 exon 4 and intron 3, resulting in a significantly poorer prognosis in NSCLC. This approach highlights the value of examining multiple polymorphisms in genes to improve survival estimates.
    Cancer Investigation 04/2008; 26(2):168-72. · 2.24 Impact Factor
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    ABSTRACT: The discovery that somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with sensitivity to the EGFR tyrosine kinase inhibitors (TKIs) in lung adenocarcinomas, whereas Kras mutations are associated with resistance, has generated excitement among both clinicians and researchers studying non-small cell lung cancer (NSCLC). Mutational analysis may soon be very useful in choosing among a wide range of targeted therapies to individualize treatment to tumor characteristics. This analysis would be even more useful in patients with advanced NSCLC, in whom cytological specimens are often the only material available. We analyzed 23 archived cytologic specimens of advanced/metastatic lung adenocarcinomas for mutations in EGFR exons 18 to 21, and Kras exon 2. Our data show that our cytological specimens were perfectly adequate for the molecular analysis of EGFR and Kras mutations. EGFR TK domain mutations were found in three cases (13.04%) and were associated with both female gender (p = 0.02) and a nonsmoking history (p = 0.008). Moreover, we explored the relationship between EGFR mutation status and the presence of Kras mutations. Kras mutations involving codon 12 in exon 2 were found in 5 (21.73%) of the 23 adenocarcinomas and were associated, where known, with smoking habits. We never found EGFR alterations in tumors with Kras mutations. Our results provide oncologists with a highly accurate laboratory method to identify biological predictors of the efficacy of different therapies, and they may have an important impact on clinical practice. This method may be particularly useful in patients with advanced/metastatic NSCLC.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 01/2008; 2(12):1086-90. · 4.55 Impact Factor
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    ABSTRACT: The CDC25 phosphatases are cell cycle regulators known to play an important role in cancer cell growth. Increased expression of CDC25B has been reported in tumors of different tissue origins, including non-small cell lung carcinoma (NSCLC). We analyzed primary tumors and corresponding healthy lung tissues from 177 patients with NSCLC for relative expression levels of CDC25B by reverse transcription-polymerase chain reaction, with the dual aims of investigating the relationships between CDC25B expression and angiogenesis as well as prognosis. Eighty-one (45.76%) of the 177 patients with NSCLC overexpressed the CDC25B gene; there was no significant difference in CDC25B expression among sex, age, T or N status, or clinical stages of NSCLC. Concerning the possible involvement of CDC25B in angiogenesis, high expression of CDC25B correlated with positive expression of endothelin-1 (chi(2) test; P = .0002), one of the major angiogenic factors in NSCLC. A significant association was also found with the number of intratumoral microvessels (chi(2) test; P = .03). Statistical analysis of survival data revealed that elevated CDC25B expression was significantly associated with shorter survival in terms of both overall survival and disease-free interval (P = .04 for both), maintaining its independent prognostic role in a Cox proportional hazards model (P = .009). A rich and varied engagement of many cellular pathways could cause or maintain a cancer; our study may offer insights into these mechanisms in lung cancer, suggesting that CDC25B might play an important role in the angiogenic process and in determining the prognosis of patients with NSCLC.
    Human Pathlogy 11/2007; 38(10):1563-8. · 2.84 Impact Factor
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    ABSTRACT: COX-2 expression was evaluated in intracranial meningiomas, relating this molecule to grade, vasculature, VEGF and brain edema. Fifty-six tumors were evaluated for COX-2 and VEGF expression and for microvessel density. In 34/56 cases, the edema was evaluated by CT scan. COX-2 was detected in 46/56 meningiomas (82.14%), and it resulted as being related to histologic grade (t-test: p = 0.006) and to edema (t-test: p = 0.002). No statistical association between COX-2 and VEGF or MVD was found. In conclusion, COX-2 seems to be related to the more aggressive meningiomas and, somehow, to the development of meningioma-associated brain edema.
    Cancer Investigation 11/2007; 25(7):555-62. · 2.24 Impact Factor
  • Journal of Thoracic Oncology - J THORAC ONCOL. 01/2007; 2.
