600 research outputs found
Fetal hemoglobin reactivation and cell engineering in the treatment of sickle cell anemia
The natural history of severe hemoglobinopathies like sickle cell disease (SCD) is rather variable, depending on the circumstances, but the main influence on such variability is the level of fetal hemoglobin (HbF) in the patient’s red cells. It is well known that a significant HbF level is associated with a milder course of disease and fewer complications. Therefore, attempts have been made to reactivate using various means the HbF production, which is normally switched off perinatally. A pharmacological approach has been attempted since the 1980s, ranging from drugs like 5-azacytidine and its derivative, decitabine, to a series of compounds like hydroxyurea and a number of histone deacetylase inhibitors like butyrate, which seem to act as epigenetic modifiers. Many other disparate agents have been tried with mixed results, but hydroxyurea remains the most effective compound so far available. Combinations of different compounds have also been tried with some success. Established treatments like bone marrow or cord blood transplantation are so far the only real cure for a limited number of patients with severe hemoglobinopathies. Improved chemotherapy regimens of milder toxicity than those employed in the past have made it possible recently to obtain a stable, mixed donor-recipient chimerism, with reversal of the SCD phenotype. However, great effort is directed to cell engineering, searching for an effective gene vector by which a desired gene can be transferred into new classes of vectors for autologous hemopoietic stem cells. Recent studies are also aiming at targeted insertion of the therapeutic gene into hemopoietic cells, which can also be “induced” human stem cells, obtained from somatic dedifferentiated cells. Attention in this area must be paid to the possibility of undesired effects, like the emergence of potentially oncogenic cell populations. Finally, an update is presented on improved HbF determination methods, because common international standards are becoming mandatory
Extra-virgin olive oil phenols block cell cycle progression and modulate chemotherapeutic toxicity in bladder cancer cells
Epidemiological data indicate that the daily consumption of extra‑virgin olive oil (EVOO), a common dietary habit of the Mediterranean area, lowers the incidence of certain types of cancer, in particular bladder neoplasm. The aim of the present study was to evaluate the antiproliferative activity of polyphenols extracted from EVOO on bladder cancer (BCa), and to clarify the biological mechanisms that trigger cell death. Furthermore, we also evaluated the ability of low doses of extra‑virgin olive oil extract (EVOOE) to modulate the in vitro activity of paclitaxel or mitomycin, two antineoplastic drugs used in the management of different types of cancer. Our results showed that EVOOE significantly inhibited the proliferation and clonogenic ability of T24 and 5637 BCa cells in a dose‑dependent manner. Furthermore, cell cycle analysis after EVOOE treatment showed a marked growth arrest prior to mitosis in the G2/M phase for both cell lines, with the subsequent induction of apoptosis only in the T24 cells. Notably, simultaneous treatment of mitomycin C and EVOOE reduced the drug cytotoxicity due to inhibition of ROS production. Conversely, the co‑treatment of T24 cells with paclitaxel and the polyphenol extract strongly increased the apoptotic cell death at each tested concentration compared to paclitaxel alone. Our results support the epidemiological evidence indicating that olive oil consumption exerts health benefits and may represent a starting point for the development of new anticancer strategies
Pediatric liver diseases: current challenges and future perspectives
Chronic liver diseases in children represent a rising problem with significant effects on public health. In fact, several pediatric liver diseases are precursors of adult chronic hepatopathies, cirrhosis and hepatocellular carcinoma. The prevalence of liver diseases in children is unknown. In the USA, every year, 15,000 children are hospitalized for liver diseases, but these disorders continue to be under-recognized or diagnosed late. The main reason is due to the frequent absence of symptoms in the vast majority of liver diseases, especially in the early stages. In the last few decades several advances have been made in understanding the pathogenesis of liver diseases, permitting the discovery of new therapeutic targets to treat liver diseases, thus improving the natural history of these disorders. In this article we discuss the most recent advances in the understanding of the pathogenesis, diagnosis and treatment of the most frequent pediatric liver diseases
Evaluation of a new semi-automated high-performance liquid chromatography method for glycosylated haemoglobins
The authors report data on the evaluation of a new ion-exchange high performance liquid chromatographic system (HLC-723GHb Glycopack-Dyamat), recently introduced by Bio-Rad Laboratories (Segrate, Milano, Italy) to measure the glycosylated haemoglobins in blood samples. The system operates on haemolysates, which have to be performed separately, by diluting 5 \u3bcl of blood with 1 ml of haemolysing reagent. Each analysis takes about 8 min and the results are printed-out, together with a chromatogram. Precision and accuracy (comparison with the minicolumn ion-exchange method) were found to be excellent. The analysis if not affected by the presence of the so-called 'labile fractions', as demonstrated by experiments of incubation with glucose or saline solutions at 37\ub0 C. Some haemolysates containing abnormal haemoglobins (HbS, HbE, HbJ Paris and Hb Lepore) were also analysed. The effects of the different mutants on the glycated haemoglobins assay are discussed. The HbF content is also measured by this system, but the accuracy, concerning this particular determination, at the lower concentrations (HbF <2%) is not satisfactory, and needs further improvement
Reactivation of fetal hemoglobin in thalassemia and sickle cell disease
