Search

β-Thalassemias are inherited anemias that are caused by the absent or insufficient production of the β chain of hemoglobin. Here we report 6-8-year follow-up of four adult patients with transfusion-dependent β-thalassemia who were infused with autologous CD34 + cells transduced with the TNS9.3.55 lentiviral globin vector after reduced-intensity conditioning (RIC) in a phase 1 clinical trial ( NCT01639690) . Patients were monitored for insertional mutagenesis and the generation of a replication-competent lentivirus (safety and tolerability of the infusion product after RIC-primary endpoint) and engraftment of genetically modified autologous CD34 + cells, expression of the transduced β-globin gene and post-transplant transfusion requirements (efficacy-secondary endpoint). No unexpected safety issues occurred during conditioning and cell product infusion. Hematopoietic gene marking was very stable but low, reducing transfusion requirements in two patients, albeit not achieving transfusion independence. Our findings suggest that non-myeloablative conditioning can achieve durable stem cell engraftment but underscore a minimum CD34 + cell transduction requirement for effective therapy. Moderate clonal expansions were associated with integrations near cancer-related genes, suggestive of non-erythroid activity of globin vectors in stem/progenitor cells. These correlative findings highlight the necessity of cautiously monitoring patients harboring globin vectors., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Primary laryngeal neoplasms are rare in cats, with lymphoma and squamous cell carcinoma being the most commonly diagnosed tumour types. These tumours are usually highly aggressive, difficult to treat, and have a poor prognosis. Here an undifferentiated laryngeal carcinoma with hyaline bodies in a cat is reported., Case Presentation: A 13-year-old cat was presented for progressive respiratory signs. Diagnostic procedures revealed a partially obstructive laryngeal mass. Cytology was compatible with a poorly differentiated malignant tumour, with neoplastic cells frequently containing large intracytoplasmic hyaline bodies. After 1 month the patient was euthanised due to a worsening clinical condition and submitted for post-mortem examination, which confirmed the presence of two laryngeal masses. Histopathology confirmed the presence of an undifferentiated neoplasm with marked features of malignancy. Strong immunolabelling for pancytokeratin led to a diagnosis of undifferentiated carcinoma, however, histochemical and immunohistochemical investigations could not elucidate the origin of the large intracytoplasmic hyaline bodies observed in tumour cells, which appeared as non-membrane bound deposits of electron-dense material on transmission electron microscopy., Conclusion: This is the first report of primary undifferentiated laryngeal carcinoma in a cat. Our case confirms the clinical features and the short survival that have been reported in other studies describing feline laryngeal tumours. Moreover, for the first time in feline literature, we describe the presence of intracytoplasmic hyaline bodies in neoplastic cells that were compatible with the so-called hyaline granules reported in different human cancers and also in the dog., (© 2021. The Author(s).)

Dystrophic muscle is characterized by chronic injury and a steady recruitment of inflammatory Ly6Chi monocytes. Recent studies have identified the spleen as the dominant reservoir of these cells during chronic inflammation. Here, we investigated the contribution of splenic Ly6Chi monocytes to dystrophic muscle pathology. Using the mdx mouse model of muscular dystrophy, we show that Ly6Chi monocytes accumulate in great numbers in the spleen over the course of the disease. The chemokine receptor CCR2 was upregulated on Ly6Chi monocytes in mdx spleen before disease onset, thereby enabling their recruitment to dystrophic muscle. Splenectomy performed before disease onset significantly reduced the number of Ly6Chi monocytes infiltrating dystrophic limb muscle. Moreover, in the absence of splenic Ly6Chi monocytes there was a significant reduction in dystrophic muscle inflammation and necrosis, along with improved regeneration during early disease. However, during late disease, a lack of splenic Ly6Chi monocytes adversely affected muscle fiber repair, due to a delay in the phenotypic shift of proinflammatory F4/80+Ly6ChiCD206lo to antiinflammatory F4/80+Ly6CloCD206+ macrophages. Overall, we show that the spleen is an indispensable source of Ly6Chi monocytes in muscular dystrophy and that splenic monocytes are critical players in both muscle fiber injury and repair.

Frailty is defined as a decline in an organism's physiological reserves resulting in increased vulnerability to stressors. In humans, a single continuous variable, the so-called Frailty Index (FI), can be obtained by multidimensionally assessing the biological complexity of an ageing organism. Here, we evaluate this variability in dogs and compare it to the data available for humans. In dogs, there was a moderate correlation between age and the FI, and the distribution of the FI increased with age. Deficit accumulation was strongly related to mortality. The effect of age, when combined with the FI, was negligible. No sex-related differences were evident. The FI could be considered in epidemiological studies and/or experimental trials to account for the potential confounding effects of the health status of individual dogs. The age-related deficit accumulation reported in dogs is similar to that demonstrated in humans. Therefore, dogs might represent an excellent model for human aging studies.

