Reggio nell'Emilia, Italy
Reggio nell'Emilia, Italy

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Asti M.,Santa Maria Nuova Hospital IRCCS | Pignedoli F.,Santa Maria Nuova Hospital IRCCS
Dalton Transactions | Year: 2013

Theoretical calculations employing DFT at the B3LYP/6-311G++** level are used to investigate the tautomeric equilibrium in curcumin derivatives. The solvent effect is evaluated using the CPCM continuum solvation method. The results are compared with experimental data obtained from the X-ray crystal structure of K2A23 and UV-vis data. The KE tautomer is more stable in a vacuum and in the solid state, while in water the DK tautomer reaches a population of 90%. In agreement with spectroscopic data, theoretical calculations predict a slight prevalence of the DK form in non-aqueous solvent systems. The ability to chelate metal ions [Fe3+, Ga3+ and Cu2+] is then explored by means of 1H, 13C NMR and UV-Vis spectroscopy. From the calculation of the overall stability constants of metal complexes and 1H NMR titrations with Ga 3+, it is clear that the more stable species has a 1:2 M/L molar ratio. The curcuminoid coordinates the metal ion through the keto-enol function in the dissociated form; in addition 2D 1H 13C NMR experiments suggest the involvement of carboxylic oxygen in metal coordination it was found in the solid state for the complex [Ga(K2A33)2]PF 6. The rate of the complexation reaction is strongly influenced by the type of substituent on the aromatic ring of the curcuminoid (K2A33 ≈ K2A23 ≫ K2A21). In addition DPPH assay evidences how antioxidant ability of curcumin derivatives is mainly due to the presence of a phenolic group and metal coordination by a keto-enolic moiety does not affect it, especially for K2A21. © 2013 The Royal Society of Chemistry.


Gardeitchik T.,Radboud University Nijmegen | Mohamed M.,Radboud University Nijmegen | Fischer B.,Charité - Medical University of Berlin | Lammens M.,Radboud University Nijmegen | And 19 more authors.
European Journal of Human Genetics | Year: 2014

Patients with cutis laxa (CL) have wrinkled, sagging skin with decreased elasticity. Skin symptoms are associated with variable systemic involvement. The most common, genetically highly heterogeneous form of autosomal recessive CL, ARCL2, is frequently associated with variable metabolic and neurological symptoms. Progeroid symptoms, dysmorphic features, hypotonia and psychomotor retardation are highly overlapping in the early phase of these disorders. This makes the genetic diagnosis often challenging. In search for discriminatory symptoms, we prospectively evaluated clinical, neurologic, metabolic and genetic features in our patient cohort referred for suspected ARCL. From a cohort of 26 children, we confirmed mutations in genes associated with ARCL in 16 children (14 probands), including 12 novel mutations. Abnormal glycosylation and gyration abnormalities were mostly, but not always associated with ATP6V0A2 mutations. Epilepsy was most common in ATP6V0A2 defects. Corpus callosum dysgenesis was associated with PYCR1 and ALDH18A1 mutations. Dystonic posturing was discriminatory for PYCR1 and ALDH18A1 defects. Metabolic markers of mitochondrial dysfunction were found in one patient with PYCR1 mutations. So far unreported white matter abnormalities were found associated with GORAB and RIN2 mutations. We describe a large cohort of CL patients with neurologic involvement. Migration defects and corpus callosum hypoplasia were not always diagnostic for a specific genetic defect in CL. All patients with ATP6V0A2 defects had abnormal glycosylation. To conclude, central nervous system and metabolic abnormalities were discriminatory in this genetically heterogeneous group, although not always diagnostic for a certain genetic defect in CL. © 2014 Macmillan Publishers Limited All rights reserved.


Sasanelli M.,University Paris Est Creteil | Meignan M.,University Paris Est Creteil | Haioun C.,University Paris Est Creteil | Berriolo-Riedinger A.,Le Bocage Hospital | And 9 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2014

Purpose: We investigated the prognostic value of total metabolic tumour volume (TMTV) in diffuse large B-cell lymphoma (DLBCL).Methods: TMTV was measured in 114 patients with newly diagnosed DLBCL who underwent 18F-FDG PET/CT at baseline before immunochemotherapy. TMTV was computed by summing the volumes of all lymphomatous lesions after applying the local SUVmax threshold of 41 % using semiautomatic software. Prognostic value was assessed by Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS).Results: Median follow-up was 39 months. Average pretherapy TMTV was 509 ± 568 cm3. The 3-year estimates of PFS were 77 % in the low metabolic burden group (TMTV ≤550 cm3) and 60 % in the high metabolic burden group (TMTV >550 cm3, p = 0.04), and prediction of OS was even better (87 % vs. 60 %, p = 0.0003). Cox regression showed independence of TMTV for OS prediction (p = 0.002) compared with other pretherapy indices of tumour burden, such as tumour bulk and the International Prognostic Index.Conclusion: Pretherapy TMTV is an independent predictor of outcome in patients with DLBCL. © 2014, Springer-Verlag Berlin Heidelberg.


