Is there a difference in phenotype between males and females with non-transfusion-dependent thalassemia? A cross-sectional evaluation.

Non-transfusion-dependent thalassemia includes a variety of phenotypes and genotypes that rarely require regular transfusions. However, these patients can experience a wide range of complications. The objective of this retrospective study was to verify whether there is a significant difference in non-transfusion-dependent thalassemia-related complications and treatment among males and females.We performed a re-analysis of samples evaluated in a previously published cross-sectional study, regarding 96 non-transfusion-dependent thalassemia patients followed at the 'UOSD Malattie Rare del Globulo Rosso' Centre of the Cardarelli Hospital in Naples, Italy.We found that females were more anemic than males, but there was no significant difference in prevalence of common complications among genders, except for hypogonadism. Furthermore, the transitory regular transfusions regimen in women who had been pregnant does not seem to have a significant impact on overall prognosis.In non-transfusion-dependent thalassemia patients, the lower levels of hemoglobin found in females do not seem to indicate a higher prevalence of complications.This data should be considered in studies with experimental treatments aiming to correct anemia in patients with non-transfusion-dependent thalassemia. It should probably also be taken into account in order to set up different transfusion regimens among genders in transfusion-dependent patients

Improved thrombin binding aptamer analogues containing inversion of polarity sites: structural effects of extra-residues at the ends

In this paper, we report the investigations, based on NMR, molecular modelling, CD measurements and electrophoresis, of thrombin binding aptamer (TBA) analogues containing an extra-residue at the 3’-end or at both the ends of the original TBA sequence, linked through 3’–3’ or 5’–5’ phosphodiester bonds. The data indicate that most of the modified aptamers investigated adopt chair-like G-quadruplex structures very similar to that of the TBA and that stacking interactions occur between the 3’–3’ or 5’–5’ extra residues and the deoxyguanosines of the upper G-tetrad. A comparison of the thermodynamic data of TBA-A and TBA-T containing a 3’–3’ extra residue and their canonical versions clearly indicates that the 3’–3’ phosphodiester bond is fundamental in endowing the modified aptamers with remarkably higher thermal stabilities than the original TBA

Design, synthesis, biophysical and biological studies of trisubstitutednaphthalimides as G-quadruplex ligands

A series of trisubstituted naphthalimides have been synthesized and evaluated as telomeric G-quadruplex ligands by biophysical methods. Affinity for telomeric G-quadruplex AGGG(TTAGGG)3 binding was first screened by fluorescence titrations. Subsequently, the interaction of the telomeric G-quadruplex with compounds showing the best affinity has been studied by isothermal titration calorimetry and UVmelting experiments. The two best compounds of the series tightly bind the telomeric quadruplex with a 2:1 drug/DNA stoichiometry. These derivatives have been further evaluated for their ability to inhibit telomerase by a TRAP assay and their pharmacological properties by treating melanoma (M14) and human lung cancer (A549) cell lines with increasing drug concentrations. A dose-dependent inhibition of cell proliferation was observed for all cellular lines during short-term treatment

Urinary Metabolic Profile of Patients with Transfusion-Dependent β-Thalassemia Major Undergoing Deferasirox Therapy

Introduction: Renal dysfunction is a frequent complication in patients suffering from β-thalassemia major (β-TM). The aim of this study was to analyze the renal function and urine metabolomic profile of β-TM patients undergoing transfusions and deferasirox (DFX) therapy, in order to better characterize and shed light on the pathogenesis of renal disease in this setting. Methods and Subjects: 40 patients affected by β-TM treated with DFX and 35 age- and gender-matched healthy controls were enrolled in the study. Renal function was assessed. Glomerular filtration rate (GFR) was estimated with CKD-EPI and Schwartz formula for adults and children, respectively. Renal tubular function and maximal urine concentration ability were tested. Urine specimens were analyzed by nuclear magnetic resonance spectroscopy to identify the urinary metabolite profiles. Results: The study of renal function in β-TM patients revealed normal estimated (e)GFR mean values and the albumin-to-creatinine ratio was <30 mg/g. The analysis of tubular function showed normal basal plasma electrolyte levels; 60% of patients presented hypercalciuria and many subjects showed defective urine concentration. Several amino acids, N-methyl compounds, and organic acids were overexcreted in the urine of thalassemic patients compared with controls. Discussion: The major finding of this work is that β-TM patients and controls exhibit different concentrations of some metabolites in the urine. Early recognition of urinary abnormalities may be useful to detect and prevent kidney damage

