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51. PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity

Author

Stocco, G, Yang, W, Crews, K, Thierfelder, W, Decorti, G, Londero, M, Franca, R, Rabusin, M, Valsecchi, M, Pei, D, Cheng, C, Paugh, S, Ramsey, L, Diouf, B, Mccorkle, J, Jones, T, Pui, C, Relling, M, Evans, W, VALSECCHI, MARIA GRAZIA, McCorkle, J, Evans, W., Stocco, G, Yang, W, Crews, K, Thierfelder, W, Decorti, G, Londero, M, Franca, R, Rabusin, M, Valsecchi, M, Pei, D, Cheng, C, Paugh, S, Ramsey, L, Diouf, B, Mccorkle, J, Jones, T, Pui, C, Relling, M, Evans, W, VALSECCHI, MARIA GRAZIA, McCorkle, J, and Evans, W.

Abstract

Treatment-related toxicity can be life-threatening and is the primary cause of interruption or discontinuation of chemotherapy for acute lymphoblastic leukemia (ALL), leading to an increased risk of relapse. Mercaptopurine is an essential component of continuation therapy in all ALL treatment protocols worldwide. Genetic polymorphisms in thiopurine S-methyltransferase (TPMT) are known to have a marked effect on mercaptopurine metabolism and toxicity; however, some patients with wild-type TPMT develop toxicity during mercaptopurine treatment for reasons that are not well understood. To identify additional genetic determinants of mercaptopurine toxicity, a genome-wide analysis was performed in a panel of human HapMap cell lines to identify trans-acting genes whose expression and/or single-nucleotide polymorphisms (SNPs) are related to TPMT activity, then validated in patients with ALL. The highest ranking gene with both mRNA expression and SNPs associated with TPMT activity in HapMap cell lines was protein kinase C and casein kinase substrate in neurons 2 (PACSIN2). The association of a PACSIN2 SNP (rs2413739) with TPMT activity was confirmed in patients and knock-down of PACSIN2 mRNA in human leukemia cells (NALM6) resulted in significantly lower TPMT activity. Moreover, this PACSIN2 SNP was significantly associated with the incidence of severe gastrointestinal (GI) toxicity during consolidation therapy containing mercaptopurine, and remained significant in a multivariate analysis including TPMT and SLCO1B1 as covariates, consistent with its influence on TPMT activity. The association with GI toxicity was also validated in a separate cohort of pediatric patients with ALL. These data indicate that polymorphism in PACSIN2 significantly modulates TPMT activity and influences the risk of GI toxicity associated with mercaptopurine therapy.

Published
2012

54. In vitro sensitivity to methyl-prednisolone is associated with clinical response in pediatric idiopathic nephrotic syndrome.

Author

Cuzzoni, E, De Iudicibus, S, Stocco, G, Favretto, D, Pelin, M, Messina, G, Ghio, L, Monti, E, Pasini, A, Montini, G, and Decorti, G

Subjects
METHYLPREDNISOLONE, NEPHROTIC syndrome in children, GLUCOCORTICOIDS, CELL proliferation, THYMIDINE
Abstract

The aim of this study was to evaluate the in vitro steroid sensitivity as a predictor of clinical response to glucocorticoids in childhood idiopathic nephrotic syndrome (INS). Seventy-four patients (median age 4.33, interquartile range [IQR] 2.82-7.23; 63.5% male) were enrolled in a prospective multicenter study: in vitro steroid inhibition of patients' peripheral blood mononuclear cell proliferation was evaluated by [methyl-3H] thymidine incorporation assay at disease onset (T0) and after 4 weeks (T4) of treatment. Steroid dependence was associated with increased in vitro sensitivity at T4 assessed both as drug concentration inducing 50% of inhibition (IC50; odds ratio [OR] = 0.48, 95% confidence interval [CI] = 0.24-0.85; P = 0.0094) and maximum inhibition at the highest drug concentration (Imax; OR = 1.13, 95% CI = 1.02-1.31; P = 0.017). IC50 > 4.4 nM and Imax < 92% at T4 were good predictors for optimal clinical response. These results suggest that this test may be useful for predicting the response to glucocorticoid therapy in pediatric INS. [ABSTRACT FROM AUTHOR]

Published
2016
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64. Dissolved gas analysis (DGA) of natural ester insulating fluids with different chemical compositions.