Cu 2 ZnSnS 4 (CZTS) nanocrystals in oleylamine (OLA) and 1-dodecanethiol (1-DDT) solvents were successfully prepared via hot-injection method, to produce inks for the deposition of absorber layers in photovoltaic cells. In this process, 1-DDT acts as a coordinating ligand to control the nucleation and growth of CZTS nanocrystals, whereas lower amounts of OLA promote a homogeneous growth of the grains in the absorber layer. X-Ray Diffraction (XRD) revealed both tetragonal and hexagonal phases of CTZS in films obtained after soft thermal treatments (labeled TT0). In particular, 1-DDT is responsible for the formation of a greater percentage of the hexagonal phase (ZnS-wurtzite type) than that formed when only OLA is used. The thermal treatments have been varied from 500 °C to 600 °C for improving crystallization and eliminating secondary phases. Both features are known to promote CZTS thin films with band gap values typical of CZTS (1.5-1.6 eV) and suitable resistivity. This study let to compare also the CZTS post-annealing without (TT1) and with sulfur vapor (TT2) in a tubular furnace. Only tetragonal CZTS phase is observed in the XRD pattern of CZTS thin films after TT2. A small presence of localized residues of secondary phases on the same samples was revealed by μRaman measurements. The best values of band gap (1.50 eV) and resistivity (1.05 ohm.cm) were obtained after thermal treatment at 500 °C, which is suitable for absorber layer in photovoltaic application.

Background: Thalassemia minor (Tm) individuals, are generally considered healthy. However, the prognosis of Tm individuals has not been extensively studied. The aim of this study was to evaluate the prognosis of Tm versus controls without β-thalassemia carrier state., Methods: A total of 26,006 individuals seeking thalassemia screening at the AOOR Villa Sofia-V. Cervello, Palermo (Italy) were retrospectively studied. Logistic penalised regression model was used to estimate risk of potential complications and survival techniques were used to study mortality., Results: We identified a total of 4943 Tm and 21,063 controls. Tm was associated with significantly higher risks of hospitalisation for cirrhosis (OR 1·94, 95% CI 1·30 to 2·90, p = 0·001), kidney disorders (OR 2·11, 95% CI 1·27 to 3·51, p = 0·004), cholelithiatis (OR 1·39, 95% CI 1·08 to 1·79, p = 0·010), and mood disorders (OR 2·08, 95% CI 1·15 to 3·75, p = 0·015). No statistically difference in life expectancy between thalassemia minor and control group was found (HR 1·090, 95% CI 0·777 to 1·555, p < 0·590; log-rank test p = .426)., Conclusion: This study shows that Tm affects the prognosis of Tm carriers regarding health expectation. Probably, iron overload and anaemia for several years may be at the basis of these effects., (Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Chronic muscle inflammation is a critical feature of Duchenne muscular dystrophy and contributes to muscle fibre injury and disease progression. Although previous studies have implicated T cells in the development of muscle fibrosis, little is known about their role during the early stages of muscular dystrophy. Here, we show that T cells are among the first cells to infiltrate mdx mouse dystrophic muscle, prior to the onset of necrosis, suggesting an important role in early disease pathogenesis. Based on our comprehensive analysis of the kinetics of the immune response, we further identify the early pre-necrotic stage of muscular dystrophy as the relevant time frame for T-cell-based interventions. We focused on protein kinase C θ (PKCθ, encoded by Prkcq), a critical regulator of effector T-cell activation, as a potential target to inhibit T-cell activity in dystrophic muscle. Lack of PKCθ not only reduced the frequency and number of infiltrating T cells but also led to quantitative and qualitative changes in the innate immune cell infiltrate in mdx/Prkcq -/- muscle. These changes were due to the inhibition of T cells, since PKCθ was necessary for T-cell but not for myeloid cell infiltration of acutely injured muscle. Targeting T cells with a PKCθ inhibitor early in the disease process markedly diminished the size of the inflammatory cell infiltrate and resulted in reduced muscle damage. Moreover, diaphragm necrosis and fibrosis were also reduced following treatment. Overall, our findings identify the early T-cell infiltrate as a therapeutic target and highlight the potential of PKCθ inhibition as a therapeutic approach to muscular dystrophy. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

