Design of a regulated lentiviral vector for hematopoietic stem cell gene therapy of globoid cell leukodystrophy

Globoid cell leukodystrophy (GLD) is a demyelinating lysosomal storage disease due to the deficiency of the galactocerebrosidase (GALC) enzyme. The favorable outcome of hematopoietic stem and progenitor cell (HSPC)-based approaches in GLD and other similar diseases suggests HSPC gene therapy as a promising therapeutic option for patients. The path to clinical development of this strategy was hampered by a selective toxicity of the overexpressed GALC in the HSPC compartment. Here, we presented the optimization of a lentiviral vector (LV) in which miR-126 regulation was coupled to codon optimization of the human GALC cDNA to obtain a selective and enhanced enzymatic activity only upon transduced HSPCs differentiation. The safety of human GALC overexpression driven by this LV was extensively demonstrated in vitro and in vivo on human HSPCs from healthy donors. No perturbation in the content of proapoptotic sphingolipids, gene expression profile, and capability of engraftment and mutlilineage differentiation in chimeric mice was observed. The therapeutic potential of this LV was then assessed in a severe GLD murine model that benefited from transplantation of corrected HSPCs with longer survival and ameliorated phenotype as compared to untreated siblings. This construct has thus been selected as a candidate for clinical translatio

BMQ

BMQ: Boston Medical Quarterly was published from 1950-1966 by the Boston University School of Medicine and the Massachusetts Memorial Hospitals

Correction of Recessive Dystrophic Epidermolysis Bullosa by Transposon-Mediated Integration of COL7A1 in Transplantable Patient-Derived Primary Keratinocytes

Therapeutic cell differentiatio

The descriptive content of names as predicate modifiers

In this paper I argue that descriptive content associated with a proper name can serve as a truth-conditionally relevant adjunct and be an additional contribution of the name to the truth-conditions. Definite descriptions the so-and-so associated by speakers with a proper name can be used as qualifying prepositional phrases as so-and-so, so sentences containing a proper name NN is doing something could be understood as NN is doing something as NN (which means as so-and-so). Used as an adjunct, the descriptive content of a proper name expresses the additional circumstances of an action (a manner, reason, goal, time or purpose) and constitute a part of a predicate. I argue that qualifying prepositional phrases should be analyzed as predicate modifiers and propose a formal representation of modified predicates. The additional truth-conditional relevance of the descriptive content of a proper name helps to explain the phenomenon of the substitution failure of coreferential names in simple sentences

Personalizing Cancer Pain Therapy: Insights from the Rational Use of Analgesics (RUA) Group

Introduction: A previous Delphi survey from the Rational Use of Analgesics (RUA) project involving Italian palliative care specialists revealed some discrepancies between current guidelines and clinical practice with a lack of consensus on items regarding the use of strong opioids in treating cancer pain. Those results represented the basis for a new Delphi study addressing a better approach to pain treatment in patients with cancer. Methods: The study consisted of a two-round multidisciplinary Delphi study. Specialists rated their agreement with a set of 17 statements using a 5-point Likert scale (0 = totally disagree and 4 = totally agree). Consensus on a statement was achieved if the median consensus score (MCS) (expressed as value at which at least 50% of participants agreed) was at least 4 and the interquartile range (IQR) was 3–4. Results: This survey included input from 186 palliative care specialists representing all Italian territory. Consensus was reached on seven statements. More than 70% of participants agreed with the use of low dose of strong opioids in moderate pain treatment and valued transdermal route as an effective option when the oral route is not available. There was strong consensus on the importance of knowing opioid pharmacokinetics for therapy personalization and on identifying immediate-release opioids as key for tailoring therapy to patients’ needs. Limited agreement was reached on items regarding breakthrough pain and the management of opioid-induced bowel dysfunction. Conclusion: These findings may assist clinicians in applying clinical evidence to routine care settings and call for a reappraisal of current pain treatment recommendations with the final aim of optimizing the clinical use of strong opioids in patients with cancer

Il convento di San Severo alla Sanità: geometria e vulnerabilità della configurazione

(Incipit) La delicata e complessa problematica del recupero e della salvagiardia del patrimonio architettonico ed ambientale si avvale, in sede operativa, di una precisa sequenza di operazioni critiche, distinte nei tre momenti essenziali della 'conoscenza', della 'diagnosi', ed infine del 'programma' o 'progetto' di intervento. Il presente scritto si rivolte ad un particolare aspetto del momento della 'diagnosi', precisamente alla valutazione della "vulnerabilità per geometria", applicata allo studio del complesso conventuale di San Severo alla Sanità. (...