Author

Wilhelm, H., Santos, C., and Stocco, G.

Subjects
GAS analysis, ESTERS, ELECTRIC insulators & insulation, FLUID dynamics, ELECTRIC discharges
Abstract

This study presents experimental results of the application of the dissolved gas-inoil analysis (DGA) technique to natural ester insulating fluids. The investigations covered two common types of transformer faults, discharge and overheating, and four different commercial insulating oils, one mineral and three natural esters: Biovolt A (from corn oil), Biovolt HW (from sunflower oil with high oleic acid) and Envirotemp FR3 (from soya oil). The natural esters insulating fluids (NEIFs) analyzed had different chemical compositions. Experiments were performed in the laboratory with the test oils at three different moisture levels (low, medium and high). The purpose was to see the effect of moisture content and oil composition on the quantities of fault gases dissolved in the different oil types. The overheating tests were performed by heating the oils in an oven at 150 ?C. Discharges were generated using a flat plate-plate electrode arrangement immersed in oil. Five key dissolved hydrocarbon gases ? hydrogen (H2), methane (CH4), ethane (C2H6), ethylene (C2H4) and acetylene (C2H2) ? generated by the two fault types in NEIFs were analyzed and compared with mineral oil (MIO) fault gases. The classic Duval triangle 1, modified Duval triangle 3, Roger?s ratio, Dornenburg and IEC 60599 methods were applied to predict the fault type. The findings confirmed that the direct application of classic DGA fault interpretation methods, developed for mineral oils, to non-mineral oils needs some modifications. IR and RMN spectroscopy analyses were performed to observe differences in triacylglycerol group compositions before and after heating tests. [ABSTRACT FROM AUTHOR]

Published
2014
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74. Reclaiming of in-service natural ester-based insulating fluids.

Author

Wilhelm, H., Stocco, G., and Batista Jr., S.

Subjects
*ESTERS, *ELECTRIC insulators & insulation, *FLUID dynamics, *VISCOSITY, *ACIDITY, *ENERGY dissipation
Abstract

The degradation of in-service natural ester-based insulating fluid could result in oil viscosity, acidity and dissipation factor increases. In this work, natural ester-based insulating fluid samples aged in the laboratory and in-service (collected from a Recloser) were reclaimed with different adsorbent materials. All the tested samples showed some properties above the provisional limit for triggering prompt additional investigation suggested by the IEEE guide for in-service natural ester fluids, such as viscosity increase > 10% from value at time of initial energization, acid number > 0.3 mg KOH/g or dissipation factor at 25 0C > 3%. The reclamation process was accomplished by the use of two methods: 1) by mechanical agitation of the aged oil in the presence of several adsorbents and 2) by percolation of the aged oil through the adsorbent material. The reclaimed fluids were monitored by evaluation of viscosity, acid number and dissipation factor and the results were compared with unused oil. The results showed that viscosity is the main criterion to evaluate whether or not in-service natural ester-based insulating fluid can be reclaimed. [ABSTRACT FROM AUTHOR]

Published
2013
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84. Spectroscopic characterization and biological activity of L‐methionyl‐Lhistidinato complexes of R2Sn(IV) ions (R = Me, nBu, Ph) and X‐ray structure of Me2SnMetHis ˙ 0.5MeOH

Author

Girasolo, M. A., Pizzino, T., Mansueto, C., Valle, G., and Stocco, G. C.

Abstract

Complexes of L‐methionyl‐L‐histidine (H2MetHis) with R2Sn(IV) ions (R = Me, nBu, Ph) have been synthesized. The crystal and molecular structures of Me2SnMetHis·0.5MeOH have been determined by X‐ray diffraction. The title compound contains two crystallographically independent molecular units possessing the same trigonal‐bipyramidal geometry at tin, each dimethyltin(IV) moiety being coordinated by the terminal amino nitrogen, deprotonated peptide nitrogen and terminal carboxylate group, neither the imidazole nor thioether groups being involved in bonding.

