Esiste un’epica germanica? Alcune note su una questione sfuggente

Ogni tentativo di individuare un gruppo di testi che, nell’ambito delle letterature germaniche medievali, possano essere definiti come “poemi epici” incontra difficoltà apparentemente insormontabili. Tali difficoltà sono dovute principalmente al fatto che il concetto stesso di epica è stato elaborato a partire da esempi appartenenti alle culture classiche e, in un momento successivo, anche a partire da esempi romanzi. L’articolo, dopo una discussione generale dei criteri di classificazione adottati da trattazioni comparatistiche e storico-letterarie, prende in esame tre testi narrativi in versi appartenenti a tre distinte tradizioni germaniche – Beowulf, Nibelungenlied ed Erikskrönika – cercando di mettere in luce le difficoltà di collocazione in un tradizionale sistema di generi. Opinione dell’autore è che solo adottando criteri di definizione non rigidi, che tengano conto caso per caso delle interazioni tra generi e tradizioni, è possibile parlare di “epica germanica”.Any attempt to identify a group of texts that, in the context of medieval Germanic literatures, could be defined as “epic poems” encounters seemingly insurmountable difficulties. Such difficulties are mainly due to the fact that the concept of epic itself was developed starting from examples belonging to classical cultures and, at a later time, also starting from Old French examples. The article, after a general discussion of the classification criteria adopted by comparative and historical-literary treatises, examines three narrative texts in verse belonging to three distinct Germanic traditions: Beowulf, Nibelungenlied and Erikskrönika. The aim of the analysis is to highlight the difficulties of placing them into a traditional system of genres. The author’s opinion is that only by adopting non-rigid definition criteria, which take into account the interactions between genres and traditions on a case-by-case basis, is it possible to speak of a “Germanic epic”

Chi racconta il racconto? Strategie enunciative nelle Saghe degli Islandesi

Nel vasto panorama delle saghe nordiche, quelle raggruppate nel corpus “Saghe degli Islandesi” sono state particolarmente apprezzate, da lettori e studiosi, per la capacità di creare un effetto di oggettività e di imparzialità nella narrazione. Anche queste saghe, tuttavia, non lasciano dubbi su quali comportamenti vengano giudicati legittimi o virtuosi e quali, invece, incontrino la disapprovazione della comunità. Il contributo intende indagare, facendo uso degli strumenti forniti dalla narratologia e tenendo conto del dibattito critico, i meccanismi di costruzione testuale che rendono possibile questo doppio effetto, dedicando particolare attenzione alle strategie di uso della voce narrante

Old Norse in Italy: From Francesco Saverio Quadrio to Fóstbræðra saga

ABSTRACT: Old Norse texts and literary motifs have been circulating in Italian literature since an early period of its history. Already in the second half of the eighteenth century, we find evidence of the interest of some Italian intellectual circles in the cultural tradition of ancient Scandinavia. The aim of this article is to show how and why Italian culture “imported” Old Norse texts during the last two centuries, especially how the mandates of different projects determined which texts to translate, how to translate them, and how to present them to an Italian readership. In keeping with the theme of this special volume, particular attention is paid to the case of Fóstbræðra saga and the context of its appearance in Italian translation, including associated references to the twentieth-century rewriting of this saga by the Icelandic writer Halldór Kiljan Laxness

The GATA1-HS2 Enhancer Allows Persistent and Position-Independent Expression of a β-globin Transgene

Gene therapy of genetic diseases requires persistent and position-independent expression of a therapeutic transgene. Transcriptional enhancers binding chromatin-remodeling and modifying complexes may play a role in shielding transgenes from repressive chromatin effects. We tested the activity of the HS2 enhancer of the GATA1 gene in protecting the expression of a β-globin minigene delivered by a lentiviral vector in hematopoietic stem/progenitor cells. Gene expression from proviruses carrying GATA1-HS2 in both LTRs was persistent and resistant to silencing at most integration sites in the in vivo progeny of human hematopoietic progenitors and murine long-term repopulating stem cells. The GATA1-HS2-modified vector allowed correction of murine β-thalassemia at low copy number without inducing clonal selection of erythroblastic progenitors. Chromatin immunoprecipitation studies showed that GATA1 and the CBP acetyltransferase bind to GATA1-HS2, significantly increasing CBP-specific histone acetylations at the LTRs and β-globin promoter. Recruitment of CBP by the LTRs thus establishes an open chromatin domain encompassing the entire provirus, and increases the therapeutic efficacy of β-globin gene transfer by reducing expression variegation and epigenetic silencing

Stem cell plasticity: time for a reappraisal?