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    ABSTRACT: Meningiomas are one of the most frequent central nervous system tumours. Although slow-growing at times, they continue to be a cause of morbidity and mortality. The endothelin (ET) family consists of three isoforms: ET-1 is the most abundant one. ET-1 may be involved in meningioma tumourigenesis in concert with other growth factors, in particular with angiogenic agents. We analysed ET-1 expression by immunohistochemistry and its activating system by reverse-transcription-polymerase chain reaction in 56 cases of meningioma. We found an association between high-grade meningiomas and high ET-1 expression levels (p=0.002). Moreover, we evaluated the potential angiogenic role of ET-1, finding an elevated microvessel count in tumours with high ET expression levels (p=0.004). ET-1 may contribute to meningioma growth by inducing formation of new blood vessels. The finding that ET-1 expression positively correlates with vascular endothelial growth factor (VEGF) expression in meningiomas (p=0.03) also supports the hypothesized modulating effect of ET-1 on angiogenesis. Thus, the influence of the ET system on the progression of meningiomas may occur through stimulation of VEGF. The association of ET-1 and meningioma represents a potential area for therapeutic intervention with selective ET inhibitors. Additional clinical studies will be needed before inhibitors can be incorporated in clinical practice.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 12/2006; 449(5):546-53. · 2.68 Impact Factor
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    ABSTRACT: Human telomerase is a structurally complex ribonucleoprotein that is responsible for the maintenance of telomeric DNA at the ends of the chromosomes. The enzyme is proposed as having an important role in cell immortalization and oncogenesis. A limited number of studies have been performed on the telomerase system in brain tumors, and these studies are somewhat conflicting. The relative ineffectiveness of current therapies for malignant gliomas led to the need for novel targets for more promising approaches. In order to clarify the prognostic significance of telomerase expression in gliomas and to speculate on therapeutic implications, we examined telomerase activity by the telomeric repeat amplification protocol (TRAP) assay in 42 gliomas, (32 multiform glioblastomas, 4 anaplastic astrocytomas, 4 differentiated astrocytomas, 1 oligoastrocytoma and 1 oligosarcoma). Telomerase messenger expression (hTERT mRNA) was evaluated by reverse transcription-PCR analysis in the same group of tumors. High telomerase activity was detected in 21/42 gliomas (50%). The levels of telomerase in terms of its messenger level expression overlapped the activity; in fact, a significant association between telomerase activity and hTERT mRNA expression was found (chi2 test; p<0.0001). At univariate analysis, advanced age as well as high telomerase activity and hTERT mRNA levels were seen to be significant predictors of worse prognosis regarding both overall survival (p=0.007, p=0.007, p=0.04, respectively) and disease-free interval (p=0.008, p=0.008, p=0.04, respectively). All these variables maintained a significant independent prognostic role in multivariate analysis. Telomerase may represent an indicator of progression and poor prognosis in this type of cancer, with interesting therapeutic implications.
    International Journal of Oncology 07/2006; 28(6):1555-60. · 2.66 Impact Factor
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    ABSTRACT: Cytokines mediate numerous physiological and immune reactions, which are manifested in various biological effects, including tumouricidal activity. We evaluated the expression of the pleiotropic cytokine, tumour necrosis factor-alpha (TNF-alpha), by competitive PCR technique in 47 non-small cell lung cancer (NSCLC) cases and the impact of TNF-alpha on their clinical behaviour. Using univariate analysis, our study demonstrated a positive correlation between high TNF-alpha expression and favourable prognosis in NSCLC in terms of overall survival and disease free interval (p=0.03 and 0.04, respectively) and TNF-alpha maintained its independent role in multivariate analysis. TNF-alpha can stimulate the expression of many molecules, including interleukin-8 (IL-8) and endothelin-1 (ET-1); in our study, the expression of TNF-alpha was significantly associated with high IL-8 mRNA levels (p=0.008) and ET-1 mRNA positivity (p=0.03). We suggested that TNF-alpha can induce ET-1 mRNA expression in NSCLC, similarly to IL-8 expression. Our study may also contribute to advancing the knowledge of the molecular relationship between cytokines and endothelial functions in NSCLC.
    International Journal of Molecular Medicine 06/2006; 17(5):887-92. · 1.96 Impact Factor
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    ABSTRACT: Progression of solid tumors, including NSCLC, is associated with increase in MVC (microvessel count), as a measure of tumor angiogenesis resulting from an imbalance between angiogenic factors and inhibitors. However, since tumor angiogenesis is a multi-step process under the control of various molecules, the mechanism of angiogenesis has not been fully clarified. Interleukin (IL)-8 has been shown to have a potential angiogenic effect in vitro and in vivo, and is overexpressed in several human solid cancers. Among the various angiogenic factors, vascular endothelial growth factor (VEGF) has been shown to correlate with a high MVC and with adverse prognosis in several human cancers, including NSCLC. Alterations of p53 suppressor gene are the most common genetic changes found in malignant tumors; several studies examined the link between aberrant p53 and angiogenesis in lung cancer, but only a few studies report data regarding a relation between p53 mutations and IL-8 expression. In this study we observed a correlation between IL-8 mRNA expression, intratumoral MVC and VEGF mRNA expression levels; furthermore, an aberrant p53 status was related to IL-8 expression. However, in our samples IL-8 levels did not significantly affect prognosis of NSCLC; more studies are required to elucidate the precise role of IL-8 in a large series of patients with non-small cell lung carcinoma.