Published
2000
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85. Spectroscopic characterization and biological activity of <SC>L</SC>-methionyl-<SC>L</SC> histidinato complexes of R<INF>2</INF>Sn(IV) ions (R = Me, nBu, Ph) and X-ray structure of Me<INF>2</INF>SnMetHis ˙ 0.5MeOH

Author

Girasolo, M. A., Pizzino, T., Mansueto, C., Valle, G., and Stocco, G. C.

Abstract

Complexes of L-methionyl-L-histidine (H2MetHis) with R2Sn(IV) ions (R = Me, nBu, Ph) have been synthesized. The crystal and molecular structures of Me2SnMetHis·0.5MeOH have been determined by X-ray diffraction. The title compound contains two crystallographically independent molecular units possessing the same trigonal-bipyramidal geometry at tin, each dimethyltin(IV) moiety being coordinated by the terminal amino nitrogen, deprotonated peptide nitrogen and terminal carboxylate group, neither the imidazole nor thioether groups being involved in bonding. IR spectroscopy was used to probe the structure of the complexes in the solid state, and the structure in solution (CD3OD) was assessed by 1H and 13C NMR. Me2Sn(IV)dipeptide complexes appear to be undissociated and to retain a pentacoordinated structure. Rotamer population of C-terminal histidine was determined by analysis of vicinal coupling constants and side-chain orientations have been interpreted with a view to potential applications of the compounds as recognition agents. Biological activity was tested on Ascidian embryos of Ciona intestinalis at different stages of development. Copyright © 2000 John Wiley & Sons, Ltd.

Published
2000

86. SYNTHESIS, LASER-RAMAN, INFRARED AND PROTON MAGNETIC RESONANCE SPECTRA OF (CH3)3PtX2-3 IONS (X = Cl-, Br-) AND (CH3)3Ptiv ISOCYANIDE COMPLEXES

Author

Stocco, G. C., Gattuso, F. Stocco, Bertazzi, N., and Pellerito, L.

Abstract

The novel ionic complexes [(C6H5)4As]2 [(CH3)3PtX3](X = Cl- and Br-) and [(CH3)3Pt(bipy)L]+[B(C6H5)4]- (bipy = 2,2'-bipyridine, L = aliphatic and aromatic isocyanide) have been prepared. The structure of the complex ions has been inferred from Laser-Raman and infrared spectra in the solid state and 1H NMR in solution. These data are consistent with a facial configuration of the organometallic moiety. Trends in vibrational frequencies ν(Pt-C) and ν(Pt-X) indicate a "trans" influence sequence for the ligands, which in the case of (CH3)3PtX2-3 is related with that found for (CH3)2AuX-2 ions.

Published
1976
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87. Attività anti-proliferativa di derivati di organostagno(IV) con Na-Boc-Ornitina e studio dell’azione pro-apoptotica del derivato Ph3Sn(Boc- Orn)

Author

Attanzio, Alessandro, Maria Assunta Girasolo, Luisa tesoriere, Capobianco, M., Giampaolo Barone, Simona Rubino, Riccardo Bonsignore, Sabatino, P., Stocco, G., Attanzio,A, Girasolo,MA, Tesoriere,L, Capobianco,M, Barone, G, Rubino,S, Bonsignore,R, Sabatino,P, Stocco,G, A.Attanzio, M.A. Girasolo1, L.Tesoriere, M.Capobianco, G.Barone, S.Rubino, R.Bonsignore, P.Sabatino, and G. Stocco