n recent years an increasing number of publications have claimed that adult mammalian stem cells (SC) may be capable of differentiating across tissue lineage boundaries and that this plasticity may represent a novel therapeutic strategy for tissue regeneration. However, after a first phase of excitement, the issue of somatic SC plasticity remains controversial and the therapeutic perspectives are still elusive. In this review, we examine the general mechanisms which govern the function of SC, the identification and functional characterization of adult SC of different tissues and their putative capacity to transdifferentiate into mature cells of different origin. The potential clinical applications of adult SC for regenerative medicine are also discussed in each chapter. The method employed for preparing this review was the informal consensus development. Members of the Working Group on SC met four times and discussed the single points, previously assigned by the Chairman (S.T.), in order to achieve an agreement on different opinions and approve the final manuscript. All the authors of the present review have been working in the field of SC and have contributed original papers to peer-reviewed journals. In addition to the authors' own work, the present review examines articles published in journals covered by the Science Citation Index and Medline

811. Correction of Laminin-5 β3 Chain Deficiency in Human Epidermal Stem Cells by Transcriptionally Targeted Lentiviral Vectors

Mutations in any of the genes encoding the laminin 5 heterotrimer (|[alpha]|3, |[beta]|3 and |[gamma]|2) cause junctional epidermolysis bullosa (JEB), a severe and often fatal skin adhesion defect. We and others have shown that expression of a retrovirally transferred |[beta]|3-chain cDNA in keratinocytes from affected patients reconstitutes normal synthesis, assembly and secretion of laminin 5, and corrects the adhesion defect in vitro and in vivo. We have recently started a phase-I clinical trial of gene therapy of JEB based on transplantation of cultured skin derived from autologous epidermal stem cells transduced with a MLV-derived retroviral vector. Since gamma- retroviral vectors have raised safety concerns for the genotoxic risk associated with the insertion of LTR elements into the human genome, we developed an alternative gene transfer strategy based on LTR- modified, HIV-derived lentiviral vectors. Two self-inactivating (SIN) lentiviral vectors were built, in which expression of either GFP or a LAMB3 cDNA is under the control of either a constitutive promoter (PGK) or the keratinocyte-specific, 2.2-kb promoter-enhancer of keratin 14 (K14). In a third construct, expression of the transgene is under the control of the viral LTR, modified by replacing the U3 region with two K14 enhancer elements. Analysis in human keratinocyte cultures and in full-thickness human skin equivalents reconstituted onto immunodeficient mice showed that GFP expression directed by the K14 elements is tissue-specific and restricted to the basal layer of the epidermis. Expression of laminin5 from the three alternative vectors was evaluated in keratinocyte cultures derived from skin biopsies of JEB patients. Biochemical and cell kinetics assays demonstrated transduction of epidermal clonogenic stem/progenitor cells and full phenotypic correction of JEB keratinocytes with all vectors. Southern blot analysis of individual cell clones showed that LTR-modified lentiviral vectors are genetically stable and integrate in multiple copies in the human genome. This study shows that the use of lentiviral vectors transcriptionally targeted to the basal keratinocytes by the insertion of restricted enhancer elements is an effective, and potentially safer, alternative for gene therapy of JEB

Transcription factor binding sites are genetic determinants of retroviral integration in the human genome.

Gamma-retroviruses and lentiviruses integrate non-randomly in mammalian genomes, with specific preferences for active chromatin, promoters and regulatory regions. Gene transfer vectors derived from gamma-retroviruses target at high frequency genes involved in the control of growth, development and differentiation of the target cell, and may induce insertional tumors or pre-neoplastic clonal expansions in patients treated by gene therapy. The gene expression program of the target cell is apparently instrumental in directing gamma-retroviral integration, although the molecular basis of this phenomenon is poorly understood. We report a bioinformatic analysis of the distribution of transcription factor binding sites (TFBSs) flanking >4,000 integrated proviruses in human hematopoietic and non-hematopoietic cells. We show that gamma-retroviral, but not lentiviral vectors, integrate in genomic regions enriched in cell-type specific subsets of TFBSs, independently from their relative position with respect to genes and transcription start sites. Analysis of sequences flanking the integration sites of Moloney leukemia virus (MLV)- and human immunodeficiency virus (HIV)-derived vectors carrying mutations in their long terminal repeats (LTRs), and of HIV vectors packaged with an MLV integrase, indicates that the MLV integrase and LTR enhancer are the viral determinants of the selection of TFBS-rich regions in the genome. This study identifies TFBSs as differential genomic determinants of retroviral target site selection in the human genome, and suggests that transcription factors binding the LTR enhancer may synergize with the integrase in tethering retroviral pre-integration complexes to transcriptionally active regulatory regions. Our data indicate that gamma-retroviruses and lentiviruses have evolved dramatically different strategies to interact with the host cell chromatin, and predict a higher risk in using gamma-retroviral vs. lentiviral vectors for human gene therapy applications

725. Correction of Laminin-5-Deficient Junctional Epidermolysis Bullosa by Transplantation of Genetically Modified Epidermal Stem Cells. A Phase-I Clinical Trial