In sickle cell disease (SCD), hydroxyurea (HU) treatment decreases the number of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) by increasing fetal hemoglobin (HbF). Data are lacking regarding the frequency of HU dose modification or whether sub-therapeutic doses (<15 mg/kg/day) are beneficial. We reviewed the medical records of 140 patients from 2010 to 2014. The laboratory parameters and SCD complications were compared between the first and last visits based on HU use. Fifty patients (36%) never took HU or suspended HU ("no HU" group). Among patients taking <15 mg/kg/day HU on their first visit, half remained at the same dose, and the other half increased to ≥15 mg/kg/day. Among patients taking ≥15 mg/kg/day, 17% decreased to <15 mg/kg/day, and 83% stayed at ≥15 mg/kg/day. The "no HU" group had fewer episodes of VOC and ACS. Both HU treatment groups had a reduction in both complications ( p < 0.0001). This improvement was observed in all SCD phenotypes. The white blood cell (WBC) counts were found to be lower, and HbF increased in both HU groups ( p = 0.004, 0.001). The maximal HbF response to HU in HbS/β⁺-thalassemia was 20%, similar to those observed for HbSS (19%) and HbS/β⁰-thalassemia (22%). HbS/β⁺-thalassemia could have a similar disease severity as HbSS or HbS/β⁰-thalassemia. Patients with HbS/β⁰-thalassemia or HbS/β⁺-thalassemia phenotypes responded to HU., Competing Interests: The authors declare no conflict of interest.

Objectives: The liver remains the primary site of iron storage, with liver iron concentration (LIC) being a strong surrogate of total body iron. MRI-R2 can accurately measure LIC. The LICNET (Liver Iron Cutino Network) was established to diagnostics of liver iron overload by MRI-R2 subjects with hemochromatosis in hematological disorders. The aims of the study were to look at variation in LIC measurements during time across different chelation regimens., Methods: This was a cross-sectional study of 130 patients attending 9 Italian centers participating in the LICNET. LIC comparisons over time (T 0 and T 1 ) were made using t test and/or Wilcoxon test., Results: LIC significantly decreased from MRI1 to MRI2 although at high variance (median change -0.8 mg Fe/g dw, range: -29.0 to 33.0; P = .011) and 7.7% of patients shifted from LIC values of high risk (>15 mg Fe/g dw) to an intermediate-risk category (7-15 mg Fe/g dw). Median change in LIC and correlation with serum ferritin levels (SF), during different chelation regimens, is reported., Conclusions: These findings suggest as longitudinal variation in the LIC is possible, across all chelation regimens. It confirms as SF levels not always can be used for estimating changes in LIC., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This review outlines the effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major (TM). For each treatment, the strength of the evidence was documented according to the guidelines of the American College of Cardiology and the American Heart Association. Serum ferritin (SF), liver iron concentration (LIC), heart T2* signal, heart damage and survival were used to assess effectiveness. Five chelation regimens out of 10 showed Level A Evidence in controlling iron overloading, as determined by SF levels and LIC. Three out of 10 chelation regimens were able to control heart iron levels, as determined by T2* signals with Level A Evidence. Two chelation regimens were able to improve/reverse heart damage and four increased of survival with Level B Evidence. These advances mean that the current survival of TM patients is now similar to that of thalassaemia intermedia patients., (© 2017 John Wiley & Sons Ltd.)

In the last few decades, the life expectancy of regularly transfused β-thalassaemia major (TM) patients has dramatically improved following the introduction of safe transfusion practices, iron chelation therapy, aggressive treatment of infections and improved management of cardiac complications. How such changes, especially those attributed to the introduction of iron chelation therapy, improved the survival of TM patients to approach those with β-thalassaemia intermedia (TI) remains unknown. Three hundred and seventy-nine patients with TM (n = 284, dead 40) and TI (n = 95, dead 13) were followed retrospectively since birth until 30 June 2015 or death. Kaplan-Meir curves showed statistically significant differences in TM and TI survival (P < 0·0001) before the introduction of iron chelation in 1965, which were no longer apparent after that date (P = 0·086), reducing the Hazard Ratio of death in TM compared to TI from 6·8 [95% confidence interval (CI) 2·6-17·5] before 1965 to 2·8 (95% CI 0·8-9·2). These findings suggest that, in the era of iron chelation therapy and improved survival for TM, the major-intermedia dichotomy needs to be revisited alongside future directions in general management and prevention for both conditions., (© 2016 John Wiley & Sons Ltd.)

