Costanzo Moretti

Publications (78) View all

• Article: Aurora kinases: new molecular targets in thyroid cancer therapy.

  E Baldini, S Sorrenti, E D'Armiento, N Prinzi, E Guaitoli, P Favoriti, L Gnessi, C Moretti, M Bianchini, S Alessandrini, A Catania, E De Antoni, S Ulisse
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  ABSTRACT: Genetic instability, a hallmark of solid tumors including thyroid cancers, is thought to represent the mean by which premalignant cells acquire novel functional capabilities responsible for cancer cell growth and tumour progression. Over the last few years, the knowledge of the molecular processes controlling the mitotic phase of the cell cycle has increased considerably, and different mitotic proteins, whose expression or function has been found altered in human cancer tissues, have been associated to tumour genetic instability and aneuploidy. These include the three members of the Aurora kinase family (Aurora-A, -B and -C), serine/threonine kinases that regulate multiple aspects of chromosome segregation and cytokinesis. The genes encoding the Aurora kinases have been shown to induce cell malignant transformation, and their overexpression has been detected in several tumor derived cell lines and tissues, being often associated with a poor prognosis. Over the last decade, specific inhibitors of Aurora kinases exhibited in preclinical and early phase clinical studies a good therapeutic efficacy against several tumour types, including the highly aggressive anaplastic thyroid cancer and the medullary thyroid cancer. In the present review we'll first focus on the Aurora mitotic functions in normal cells; then we shall describe the main implications of their overexpression in the onset of genetic instability and consequent aneuploidy. We shall finally discuss on the effects of the functional inhibition of Aurora kinases on thyroid cancer cells growth and tumorigenicity. Clin Ter 2012; 163(6):e457-462.
  La Clinica terapeutica 11/2012; 163(6):e457-62. · 0.27 Impact Factor
• Article: Effects of the Aurora kinases pan-inhibitor SNS-314 mesylate on anaplastic thyroid cancer derived cell lines.

  E Baldini, S Sorrenti, E D'Armiento, E Guaitoli, S Morrone, V D'Andrea, L Gnessi, C Moretti, A Antonelli, A Catania, E De Antoni, S Ulisse
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  ABSTRACT: Objectives. Anaplastic thyroid carcinomas (ATC) are highly aggressive tumours unresponsive to any available radio- or chemotherapeutic protocol, with a median survival rate of 4-5 months from the time of diagnosis. We previously demonstrated that ATC are characterized by increased expression of the kinases Aurora-A, -B and -C, involved in the regulation of multiple steps of the mitotic phase. In this study, the in vitro effects of SNS-314 mesylate, a pan-inhibitor of the Aurora kinases, on growth and tumorigenicity of ATC cells were evaluated. Materials and Methods. The effects of SNS-314 mesylate were assessed on the ATC derived cell lines CAL-62, 8305C, 8505C and BHT-101 by means of cell proliferation assay, immunofluorescence, cytofluorimetry, time lapse microscopy, and colony formation in soft agar. Results. Treatment of the different ATC cells with SNS-314 mesylate inhibited proliferation in a time- and dose-dependent manner, with IC50 comprised between 2.6 nM and 26.6 nM. CAL-62 cells exposed for 24 h to SNS-314 mesylate 100 nM evidenced a significant augmentation of the apoptotic index. Time-lapse video-microscopy of CAL-62 cells showed that SNS-314 mesylate prevents the completion of mitosis leading to polyploidy. Western blot experiments demonstrated that the auto-phosphorylation of the Aurora kinases as well as histone H3 phosphorylation in CAL-62 treated cells was inhibited. Finally, the drug inhibited colony formation in soft agar of all cell lines. Conclusions. Our results demonstrated that SNS-314 mesylate is capable to efficiently reduce cell growth and tumorigenicity of different ATC derived cell lines suggesting its potential therapeutic value for ATC treatment. Clin Ter 2012; 163(5):e307-313.
  La Clinica terapeutica 09/2012; 163(5):e307-13. · 0.27 Impact Factor
• Article: Lack of Influence of the Androgen Receptor Gene CAG-Repeat Polymorphism on Clinical and Electrocardiographic Manifestations of the Brugada Syndrome in Man.