Mutations in genes encoding the laminin-5 heterotrimer, a key component of the epidermal-dermal junction, cause junctional epidermolysis bullosa (JEB), a severe and often fatal skin adhesion defect. Epidermal stem cells isolated from patients affected by |[beta]|3 chain-deficient JEB were transduced with a retroviral vector expressing a |[beta]|3 cDNA, and used to generate uniformly transduced cultured skin implants. The transgene was steadily expressed for >160 cell doublings in culture, leading to restoration of normal laminin 5 levels, assembly of functional hemidesmosomes, and full phenotypic correction. Cloning and sequencing of vector integrations showed that <20 stem cells are responsible for long-term maintenance of a transplantable skin culture. A phase-I clinical trial started in October 2005, aimed at proving the safety of the transduction/transplantation procedure, and analyzing persistence of transgene expression and long-term survival of transduced stem cells. The first patient was a 30-yr-old male affected by non-lethal JEB, carrying a null mutation in one LAMB3 allele and a point mutation (E212K) in the other one. The mutation affects the assembly of the laminin-5 heterotrimer, present at residual levels (<5%) in vitro and in vivo. Six genetically modified, cultured epidermal sheets of 100 sq cm were transplanted on both legs after removal of the outer skin layer using a minimally invasive technique. The procedure was well tolerated, and the patient discharged after five days. Engraftment was completed after 10 days, and transplanted skin remained stable on both legs in the absence of blistering or inflammation for the duration of the follow-up (4 months at the time of writing). 3-mm punch biopsies were taken 1 and 3 months after transplantation, and analyzed for vector presence by quantitative PCR and for protein expression by immunohistochemistry. A vector signal compatible with full transduction of the transplanted epidermis was observed at both time points. Synthesis and assembly of normal levels of heterotrimeric laminin-5 and |[alpha]|6|[beta]|4 integrin was observed at the level of the basal lamina in all biopsies, together with the development of a firmly adherent, fully differentiated epidermis. Epidermal stem cells (p64+) were detected in the basal layer of the transplanted skin in normal numbers. These data show that gene therapy of JEB by transplantation of genetically corrected stem cells is feasible, and leads to full phenotypic correction of the adhesion defect in vivo. Safety studies are under way, which include detection or humoral or cytotoxic immune responses against laminin-5, and ex vivo cloning and sequencing of the integrated proviruses

Older people with hip fracture and IADL disability require earlier surgery

Background: Hip fractures represent a major challenge for physicians as well as society as a whole. Both poor functional status and delay to surgery are well known risk factors for negative outcomes. We hypothesized that the timing of the operation is more important for frail older people than older people without functional limitations before fracture. Methods: We performed a prospective multicenter cohort study on 806 consecutive patients, 75 years of age or older, admitted with a fragility hip fracture to three hospitals in the Emilia-Romagna Region (Italy). All three hospitals had a comanaged care model, and the patients were under the shared responsibility of an orthopedic surgeon and a geriatrician. Results: Functional status assessed as instrumental activities of daily living was an important predictor of survival after 1 year from fracture. After adjusting for confounders, the hazard ratios per 1 point score of increase from 0 to 8 was 1.30 (95% confidence interval 1.19-1.42, p =. 000). Time to surgery increased 1-year mortality in patients with a low instrumental activities of daily living score (hazard ratios per day of surgical delay 1.14, 95% confidence interval 1.06-1.22, p &lt;. 001) and intermediate instrumental activities of daily living score (hazard ratios 1.21, 95% confidence interval 1.09-1.34, p &lt;. 001) but was an insignificant risk factor in functionally independent patients (hazard ratios 1.05 95% confidence interval 0.79-1.41, p =. 706). Conclusions: Surgery delay is an independent factor for mortality in older patients after hip fracture but only for the frail older people with prefracture functional impairment. If our results are confirmed, a more intensive approach should be adopted for older people with hip fractures who have disabilities. © 2012 The Author

Management of peritoneal carcinomatosis with cytoreductive surgery combined with intraperitoneal chemohyperthermia at a novel italian center

Background: Peritoneal carcinomatosis (PC) is a common manifestation of many gastrointestinal (GI) malignancies and is an advanced stage that is often associated with disseminated disease. Considerable progress has been made to achieve safe elimination of macroscopic disease using cytoreductive surgery (CRS) and more recently in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of microscopic disease or disease with minimal volume. The aim of this study was to assess the effects of such procedures on the quality of life (QoL), the long-term benefit and the functional status of the treated patients. Patients and Methods: Data from patients who underwent CRS-HIPEC for peritoneal metastasis (PM) at our center from November 2016 to November 2018 were analyzed retrospectively. The drugs administered were mitomycin and cisplatin. Quality of life (QoL) was assessed using the Euroquol-5D-5L and National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index v2 questionnaires before CRS-HIPEC, and 1, 3 and 6 months after were administered. Results: In our series, the survival efficacy of CRS plus HIPEC was confirmed in the treatment of primary and secondary peritoneal pathologies, particularly in ovarian cancer, although larger studies are needed to investigate its role in the pathology of gastric, colonic and rectal cancer. The QoL data were promising, with essentially stable values between the preoperative and the 1-month follow-up, but with incremental benefits from the second to the third month