Unrelated bone marrow transplantation in Thalassemia. The experience of the Italian Bone Marrow transplant Group (GITMO)

BACKGROUND AND OBJECTIVES: Allogeneic bone marrow transplantation (BMT) is a widely accepted therapeutic approach in homozygous beta-thalassemia. However, the majority of patients do not have a genotypically identical donor within the family. This prompted us to conduct a pilot study to investigate the feasibility of matched unrelated bone marrow transplantation in thalassemia. The major drawback was the high risk of immunologic and transplant-related complications, mainly graft-versus-host disease (GvHD) and graft failure. DESIGN AND METHODS: Our aim was to reduce this risk through careful selection of donor/recipient pairs. HLA haplotypes that show a high linkage disequilibrium among their class I, class II and class III alleles are considered extended or ancestral haplotypes. RESULTS: These haplotypes are conserved and can be shared by apparently unrelated individuals. Our study shows that matching for these haplotypes significantly improves the outcome of unrelated bone marrow transplantation in thalassemia. In fact, results were comparable to those obtained in transplants using HLA-identifical family donors. INTERPRETATION AND CONCLUSIONS: Better results were obtained in patients with lesser iron overload and when the donor shared an identity for the DPB1 alleles

Estimates of the effect on hepatic iron of oral deferiprone compared with subcutaneous desferrioxamine for treatment of iron overload in thalassemia major: a systematic review

BACKGROUND: Beta thalassemia major requires regular blood transfusions and iron chelation to alleviate the harmful accumulation of iron. Evidence on the efficacy and safety of the available agents, desferrioxamine and deferiprone, is derived from small, non-comparative, heterogeneous observational studies. This evidence was reviewed to quantitatively compare the ability of these chelators to reduce hepatic iron. METHODS: The literature was searched using Medline and all reports addressing the effect of either chelator on hepatic iron were considered. Data were abstracted independently by two investigators. Analyses were performed using reported individual patient data. Hepatic iron concentrations at study end and changes over time were compared using ANCOVA, controlling for initial iron load. Differences in the proportions of patients improving were tested using χ(2). RESULTS: Eight of 11 reports identified provided patient-level data relating to 30 desferrioxamine- and 68 deferiprone-treated patients. Desferrioxamine was more likely than optimal dose deferiprone to decrease hepatic iron over the average follow-up of 45 months (odds ratio, 19.0, 95% CI, 2.4 to 151.4). The degree of improvement was also larger with desferrioxamine. CONCLUSIONS: This analysis suggests that desferrioxamine is more effective than deferiprone in lowering hepatic iron. This comparative analysis – despite its limitations – should prove beneficial to physicians faced with the challenge of selecting the optimal treatment for their patients

Social Closure and the Evolution of Cooperation via Indirect Reciprocity

Direct and indirect reciprocity are good candidates to explain the fundamental problem of evolution of cooperation. We explore the conditions under which different types of reciprocity gain dominance and their performances in sustaining cooperation in the PD played on simple networks. We confirm that direct reciprocity gains dominance over indirect reciprocity strategies also in larger populations, as long as it has no memory constraints. In the absence of direct reciprocity, or when its memory is flawed, different forms of indirect reciprocity strategies are able to dominate and to support cooperation. We show that indirect reciprocity relying on social capital inherent in closed triads is the best competitor among them, outperforming indirect reciprocity that uses information from any source. Results hold in a wide range of conditions with different evolutionary update rules, extent of evolutionary pressure, initial conditions, population size, and density

Visual Genome-Wide RNAi Screening to Identify Human Host Factors Required for Trypanosoma cruzi Infection

The protozoan parasite Trypanosoma cruzi is the etiologic agent of Chagas disease, a neglected tropical infection that affects millions of people in the Americas. Current chemotherapy relies on only two drugs that have limited efficacy and considerable side effects. Therefore, the development of new and more effective drugs is of paramount importance. Although some host cellular factors that play a role in T. cruzi infection have been uncovered, the molecular requirements for intracellular parasite growth and persistence are still not well understood. To further study these host-parasite interactions and identify human host factors required for T. cruzi infection, we performed a genome-wide RNAi screen using cellular microarrays of a printed siRNA library that spanned the whole human genome. The screening was reproduced 6 times and a customized algorithm was used to select as hits those genes whose silencing visually impaired parasite infection. The 162 strongest hits were subjected to a secondary screening and subsequently validated in two different cell lines. Among the fourteen hits confirmed, we recognized some cellular membrane proteins that might function as cell receptors for parasite entry and others that may be related to calcium release triggered by parasites during cell invasion. In addition, two of the hits are related to the TGF-beta signaling pathway, whose inhibition is already known to diminish levels of T. cruzi infection. This study represents a significant step toward unveiling the key molecular requirements for host cell invasion and revealing new potential targets for antiparasitic therapy

Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer

PURPOSE: To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC). METHODS:Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers. RESULTS:Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by (18)FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively).CONCLUSIONS:The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active

Repaired tetralogy of Fallot: the roles of cardiovascular magnetic resonance in evaluating pathophysiology and for pulmonary valve replacement decision support

Surgical management of tetralogy of Fallot (TOF) results in anatomic and functional abnormalities in the majority of patients. Although right ventricular volume load due to severe pulmonary regurgitation can be tolerated for many years, there is now evidence that the compensatory mechanisms of the right ventricular myocardium ultimately fail and that if the volume load is not eliminated or reduced by pulmonary valve replacement the dysfunction might be irreversible. Cardiovascular magnetic resonance (CMR) has evolved during the last 2 decades as the reference standard imaging modality to assess the anatomic and functional sequelae in patients with repaired TOF. This article reviews the pathophysiology of chronic right ventricular volume load after TOF repair and the risks and benefits of pulmonary valve replacement. The CMR techniques used to comprehensively evaluate the patient with repaired TOF are reviewed and the role of CMR in supporting clinical decisions regarding pulmonary valve replacement is discussed

De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies

Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2%of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator ofmRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients