Correction of beta-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients

Beta-thalassemia is a common monogenic disorder due to mutations in the beta-globin gene and gene therapy, based on autologous transplantation of genetically corrected haematopoietic stem cells (HSCs), holds the promise to treat patients lacking a compatible bone marrow (BM) donor. We recently showed correction of murine beta-thalassemia by gene transfer in HSCs with the GLOBE lentiviral vector (LV), expressing a transcriptionally regulated human beta-globin gene. Here, we report successful correction of thalassemia major in human cells, by studying a large cohort of pediatric patients of diverse ethnic origin, carriers of different mutations and all candidates to BM transplantation. Extensive characterization of BM-derived CD34(+) cells before and following gene transfer shows the achievement of high frequency of transduction, restoration of haemoglobin A synthesis, rescue from apoptosis and correction of ineffective erythropoiesis. The procedure does not significantly affect the differentiating potential and the relative proportion of haematopoietic progenitors. Analysis of vector integrations shows preferential targeting of transcriptionally active regions, without bias for cancer-related genes. Overall, these results provide a solid rationale for a future clinical translation

Years of life that could be saved from prevention of hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) causes premature death and loss of life expectancy worldwide. Its primary and secondary prevention can result in a significant number of years of life saved. AIM: To assess how many years of life are lost after HCC diagnosis. METHODS: Data from 5346 patients with first HCC diagnosis were used to estimate lifespan and number of years of life lost after tumour onset, using a semi-parametric extrapolation having as reference an age-, sex- and year-of-onset-matched population derived from national life tables. RESULTS: Between 1986 and 2014, HCC lead to an average of 11.5 years-of-life lost for each patient. The youngest age-quartile group (18-61 years) had the highest number of years-of-life lost, representing approximately 41% of the overall benefit obtainable from prevention. Advancements in HCC management have progressively reduced the number of years-of-life lost from 12.6 years in 1986-1999, to 10.7 in 2000-2006 and 7.4 years in 2007-2014. Currently, an HCC diagnosis when a single tumour <2 cm results in 3.7 years-of-life lost while the diagnosis when a single tumour 65 2 cm or 2/3 nodules still within the Milan criteria, results in 5.0 years-of-life lost, representing the loss of only approximately 5.5% and 7.2%, respectively, of the entire lifespan from birth. CONCLUSIONS: Hepatocellular carcinoma occurrence results in the loss of a considerable number of years-of-life, especially for younger patients. In recent years, the increased possibility of effectively treating this tumour has improved life expectancy, thus reducing years-of-life lost

Discutindo a educação ambiental no cotidiano escolar: desenvolvimento de projetos na escola formação inicial e continuada de professores

A presente pesquisa buscou discutir como a Educação Ambiental (EA) vem sendo trabalhada, no Ensino Fundamental e como os docentes desta escola compreendem e vem inserindo a EA no cotidiano escolar., em uma escola estadual do município de Tangará da Serra/MT, Brasil. Para tanto, realizou-se entrevistas com os professores que fazem parte de um projeto interdisciplinar de EA na escola pesquisada. Verificou-se que o projeto da escola não vem conseguindo alcançar os objetivos propostos por: desconhecimento do mesmo, pelos professores; formação deficiente dos professores, não entendimento da EA como processo de ensino-aprendizagem, falta de recursos didáticos, planejamento inadequado das atividades. A partir dessa constatação, procurou-se debater a impossibilidade de tratar do tema fora do trabalho interdisciplinar, bem como, e principalmente, a importância de um estudo mais aprofundado de EA, vinculando teoria e prática, tanto na formação docente, como em projetos escolares, a fim de fugir do tradicional vínculo “EA e ecologia, lixo e horta”.Facultad de Humanidades y Ciencias de la Educació

Are stem cells a potential therapeutic tool in coeliac disease?

Despite the growing understanding of its pathogenesis, the treatment of coeliac disease is still based on a lifelong gluten-free diet that, although efficacious, is troublesome for affected patients, and a definitive cure is still an unmet need. In this regard, the development of new chemical- and biological-derived agents has often resulted in unsatisfactory effects when tested in vivo, probably because of their ability to target only a single pathway, whilst the immunological cascade responsible for tissue injury is complex and redundant. The advent of cellular therapies, mainly based on the use of stem cells, is an emerging area of interest since it has the advantage of a multi-target strategy. Both haematopoietic and mesenchymal stem cells have been employed in the treatment of refractory patients suffering from autoimmune diseases, with promising results. However, the lack of immunogenicity makes mesenchymal stem cells more suitable than their haematopoietic counterpart, since their transplantation may be performed in the absence of a myeloablative conditioning regimen. In addition, mesenchymal stem cells have been shown to harbour strong modulatory effects on almost all cells involved in immune response, together with a potent regenerative action. It is therefore conceivable that over the next few years their therapeutic use will increase as their biological interactions with injured tissues become clearer

Renal function and peak exercise oxygen consumption in chronic heart failure with reduced left ventricular ejection fraction