Increased expression of fetal hemoglobin (HbF) may ameliorate the clinical course of hemoglobinopathies. Hydroxyurea (HU) is the only inducer approved for the treatment of these diseases able to stimulate HbF production but patients' response is highly variable indicating the utility of the identification of pharmacogenomic biomarkers in order to predict pharmacological treatment efficacy. To date few studies to evaluate the role of genetic determinants in HU response have been conducted showing contradictory results. In this study we analyzed BCL11A, GATA-1, KLF-1 genes and γ-globin promoter in 60 alleles from 30 hemoglobinopathies patients under HU treatment to assess the role of these markers in HU response. We did not find any association between these genetic determinants and HU response. Before treatment started, the same patients were analyzed in vitro using liquid erythroid cultures in a test able to predict their response to HU. The results of our analysis confirm the absence of pharmacogenomic biomarker associated to HU response indicating that, the quantification of γ-globin mRNA fold increase remains the only method able to predict in vivo patients response to the drug., Competing Interests: he authors declare no potential conflict of interest.

The study was aimed to verify, from a longitudinal perspective, whether perceived peer support would mediate the relationship between attachment and internalizing problems. Longitudinal participants included 482 adolescents (245 boys) aged 14-15 years in Wave 1 and 17-18 years in Wave 2. Participants in Wave 1 completed the Relationship Questionnaire, and those in Wave 2 completed the Social Support Questionnaire and the Youth Self-Report. Results showed that secure attachment positively predicted high levels of perceived peer support and negatively predicted internalizing problems, whereas fearful and preoccupied attachment negatively predicted perceived peer support and positively predicted internalizing problems. The mediation models showed that perceived peer support partially mediated the relationship between secure attachment and internalizing problems as well as between preoccupied attachment and internalizing problems and between fearful attachment and internalizing problems. Our results confirm the role of subjective perception of peer support in contributing to the prediction of internalizing problems beyond attachment styles.

Background: Real-life data on the use of R2 MRI for the assessment of liver iron concentration (LIC) remain limited., Methods: We conducted a cross-sectional analysis on 363 patients (mean age 35.6 yr, 44.1% men) with hemoglobinopathies (204 β-thalassemia major [TM], 102 β-thalassemia intermedia [TI], and 57 sickle cell disease [SCD]) that were evaluated with R2 MRI as part of LICNET, an MRI network of 13 Italian treatment centers., Results: The mean LIC was 7.8 mg/g (median: 4.0), with high LIC (>7 mg/g) noted in both transfused (TM, TI 37%; SCD 38%) and non-transfused (TI 20%) patients. Ferritin levels correlated with LIC in both transfused (TM, TI, SCD) and non-transfused (TI) patients (P < 0.001), although lower values predicted high LIC in non-transfused patients (1900 vs. 650 ng/mL in TM vs. non-transfused TI). A correlation between LIC and ALT levels was only noted in HCV-negative patients (rs = 0.316, P < 0.001). The proportion of patients with high LIC was significantly different between iron chelators used (P = 0.023), with the lowest proportion in deferasirox (30%) and highest in deferiprone (53%)-treated patients., Conclusions: High LIC values persist in subgroups of patients with hemoglobinopathy, warranting closer monitoring and management optimization, even for non-transfused patients with relatively low ferritin levels., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In patients with thalassemia intermedia (TI), such as beta-TI, alpha-thalassemia (mainly HbH disease and mild/moderate forms of HbE/beta-thalassemia), iron overload is an important challenge in terms of diagnosis, monitoring, and treatment. Moreover, to date, the only possible chelators available are deferoxamine, deferasirox, and deferiprone. Here, we report the first 5-year long-term randomized clinical trial comparing the effectiveness of deferiprone versus deferoxamine in patients with TI. Body iron burden, which was determined by measuring serum ferritin levels in the same patient over 5 years and analyzed according to the generalized linear mixed model (GLMM), showed a linear decrease over time in the mean serum ferritin levels in both treatment groups (P-value = 0.035). The overall period of observation was 235.2 person-years for the deferiprone patients compared with 214.3 person-years for the deferoxamine patients. The results of the log-rank test suggested that the deferiprone treatment did not affect survival compared with the deferoxamine treatment (P-value = 0.360). The major adverse events observed included gastrointestinal symptoms and joint pain or arthralgia. Neutropenia and agranulocytosis were also detected, suggesting needing of strict hematological control. In conclusion, long-term iron chelation therapy with deferiprone is associated with an efficacy and safety similar to that of deferoxamine, suggesting that this drug is an alternative option in cases in which deferoxamine and deferasirox are contraindicated., (© 2015 Wiley Periodicals, Inc.)