Subjects
triorganoSn(IV), attività antitumorale, organostagno(IV)
Abstract

Nuovi composti di organostagno(IV) [R3SnL e R¢2SnL2 (R = Me, Ph e R¢= Me, nBu, HL= Na-Boc-Ornitina)] sono stati sintetizzati e caratterizzati sia allo stato solido (FT-IR) che in soluzione (1H e 13C NMR) per poterne valutare la citotossicità in linee cellulari tumorali [1]. Na-Boc-Ornitina si comporta come un legante chelante dello stagno con il gruppo carbossilato, mentre il gruppo amminico Na-protetto è esente dalla coordinazione. I composti sono stati testati per l’attività citotossica in vitro su cellule neoplastiche umane HepG2 di epatocarcinoma ed MCF7 di cancro al seno. L’effetto dei composti, nel range da 0.5 a 25 μM, dopo 24 h di incubazione è stato valutato mediante saggio MTT. Il Ph3Sn(Boc-Orn) ha mostrato una forte azione citotossica (IC50 0.5-1.0 μM) su entrambe le linee cellulari, mentre fino alla concentrazione 2.5μM, non è apparso influenzare significativamente la crescita di cellule umane epatiche non-maligne (Chang), indicando preferenziale azione sulle tumorali, almeno a basse concentrazioni. Inoltre, misure citofluorimetriche ed al microscopio per fluorescenza di biomarkers di apoptosi, hanno chiaramente dimostrato che Ph3Sn(Boc-Orn) causa morte cellulare programmata in maniera concentrazione-dipendente. Al fine di valutare una possibile interazione tra questo complesso e il DNA cellulare sono stati effettuati studi di CD, UV-Vis e di misura della temperatura di melting su soluzioni contenti il dodecamero d(CGCAAATTTGCG) e il complesso Ph3Sn(Boc-Orn). L'osservazione di un incremento del Tm di circa 5°C, indica l’esistenza di una interazione tra complesso organometallico e sequenza oligonucleotidica. In conclusione, il nostro studio dimostra che il complesso Ph3Sn(Boc-Orn) mostra elevata attività antitumorale, superiore di circa una unità di grandezza a quella misurata nelle stesse condizioni dal cis-platino. Il complesso Ph3Sn(Boc-Orn) è risultato essere più attivo fra quelli studiati. [1] M. Gielen, Coord. Chem. Rev., 151, (1996) 41; M.A. Girasolo, S. Rubino, P. Portanova, G. Calvaruso, G.Ruisi, G.C. Stocco, J.Organomet. Chem.,695, (2010) 609.

91. Contribution of glutathione-s-transferases to the pharmacogenetics of azathioprine

Author

Stocco, G., Marco Pelin, Franca, R., Iudicibus, S. D., Cuzzoni, E., Favretto, D., Candussio, L., Martelossi, S., Ventura, A., Decorti, G., Wilber Ashley, Stocco, Gabriele, Pelin, Marco, Franca, Raffaella, Iudicibus, Sara De, Cuzzoni, Eva, Favretto, Diego, Candussio, Luigi, Martelossi, Stefano, Ventura, Alessandro, and Decorti, Giuliana

Subjects
Glutathione-S-transferase, oxidative stre, azathioprine, inflammatory bowel disease, pharmacogenetics, oxidative stress, pharmacogenetic
Abstract

Azathioprine is a purine antimetabolite drug commonly used as immunomodulator in the treatment of various chronic inflammatory diseases, such as inflammatory bowel disease (IBD). Azathioprine is activated in vivo after reaction with reduced glutathione (GSH) and conversion to mercaptopurine. Although this reaction may occur spontaneously, the presence of the enzyme glutathione-S-transferase (GST), in particular of isoforms GST-A1/GST-A2 and GST-M1, can increase its speed, leading to a faster activation of azathioprine to active thioguanine nucleotides. Moreover, GSTs may contribute to azathioprine effects by modulating GSH consumption, oxidative stress and apoptosis. Indeed, in young patients with IBD, deletion of GST-M1, which determines reduced enzymatic activity, was recently associated with reduced sensitivity to azathioprine and reduced production of its active metabolites. Therefore, genetic polymorphisms in genes for GSTs may be useful to predict response to azathioprine even if more in vitro and clinical validation studies are needed.

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