    Lung Cancer 01/2006; 50(3):309-17. · 3.39 Impact Factor
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    ABSTRACT: The endothelin (ET) system influences tumourigenesis and tumour progression by various mechanisms, including angiogenesis. The aim of this study was to determine whether the expression of endothelin-1 (ET-1) is related to the angiogenic phenomenon in lung cancer and whether it could be involved in its clinical behaviour. Expression of ET-1, endothelin-converting enzyme-1 (ECE-1) and endothelin-receptors ETA and ETB was examined in 201 non-small cell lung carcinoma (NSCLC) and corresponding normal tissues using real-time polymerase chain reaction (RT-PCR). Forty NSCLC were also analysed for vascular endothelial growth factor (VEGF) expression by a competitive-PCR approach to assess whether ET-1 expression was related to this angiogenic factor. A higher number of cases with ET-1, ECE-1 and ETA mRNA expression was observed in malignant lung tumours compared with normal lung tissues (45.7% versus 33% for ET-1 (P < 0.0001); 38.3% versus 16.5% for ECE-1 (P = 0.004); and 42.8% versus 28.5% for ETA (P < 0.0001)). On the other hand, ETB mRNA was higher in normal lung tissues than in tumour samples (58.5% versus 52.8% (P < 0.0001)). Immunohistochemical analysis was also performed in 78 cases, selected from among those with high ET-1 mRNA, to confirm the presence of ET-1 protein and to determine its distribution and localisation. Moreover, an interesting relationship was observed between ET-1 and VEGF mRNA levels (P = 0.02). At univariate analysis, clinical-pathological parameters, such as sex, nodal metastatic involvement and stage, and ET-1 expression were seen to be significant predictors of worse prognosis regarding both overall survival (P = 0.001, P = 0.0003, P = 0.001 and P = 0.03, respectively) and disease-free interval (P = 0.0005, P = 0.0007, P = 0.001 and P = 0.04, respectively). We conclude that ET-1 could be involved in angiogenic phenomena in NSCLC and may represent a further indicator of progression and poor prognosis in this type of cancer, with interesting therapeutic implications.
    European Journal of Cancer 12/2005; 41(18):2828-35. · 5.06 Impact Factor
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    ABSTRACT: The c-kit protein, also known as CD117, is a member of the type III receptor tyrosine kinase family. Kinase activity has been implicated in the pathophysiology of many tumors, including small-cell lung carcinoma (SCLC). Autocrine or paracrine activation of c-kit by its ligand has been postulated for lung cancer, but this receptor can also be activated by mutations of the c-kit gene. We examined c-kit expression and mutational status in SCLC to verify its putative expression and genetic alterations, as well as its eventual prognostic impact. We studied 60 SCLC samples to determine the mutations of the coding region of the gene; the exons 9 and 11 were analyzed by PCR-single-strand conformational polymorphism and automated sequencing. Moreover, c-kit expression was evaluated in 55 samples by immunohistochemical method. Expression of c-kit was demonstrated in about 40% of SCLC samples. Two mutations in exon 9 and three mutations in exon 11 were found. Kaplan-Meier analysis revealed no prognostic significance of c-kit expression for survival. In our series, the expression of c-kit and its mutational status failed to appear relevant or to have a significant impact on survival; this makes the therapeutic approach with an inhibitor of tyrosine kinase more difficult in SCLC until a sure demonstration of c-kit implication is obtained for this tumor.