Considerable attention has been recently devoted to mechanisms involved in the perinatal hemoglobin switch, as it was long ago established that the survival of fetal hemoglobin (HbF) production in significant amount can reduce the severity of the clinical course in severe disorders like β-thalassemia and sickle cell disease (SCD). For instance, when β-thalassemia is associated with hereditary persistence of fetal hemoglobin (HPFH) the disease takes a mild course, labeled as thalassemia intermedia. The same clinical amelioration occurs for the association between HPFH and SCD. As for the mechanism of this effect, some information has been obtained from the study of natural mutations at the human β-globin locus in patients with increased HbF, like the Corfu thalassemia mutations. Important evidence came from the discovery that drugs capable of improving the clinical picture of SCD, like decitabine ad hydroxycarbamide, are acting through the reactivation, to some extent, of HbF synthesis. The study of the mechanism of action of these compounds was followed by the identification of some genetic determinants, which promote this event. In particular, among a few genetic factors involved in this process, the most relevant appears the BCL11A gene, which is now credited to be able to silence γ-globin genes in the perinatal period by interaction with several erythroid-specific transcription factors and is actually considered as a barrier to HbF reactivation by known HbF inducing agents. Epigenetics is also a player in the process, mainly through DNA demethylation. This is certified by the recent demonstration that hypomethylating agents such as 5-azacytidine and decitabine, the first compounds used for HbF induction by pharmacology, act as irreversible inhibitors of demethyltransferase enzymes. Great interest has also been raised by the finding that several micro-RNAs, which act as negative regulators of gene expression, have been implicated in the progression of globin gene expression and, particularly, in the reactivation of γ-globin gene expression associated with increased HbF synthesis. Probably, this reactivation is achieved by post-transcriptional inhibition of BCL11A expression. Finally, attention is presently focused on a recently discovered BCL11A enhancer, essential for erythroid expression of BCL11A, which might become a therapeutic target for genome engineering in the β-hemoglobinopathies as its disruption affects only the erythropoietic lineage, without hurting other cell or tissue compartments
Obituary - In memory of Prof. Renzo Galanello
Prof. Renzo Galanello, a worldwide expert in thalassemic syndromes, died in Cagliari after a few months of a severe illness on May 13, 2013, at the age of 65..
Erythrocyte's aging in microgravity highlights how environmental stimuli shape metabolism and morphology
The determination of the function of cells in zero-gravity conditions is a subject of interest in many different research fields. Due to their metabolic unicity, the characterization of the behaviour of erythrocytes maintained in prolonged microgravity conditions is of particular importance. Here, we used a 3D-clinostat to assess the microgravity-induced modifications of the structure and function of these cells, by investigating how they translate these peculiar mechanical stimuli into modifications, with potential clinical interest, of the biochemical pathways and the aging processes. We compared the erythrocyte's structural parameters and selected metabolic indicators that are characteristic of the aging in microgravity and standard static incubation conditions. The results suggest that, at first, human erythrocytes react to external stimuli by adapting their metabolic patterns and the rate of consumption of the cell resources. On longer timeframes, the cells translate even small differences in the environment mechanical solicitations into structural and morphologic features, leading to distinctive morphological patterns of agin
Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome
Background: Down syndrome (DS) individuals, by the age of 40s, are at increased risk to develop Alzheimer-like dementia, with deposition in brain of senile plaques and neurofibrillary tangles. Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain, prior and after the development of Alzheimer Disease (AD). The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways, including insulin signaling and autophagy, involved in pathology onset and progression. Within this context, the therapeutic use of mTOR-inhibitors may prevent/attenuate the neurodegenerative phenomena. By our work we aimed to rescue mTOR signalling in DS mice by a novel rapamycin intranasal administration protocol (InRapa) that maximizes brain delivery and reduce systemic side effects. Methods: Ts65Dn mice were administered with InRapa for 12 weeks, starting at 6 months of age demonstrating, at the end of the treatment by radial arms maze and novel object recognition testing, rescued cognition. Results: The analysis of mTOR signalling, after InRapa, demonstrated in Ts65Dn mice hippocampus the inhibition of mTOR (reduced to physiological levels), which led, through the rescue of autophagy and insulin signalling, to reduced APP levels, APP processing and APP metabolites production, as well as, to reduced tau hyperphosphorylation. In addition, a reduction of oxidative stress markers was also observed. Discussion: These findings demonstrate that chronic InRapa administration is able to exert a neuroprotective effect on Ts65Dn hippocampus by reducing AD pathological hallmarks and by restoring protein homeostasis, thus ultimately resulting in improved cognition. Results are discussed in term of a potential novel targeted therapeutic approach to reduce cognitive decline and AD-like neuropathology in DS individuals
SĂndrome Oculoglandular de Parinaud: presentaciĂłn de un caso
Presentamos el caso de una adolescente de 14 años que consultĂł por adenopatĂas en regiĂłn preauricular izquierda.
En el interrogatorio dirigido surgiĂł el contacto con gatos, registrándose el antecedente de una conjuntivitis homolateral, por lo cual se planteĂł el SĂndrome de Parinaud por enfermedad por arañazo de gato entre los diagnĂłsticos diferenciales.We report the case of a 14-year-old patient with adenopathies in the preauricular region. During the interview, the patient stated having had contact with cats, and a history of conjunctivitis comes up. These led to the diagnosis of Parinaud syndrome caused by cat scratch disease
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