Meignan M.,University Paris Est Creteil | Meignan M.,French National Center for Scientific Research | Sasanelli M.,University Paris Est Creteil | Casasnovas R.O.,CHU le Bocage | And 8 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2014

Purpose: The presence of a bulky tumour at staging on CT is an independent prognostic factor in malignant lymphomas. However, its prognostic value is limited in diffuse disease. Total metabolic tumour volume (TMTV) determined on 18F-FDG PET/CT could give a better evaluation of the total tumour burden and may help patient stratification. Different methods of TMTV measurement established in phantoms simulating lymphoma tumours were investigated and validated in 40 patients with Hodgkin lymphoma and diffuse large B-cell lymphoma. Methods: Data were processed by two nuclear medicine physicians in Reggio Emilia and Créteil. Nineteen phantoms filled with 18F-saline were scanned; these comprised spherical or irregular volumes from 0.5 to 650 cm3 with tumour-to-background ratios from 1.65 to 40. Volumes were measured with different SUVmax thresholds. In patients, TMTV was measured on PET at staging by two methods: volumes of individual lesions were measured using a fixed 41 % SUVmax threshold (TMTV41) and a variable visually adjusted SUVmax threshold (TMTVvar). Results: In phantoms, the 41 % threshold gave the best concordance between measured and actual volumes. Interobserver agreement was almost perfect. In patients, the agreement between the reviewers for TMTV41 measurement was substantial (ρ c=0.986, CI 0.97 - 0.99) and the difference between the means was not significant (212±218 cm3 for Créteil vs. 206±219 cm3 for Reggio Emilia, P=0.65). By contrast the agreement was poor for TMTVvar. There was a significant direct correlation between TMTV41 and normalized LDH (r=0.652, CI 0.42 - 0.8, P <0.001). Higher disease stages and bulky tumour were associated with higher TMTV41, but high TMTV41 could be found in patients with stage 1/2 or nonbulky tumour. Conclusion: Measurement of baseline TMTV in lymphoma using a fixed 41% SUVmax threshold is reproducible and correlates with the other parameters for tumour mass evaluation. It should be evaluated in prospective studies. © 2014 Springer-Verlag Berlin Heidelberg.


Asti M.,Santa Maria Nuova Hospital IRCCS | Atti G.,Santa Maria Nuova Hospital IRCCS | Iori M.,Santa Maria Nuova Hospital IRCCS | Farioli D.,Santa Maria Nuova Hospital IRCCS | And 2 more authors.
Nuclear Medicine Communications | Year: 2012

OBJECTIVES: The treatment of tumours expressing somatostatin receptors with yttrium-90 (Y)-labelled and lutetium-177 (Lu)-labelled somatostatin analogues is one of the most interesting therapeutic approaches adopted in nuclear medicine in recent years. However, the process of synthesis and fractionation of these radiopharmaceuticals is still mainly carried out manually despite the high radiation exposure to the operators and the need to comply with good manufacturing practices. In this study a semiautomatic synthesizer [automatic dose dispenser (ADD-2)] using only disposable syringes and vials has been presented. MATERIALS AND METHODS: Small-scale syntheses (185-555 MBq) of Y/Lu-DOTATATE were performed by adding the appropriate amount of peptide to a Y/Lu chloride solution (n=10). The radionuclide/peptide molar ratio was 1 : 17 and 1 : 2 for Y and Lu, respectively. The solutions were buffered to 4.6 pH by ascorbate buffer and heated at 90°C for 30 min. Radiochemical purity was assessed by two independent radio-thin-layer chromatography systems. The solutions were fractioned to mimic the preparation of patient doses. RESULTS: All synthesis and fractionation steps were performed using ADD-2. The radiochemical yield was 92±3% for Y and 97±1% for Lu labelling. Radiochemical purity was more than 99.5%. The accuracy and reproducibility of the instrument in transferring and fractionating radioactive solutions were high (maximal error ∼5%). CONCLUSION: ADD-2 appears suitable for use in clinical preparations of Y/Lu-DOTATATE with therapeutic amounts of precursors (20-30 GBq). The operator's exposure to radiation by using ADD-2 in comparison with manual preparations is under investigation. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Ferrari E.,University of Modena and Reggio Emilia | Benassi R.,University of Modena and Reggio Emilia | Sacchi S.,University of Modena and Reggio Emilia | Pignedoli F.,University of Modena and Reggio Emilia | And 2 more authors.
Journal of Inorganic Biochemistry | Year: 2014