Background: Chronic kidney disease is associated with sympathetic activation and muscle abnormalities, which may contribute to decreased exercise capacity. We investigated the correlation of renal function with peak exercise oxygen consumption (V˙O2) in heart failure (HF) patients. Methods and Results: We recruited 2,938 systolic HF patients who underwent clinical, laboratory, echocardiographic and cardiopulmonary exercise testing. The patients were stratified according to estimated glomerular filtration rate (eGFR). Mean follow-up was 3.7 years. The primary outcome was a composite of cardiovascular death and urgent heart transplantation at 3 years. On multivariable regression, eGFR was predictor of peakV˙O2 (P&lt;0.0001). Other predictors were age, sex, body mass index, HF etiology, NYHA class, atrial fibrillation, resting heart rate, Btype natriuretic peptide, hemoglobin, and treatment. After adjusting for significant covariates, the hazard ratio for primary outcome associated with peakVO2 &lt;12 ml ・ kg−1 ・ min−1 was 1.75 (95% confidence interval (CI): 1.06–2.91; P=0.0292) in patients with eGFR ≥60, 1.77 (0.87–3.61; P=0.1141) in those with eGFR of 45–59, and 2.72 (1.01– 7.37; P=0.0489) in those with eGFR &lt;45 ml ・ min−1 ・ 1.73 m−2. The area under the receiver-operating characteristic curve for peakV˙O2 &lt;12 ml ・ kg−1 ・ min−1 was 0.63 (95% CI: 0.54–0.71), 0.67 (0.56–0.78), and 0.57 (0.47–0.69), respectively. Testing for interaction was not significant. Conclusions: Renal dysfunction is correlated with peakV O2. A peakV O2 cutoff of 12 ml ・ kg–1 ・ min–1 offers limited prognostic information in HF patients with more severely impaired renal function

Correlation between LDH levels and response to sorafenib in HCC patients: An analysis of the ITA.LI.CA database

Background: Lactate dehydrogenase (LDH) is a predictor of clinical outcome in hepatocellular carcinoma (HCC) patients. However, its predictive role in the clinical outcomes of sorafenib treatment has been poorly documented. The correlation between LDH levels and clinical outcomes in HCC patients treated with sorafenib and included in the nationwide Italian database ITA.LI.CA was investigated here. Patients and methods: The ITA.LI.CA database contains data for 5,136 HCC patients. All patients treated with sorafenib treatment and with available LDH values were considered. Overall survival (OS) and time to progression (TTP) were compared in patients with LDH levels above and below a defined threshold, determined through an ROC analysis. An explorative analysis investigated the relationship between the variation of LDH levels during treatment and response to sorafenib. Results: Baseline LDH levels were available for 97 patients. The most accurate cutoff value for LDH concentration was 297 U/L. Patients with LDH values above (n=45) and below (n=52) this threshold showed equal OS (12.0 months) and TTP (4.0 months) values. Data on LDH levels during sorafenib treatment were reported for 10 patients. LDH values decreased in 3 patients (mean difference = -219 U/L) who also reported a prolonged OS and TTP versus those with unmodified/increased LDH (OS: NE (not evaluated) vs. 8.0 months, p=0.0083; TTP: 19.0 vs. 3.0 months, p=0.008). Conclusions: The clinical benefits of sorafenib do not seem to be influenced by baseline LDH. According to the results of an explorative analysis, however, a decreased LDH concentration during sorafenib might be associated with improved clinical outcomes

Metabolic exercise data combined with cardiac and kidney indexes: MECKI score. Predictive role in cardiopulmonary exercise testing with low respiratory exchange ratio in heart failure

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Metabolic disorders across hepatocellular carcinoma in Italy

Background: Metabolic disorders are well-known risk factors for HCC. Conversely, their impact on the natural history of HCC is not established. This study aimed at evaluating the impact of metabolic disorders on clinical features, treatment and survival of HCC patients regardless of its aetiology. Methods: We analysed the ITA.LI.CA database regarding 839 HCC patients prospectively collected. The following metabolic features were analysed: BMI, diabetes, arterial hypertension, hypercholesterolaemia and hypertriglyceridaemia. According to these features, patients were divided into 3 groups: 0-1, 2 and 3-5 metabolic features. Results: As compared with patients with 0-1 metabolic features, patients with 3-5 features showed lower percentage of HCC diagnosis on surveillance (P\ua0=.021), larger tumours (P\ua0=.038), better liver function (higher percentage of Child-Pugh class A [P\ua0=.007] and MELD\ua0<\ua010 [P\ua0=.003]), higher percentage of metastasis (P\ua0=.024) and lower percentage of portal vein thrombosis (P\ua0=.010). The BCLC stage and treatment options were similar among the 3 groups, with the exception of a less frequent access to loco-regional therapies for BCLC stage B patients with 3-5 features (P\ua0=.012). Overall survival and survival according to BCLC stage and/or treatment did not significantly differ among the 3 groups. Only using a probabilistic sensitivity analysis, diabetic patients showed a lower survival (P\ua0=.046). MELD score, HCC morphology, nodule size, BCLC stage, portal vein thrombosis and metastasis were independent predictors of lead-time adjusted survival. Conclusions: Our \u201creal world\u201d study suggests that metabolic disorders shape the clinical presentation of HCC but do not seem to play a major role in setting patient survival