Blood transfusion and iron chelation currently represent a supportive therapy to manage anemia, vasculopathy and vaso-occlusion crises in Sickle-Cell-Disease. Here we describe the first 5-year long-term randomized clinical trial comparing Deferiprone versus Deferoxamine in patients with Sickle-Cell-Disease. The results of this study show that Deferiprone has the same effectiveness as Deferoxamine in decreasing body iron burden, measured as repeated measurements of serum ferritin concentrations on the same patient over 5-years and analyzed according to the linear mixed-effects model (LMM) (p=0.822). Both chelators are able to decrease, significantly, serum ferritin concentrations, during 5-years, without any effect on safety (p=0.005). Moreover, although the basal serum ferritin levels were higher in transfused compared with non-transfused group (p=0.031), the changes over time in serum ferritin levels were not statistically significantly different between transfused and non-transfused cohort of patients (p=0.389). Kaplan-Meier curve, during 5-years of study, suggests that Deferiprone does not alter survival in comparison with Deferoxamine (p=0.38). In conclusion, long-term iron chelation therapy with Deferiprone was associated with efficacy and safety similar to that of Deferoxamine. Therefore, in patients with Sickle-Cell-Disease, Deferiprone may represent an effective long-term treatment option., (Copyright © 2014. Published by Elsevier Inc.)

Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by an abnormal increase in red blood cells. The involvement of the heart during the course of the illness represents a common cause of morbidity and it is linked to an increased thrombogenic risk subsequent to higher blood viscosity. In our study we evaluated by echocardiography a PV patient population. Our study enrolled 44 patients affected by PV. 17 of them were women and 27 were men. Mean patient age was 66.7. The average follow-up period was 5 years and the average duration of the illness was 5.7 years, since the time of diagnosis. All patients were evaluated quarterly by a cardiovascular objective examination and an ultrasound of the heart, with regard to platelet count and hematocrit (Ht) variations during the follow-up period, according to the therapy administered. Patients were treated with hydrossiurea and pipobroman and they underwent an eritrocitoapheresis in emergency conditions in which Ht levels rose too much, in spite of the myelosuppressive therapy. The echocardiographic assessment of the heart structure and function by the B mode technique revealed the presence of a sclerocalcific degeneration of the aortic valve in 58% of patients, involving the aortic root more then the valve. An average trans-aortic flow velocity of 1.92 m/s was detected by Doppler technique; a stenosis was demonstrated in 11 patients (25.5% of the entire population). After diagnosing the presence of a stenosis, we researched a possible cause of it. PV is a systemic disease well-known causing coronary thrombosis in a more or less high percentage of patients according to the record of cases taken into account. In our experience, more then thrombotic disease, found only in 13.4% of patients, we detected a high prevalence and incidence of mild to severe aortic stenosis, found in 25.5% of the sample studied. About all possible causes of stenosis, nowadays this results dependent of Ht values at moment of diagnosis, in the light of these results, it is reasonable to infer that aortic valve stenosis could depend by high haemodynamic stress on valve that is characteristic of polycythemic patients without chemotherapy.

Novel inorganic-organic hybrid copolymers based on vinyl- or (3-mercaptopropyl)-trimethoxysilane and an organically modified zirconium-oxocluster were investigated as a wood preservation treatment. The copolymers were prepared using a modified sol-gel strategy not involving alkoxysilane pre-hydrolysis and were applied on wood through a dip coating method. Even though the copolymers were mainly present on the surface of the wood, EDX analysis showed also a uniform distribution of silicon and zirconium in the cell wall but not in the lumina. The grafting of the copolymers on wood was confirmed through FTIR, (13)C and (29)Si MAS NMR analysis. The copolymer obtained from (3-mercaptopropyl)trimethoxysilane was post-functionalized with the methacrylic ester of thymol; introduced for testing as a biocide. Preliminary accelerated biological tests against the brown rot fungus Coniophora puteana, showed resistance to the fungus for the samples coated with the vinyltrimethoxysilane copolymer, while uneven results were obtained for the samples coated with the (3-mercaptopropyl)trimethoxysilane copolymer, even when functionalized with the ester of thymol.

A multicenter randomized open-label long-term sequential deferiprone–deferoxamine (DFP-DFO) versus DFP alone trial (sequential DFP-DFO) performed in patients with thalassemia major (TM) was retrospectively reanalyzed to assess the variation in the left ventricular ejection fraction (LVEF) [1].