Curcuminoids represent new perspectives for the development of novel therapeutics for Alzheimer's disease (AD), one probable mechanism of action is related to their metal complexing ability. In this work we examined the metal complexing ability of substituted curcuminoids to propose new chelating molecules with biological properties comparable with curcumin but with improved stability as new potential AD therapeutic agents. The K2T derivatives originate from the insertion of a -CH2COOC(CH3)3 group on the central atom of the diketonic moiety of curcumin. They retain the diketo-ketoenol tautomerism which is solvent dependent. In aqueous solution the prevalent form is the diketo one but the addition of metal ion (Ga 3 +, Cu2 +) causes the dissociation of the enolic proton creating chelate complexes and shifting the tautomeric equilibrium towards the keto-enol form. The formation of metal complexes is followed by both NMR and UV-vis spectroscopy. The density functional theory (DFT) calculations on K2T21 complexes with Ga3 + and Cu2 + are performed and compared with those on curcumin complexes. [Ga(K2T21)2(H2O) 2]+ was found more stable than curcumin one. Good agreement is detected between calculated and experimental 1H and 13C NMR data. The calculated OH bond dissociation energy (BDE) and the OH proton dissociation enthalpy (PDE), allowed to predict the radical scavenging ability of the metal ion complexed with K2T21, while the calculated electronic affinity (EA) and ionization potential (IP) represent yardsticks of antioxidant properties. Eventually theoretical calculations suggest that the proton-transfer-associated superoxide-scavenging activity is enhanced after binding metal ions, and that Ga3 + complexes display possible superoxide dismutase (SOD)-like activity. © 2014 Elsevier Inc.


Menzella F.,Santa Maria Nuova Hospital IRCCS | Facciolongo N.,Santa Maria Nuova Hospital IRCCS | Piro R.,Santa Maria Nuova Hospital IRCCS | Formisano D.,Santa Maria Nuova Hospital IRCCS | And 5 more authors.
Therapeutic Advances in Respiratory Disease | Year: 2012

Objectives: The aim of this study was to assess the stability of the effectiveness of omalizumab as add-on treatment in 11 patients with severe persistent allergic asthma followed for 4 years. Secondary outcomes were safety and economic impact, in terms of use of healthcare resources.Methods: This retrospective study was designed to analyse a series of patients with severe allergic asthma treated with omalizumab. Patients were initially enrolled as part of the CIGE025A2425 international multicentre clinical trial. At the end (week 32), 11 responsive patients went on to complete the study and continued omalizumab treatment until June 2010. The monitoring visits coincided with the timescales planned for administering the drug and for the follow up. To estimate the economic impact, the PRE-POST treatment comparison was obtained by comparing the annual pretreatment costs with an annual average of the 4-year posttreatment period costsResults: After 4 years, 81.8% of patients showed a good/excellent Global Evaluation of Treatment Effectiveness scale score and 81.2% showed an excellent increase (>1.5) in the Asthma Quality of Life Questionnaire score. The average forced expiratory volume in one second (FEV1) at 4 years was 75.3% compared with the predicted normal value for each patient, with a net increase (p = 0.009) compared with baseline FEV1 values (58.6%). The frequency of serious exacerbations dropped by 94.7% compared with the pretreatment period, while mild-moderate exacerbations fell by 41.8%. A reduction in costs was observed for hospital admissions (97.3%), visits to emergency department (ED) (97.5%) and mild-moderate exacerbations (84%). The average cost reduction of concomitant drugs remained at 36%.Conclusions: This study confirms the effectiveness and reliability of omalizumab over the long term, while providing an excellent safety profile. The additional cost due the use of omalizumab was offset by the medium- and long-term savings associated with the reduction in hospital admissions and access to ED. © The Author(s), 2012.


PubMed | Santa Maria Nuova Hospital IRCCS
Type: Journal Article | Journal: Nuclear medicine communications | Year: 2012