Longitudinal follow‐up of patients with thalassaemia intermedia who started transfusion therapy in adulthood: a cohort study

SummaryWe longitudinally evaluated the effects of regular blood transfusions (BTs), in the real‐life context of the Myocardial Iron Overload in Thalassaemia network, in patients with thalassaemia intermedia (TI). We considered 88 patients with TI (52 females) who started regular BTs after the age of 18 years. Magnetic resonance imaging was used to quantify iron overload and biventricular function. For 56·8% of the patients there were more than two indications for the transition to regular BTs, with anaemia present in 94·0% of the cases. A significant decrease in nucleated red blood cells, platelets, lactate dehydrogenase, bilirubin, and uric acid levels was detected 6 months after starting regular BTs. After the transition to the regular BT regimen there was a significant increase only in the frequency of hypothyroidism and osteopenia, and a significant decrease in liver iron and cardiac index. The percentage of chelated patients increased significantly after starting regular BTs. The decision to regularly transfuse patients with TI may represent a way to prevent or slow down the natural progression of the disease, despite the more complex initial management

A: Deferasirox, deferiprone and desferrioxamine treatment in thalassemia major patients: cardiac iron and function comparison determined by quantitative magnetic resonance imaging. Haematologica 2011; 96

Background Oral deferiprone was suggested to be more effective than subcutaneous desferrioxamine for removing heart iron. Oral once-daily chelator deferasirox has recently been made commercially available but its long-term efficacy on cardiac iron and function has not yet been established. Our study aimed to compare the effectiveness of deferasirox, deferiprone and desferrioxamine on myocardial and liver iron concentrations and bi-ventricular function in thalassemia major patients by means of quantitative magnetic resonance imaging. Design and Methods From the first 550 thalassemia subjects enrolled in the Myocardial Iron Overload in Thalassemia network, we retrospectively selected thalassemia major patients who had been receiving one chelator alone for longer than one year. We identified three groups of patients: 24 treated with deferasirox, 42 treated with deferiprone and 89 treated with desferrioxamine. Myocardial iron concentrations were measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Liver iron concentrations were measured by T2* multiecho technique. Results The global heart T2* value was significantly higher in the deferiprone (34±11ms) than in the deferasirox (21±12 ms) and the desferrioxamine groups (27±11 ms) (P=0.0001). We found higher left ventricular ejection fractions in the deferiprone and the desferrioxamine versus the deferasirox group (P=0.010). Liver iron concentration, measured as T2* signal, was significantly lower in the desferrioxamine versus the deferiprone and the deferasirox group (P=0.004). Conclusions The cohort of patients treated with oral deferiprone showed less myocardial iron burden and better global systolic ventricular function compared to the patients treated with oral deferasirox or subcutaneous desferrioxamine. Key words: thalassemia, iron chelation therapy, cardiac magnetic resonance imaging. Citation: Pepe A, Meloni A, Capra M, Cianciulli P, Prossomariti L, Malaventura C, Putti MC, Lippi A, Romeo MA, Bisconte MG, Filosa A, Caruso V, Quarta A, Pitrolo L, Missere M, Midiri M, Rossi G, Positano V, Lombardi M, and Maggio A. Deferasirox, deferipron

The Introduction of Inversion of Polarity Sites in DNA G-Quadruplex Structures: Effects and Perspectives

The natural sequences of nucleic acids generally consist of nucleotides linked together by canonical 3'-5' phosphodiester bonds. An inversion of polarity site (IPS) can be defined as the point of the sequence in which a 3'-3' or a 5'-5' phosphodiester bond occurs. By extending this definition, an IPS can be described as that part of the sequence in which two 3'- or two 5'-hydroxyl groups are connected by a linker, variable in size or in chemical nature. In G-quadruplex structures an IPS can be introduced in three different positions: inside a non G-tract, inside a G-tract and just between a non Gtract and a G-tract. Investigations have been reported concerning all the three types of modification. This review describes the effects of the presence of one or more IPSs in G-quadruplex structures, particularly regarding their topological and structural characteristics, glycosidic bond preference, and thermal stability, with special attention to biologically active Gquadruplex forming aptamers. The perspectives and potential developments of this research area are also discussed