  S Mariani, B Musumeci, S Basciani, D Fiore, P Francia, A Persichetti, M Volpe, C Autore, C Moretti, S Ulisse, L Gnessi
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  ABSTRACT: Clinical studies suggest that testosterone (T) plays an important role in the male predominance of the clinical manifestations of the Brugada syndrome (BS). However, no statistically significant correlations have been observed between T levels and electrocardiogram (ECG) parameters in the BS patients. We investigated whether the hormonal pattern and the variation within CAG repeat polymorphism in exon 1 of the androgen receptor (AR) gene, affecting androgen sensitivity, are associated with the Brugada ECG phenotype in males. 16 male patients with BS (mean age 45.06 ± 11.3 years) were studied. 12-lead ECG was recorded. Blood levels of follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, free-T, dihydrotestosterone, 17-β-estradiol, estrone, 3-alpha-androstanediol-glucuronide, delta-4-androstenedione, dehydroepiandrosterone sulphate, progesterone, 17-hydroxyprogesterone, and sex hormone binding globulin were assayed. Genotyping of CAG repeats on DNA extracted from leukocytes was carried out. No relationship was found between hormone values and ECG parameters of BS. BS patients showed the CAG length normally recognized in the human polymorphism range and the number of CAG repeats did not correlate with the ECG pattern of BS. The AR CAG repeat length does not correlate with the ECG features of the patients affected by BS. The search for genes downstream AR activation as possibly responsible for the increased risk of spontaneous arrhythmias in BS males after puberty is warranted.
  Clinical Medicine Insights. Cardiology. 01/2012; 6:145-52.
• Source

  Available from: Stefano R Del Giacco

  Article: Rhinitis and asthma in athletes: an ARIA document in collaboration with GA2LEN.

  S Bonini, M Bonini, J Bousquet, V Brusasco, G W Canonica, K-H Carlsen, L Corbetta, J Cummiskey, L Delgado, S R Del Giacco, [......], S Jaeger, C Moretti, P Palange, G Passalacqua, D Passali, B K Pedersen, T Popov, G Rasi, M T Ventura, A M Vignola
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  ABSTRACT: This consensus document is aimed at reviewing evidence that the rhinitis-asthma links have peculiar features in athletes. Beside a review of epidemological data on the high prevalence of rhinitis and asthma in athletes, the effects on intense physical exercise on the immune system and repiratory functions are discussed, with special reference to the role of allergens and pollutants. In extending the Allergic Rhinitis and its Impact on Asthma (ARIA) recommendations to athletes, the issue is addressed of adapting diagnosis and management to criteria set by the International Olympic Committee (IOC) and regulations adopted by the World Anti-Doping Agency (WADA).
  Allergy 07/2006; 61(6):681-92. · 6.27 Impact Factor
• Source

  Available from: Costanzo Moretti

  Article: An uncommon large deletion in the androgen-receptor gene in a XY female with complete androgen insensitivity syndrome.

  C Moretti, T Odorisio, R Geremia, P Grimaldi
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  ABSTRACT: Androgen insensitivity is a disorder characterized by an abnormal male sexual development, in which the androgen action is impaired due to structural defects in the androgen receptor gene. We report a case of a 46,XY subject with female phenotype (normal breast and external genitalia) lacking sexual hair, affected with primary amenorrhea. In this patient, we found a deletion of a large region of the androgen receptor gene encoding the steroid-binding domain of the protein, causing a complete inability to bind the androgens. This uncommon molecular defect impaired the expression of androgen-dependent genes inducing the female phenotype.
  Journal of endocrinological investigation 06/2006; 29(5):457-61. · 1.57 Impact Factor