The treatment of tumours expressing somatostatin receptors with yttrium-90 (90Y)-labelled and lutetium-177 (177Lu)-labelled somatostatin analogues is one of the most interesting therapeutic approaches adopted in nuclear medicine in recent years. However, the process of synthesis and fractionation of these radiopharmaceuticals is still mainly carried out manually despite the high radiation exposure to the operators and the need to comply with good manufacturing practices. In this study a semiautomatic synthesizer [automatic dose dispenser (ADD-2)] using only disposable syringes and vials has been presented.Small-scale syntheses (185-555 MBq) of 90Y/177Lu-DOTATATE were performed by adding the appropriate amount of peptide to a 90Y/177Lu chloride solution (n=10). The radionuclide/peptide molar ratio was 1 : 17 and 1 : 2 for 90Y and 177Lu, respectively. The solutions were buffered to 4.6 pH by ascorbate buffer and heated at 90C for 30 min. Radiochemical purity was assessed by two independent radio-thin-layer chromatography systems. The solutions were fractioned to mimic the preparation of patient doses.All synthesis and fractionation steps were performed using ADD-2. The radiochemical yield was 92 3% for 90Y and 97 1% for 177Lu labelling. Radiochemical purity was more than 99.5%. The accuracy and reproducibility of the instrument in transferring and fractionating radioactive solutions were high (maximal error 5%).ADD-2 appears suitable for use in clinical preparations of 90Y/177Lu-DOTATATE with therapeutic amounts of precursors (20-30 GBq). The operators exposure to radiation by using ADD-2 in comparison with manual preparations is under investigation.


PubMed | Santa Maria Nuova Hospital IRCCS
Type: Journal Article | Journal: Nuclear medicine communications | Year: 2012

Biocytin analogues labelled with indium-111, yttrium-90 and lutetium-177 have shown their effectiveness in the imaging of infections/inflammation in patients with osteomyelitis and function as efficient tools in pretargeted antibody-guided radioimmunotherapy. In this study, the labelling of a biocytin analogue coupled with DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), namely, r-BHD, with gallium-68 (68Ga) was optimized, and the quality and stability of the preparations were assessed for clinical use.Synthesis of 68Ga-r-BHD was carried out by heating a fraction of the 68Ge/68Ga eluate in a reactor containing the biocytin analogue with the appropriate buffer. The influence of the precursor amount (from 2.5 to 140 nmol), the pH of the reaction (from 2 to 5.5) and the buffer species (1.5 mol/l sodium acetate, 1.5 mol/l sodium formate, 4.5 mol/l HEPES) on radiochemical yield and radiochemical purity was assessed. Studies on stability and binding to avidin (Av) were also conducted in different media.Under the best labelling condition (56 nmol of precursor, 3.8 pH, sodium formate buffer) synthesis of 68Ga-r-BHD resulted in a yield of 64 3% (not decay corrected). Radiochemical purity was around 95% because a 68Ga-coordinated sulfoxide form of the ligand was detected as a by-product of the reaction (68Ga-r-SBHD). The by-product was identified and characterized by liquid chromatography-electrospray ionization tandem mass spectrometry. At the natural 1 : 4 Av/68Ga-r-BHD molar ratio, affinity results were 62 2 and 80 2% in saline and human serum, respectively. Stability of 68Ga-r-BHD and of the radiotracer/Av complex remains almost constant over 180 min. 68Ga-r-BHD appears to be a good candidate for clinical applications.


PubMed | Santa Maria Nuova Hospital IRCCS and University of Modena and Reggio Emilia
Type: | Journal: Journal of inorganic biochemistry | Year: 2014

Curcuminoids represent new perspectives for the development of novel therapeutics for Alzheimers disease (AD), one probable mechanism of action is related to their metal complexing ability. In this work we examined the metal complexing ability of substituted curcuminoids to propose new chelating molecules with biological properties comparable with curcumin but with improved stability as new potential AD therapeutic agents. The K2T derivatives originate from the insertion of a -CH2COOC(CH3)3 group on the central atom of the diketonic moiety of curcumin. They retain the diketo-ketoenol tautomerism which is solvent dependent. In aqueous solution the prevalent form is the diketo one but the addition of metal ion (Ga(3+), Cu(2+)) causes the dissociation of the enolic proton creating chelate complexes and shifting the tautomeric equilibrium towards the keto-enol form. The formation of metal complexes is followed by both NMR and UV-vis spectroscopy. The density functional theory (DFT) calculations on K2T21 complexes with Ga(3+) and Cu(2+) are performed and compared with those on curcumin complexes. [Ga(K2T21)2(H2O)2](+) was found more stable than curcumin one. Good agreement is detected between calculated and experimental (1)H and (13)C NMR data. The calculated OH bond dissociation energy (BDE) and the OH proton dissociation enthalpy (PDE), allowed to predict the radical scavenging ability of the metal ion complexed with K2T21, while the calculated electronic affinity (EA) and ionization potential (IP) represent yardsticks of antioxidant properties. Eventually theoretical calculations suggest that the proton-transfer-associated superoxide-scavenging activity is enhanced after binding metal ions, and that Ga(3+) complexes display possible superoxide dismutase (SOD)-like activity.

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