    Clinical Cancer Research 07/2004; 10(12 Pt 1):4101-8. · 7.84 Impact Factor
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    ABSTRACT: Telomeres are the distal ends of human chromosomes composed of tandem repeats of the sequence TTAGGG. In most human somatic cells, telomerase activity is undetectable, and the telomere length is progressively shortened during cell proliferation, leading to cellular senescence. In contrast, telomerase is activated in the vast majority of cancer cells, including colorectal cancer. The human telomerase complex is comprised of multiple components, but telomerase reverse transcriptase (hTERT) is the most important component for the control of telomerase activity. The p53 protein is a transcription factor with multiple biological activities, including cell cycle arrest and/or apoptosis upon DNA damage, hypoxia and oncogene activation; this requires transactivation or repression of specific target genes by wild-type p53. To better understand if a link between hTERT/telomerase regulation and p53 status exists in colorectal carcinogenesis, we analysed 43 cases of colorectal carcinoma for hTERT mRNA expression and telomerase activity. Moreover, a complete analysis of p53 status was performed. Alterations of p53 gene were found in 44.19% of cases and missense point mutations represented a high proportion of p53. Both telomerase activity (p=0.014) and hTERT expression (p=0.03) were significantly associated with p53 mutations, suggesting a role of p53 in the signaling pathway for telomerase control.
    Oncology Reports 03/2004; 11(2):395-400. · 2.30 Impact Factor
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    ABSTRACT: Telomere length maintenance is essential for tumorigenesis; most human tumors stabilize their chromosome ends via the activity of a specialized reverse transcriptase, telomerase, that uses the template region of the RNA moiety complementary to the TTAGGG repeat to synthesize one strand of telomeric DNA. Meningiomas are estimated to constitute between 13% and 26% of primary intracranial tumors. The aim of this study was to evaluate telomerase activity and its messenger expression in meningiomas in relation to their different histologic pattern and grade of cytonuclear atypies, which are associated with relapse, and consequently represent the most important parameter for the evaluation of the clinical behavior of this tumor. Telomerase activity was examined by the telomeric repeat amplification protocol (TRAP) assay in 32 meningiomas (26 typical and 6 atypical/anaplastic). Telomerase messenger expression (hTERT mRNA) was evaluated by reverse transcription-PCR analysis in the same group of tumors. Telomerase activity ranged from undetectable to low levels in 19/26 (73%) of typical meningiomas, while all the atypical/anaplastic meningiomas showed medium-high levels of activity (>3 TPG units, median value), (chi(2) test; p=0.001). The levels of telomerase in terms of its messenger level expression overlapped the activity; a significant association between telomerase activity and hTERT mRNA expression was also found (chi(2) test; p=0.01). Moreover, 2 atypical/anaplastic meningiomas of our series relapsed; in these samples we found high levels of telomerase, both in terms of activity and mRNA expression. Telomerase activity and its hTERT mRNA expression tended to increase as the histologic grading of intracranial tumors increased, suggesting a role of telomerase reactivation in the progression of these tumors. Moreover, our results indicate RT-PCR assay as a rapid tool to identify and quantify telomerase RNA in intracranial meningiomas as in other human tumor models.
    International Journal of Molecular Medicine 12/2003; 12(6):943-7. · 1.96 Impact Factor
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    ABSTRACT: Angiogenesis is a central process in the growth of solid tumors. The purpose of our study was to analyze the angiogenic pattern in squamous and basal cell carcinomas and to point out differences in microvessel density that could explain their different biological behaviour. Thirty-nine skin tumors (26 basal and 13 squamous cell carcinomas) were analyzed. In all samples, the microvessels density (MVD) and the levels of vascular endothelial growth factor mRNA (VEGFmRNA) were analyzed, together with the inter-relationship between these two variables. Using the median value of the entire series (33 vessels per 2.22 mm2), tumors with low and high MVD were identified. The majority of cancers with high vascularization belonged to the squamous histotype (12 of 39), while 19 of the 26 basal cell carcinomas showed a lower number of microvessels than the median value (p = 0.0001). The median value of VEGFcDNA quantitation allowed us to distinguish tumors with high VEGF expression (> 470 molecules cDNA) from those with low (< or = 470 molecules) VEGF expression: 20 of the 26 basal cell carcinomas showed low VEGF expression, while 11 of the 13 squamous cell carcinomas showed high VEGFcDNA levels (p = 0.0003). Moreover, a significant association between a high microvessel density and high VEGFmRNA levels (p = 0.006) was found. Furthermore, when studying VEGF expression by immunohistochemistry, we obtained similar results and noted a correlation with VEGFmRNA expression (p < 0.0001). The association between high vascularization, high VEGF levels, and squamous cell histotype suggests the possible role of neoangiogenesis in determining the more aggressive biological behaviour of this type of cancer.
    Pathology - Research and Practice 02/2003; 199(11):705-12. · 1.21 Impact Factor