Bortezomib promotes KHSV and EBV lytic cycle by activating JNK and autophagy

KSHV and EBV are gammaherpesviruses strictly linked to human cancers. Even if the majority of cancer cells harbor a latent infection, the few cells that undergo viral replication may contribute to the pathogenesis and maintenance of the virus-associated malignancies. Cytotoxic drugs used for the therapies of cancers harboring virus-infection often have, as side effect, the activation of viral lytic cycle. Therefore it is important to investigate whether they affect viral reactivation and understand the underlying mechanisms involved. In this study, we found that proteasome inhibitor bortezomib, a cytotoxic drug that efficiently target gammaherpesvirus-associated B cell lymphomas, triggered KSHV or EBV viral lytic cycle by activating JNK, in the course of ER stress, and inducing autophagy. These results suggest that the manipulation of these pathways could limit viral spread and improve the outcome of bortezomib treatment in patients affected by gammaherpesvirus-associated lymphomas

The activation of KSHV lytic cycle blocks autophagy in PEL cells

This study confirms that autophagy is activated concomitantly with KSHV lytic cycle induction, and that autophagy inhibition by BECN1 knockdown reduces viral lytic gene expression. In addition, we extend previous observations and show that autophagy is blocked at late steps, during viral replication. This is indicated by the lack of colocalization of autophagosomes and lysosomes and by the LC3-II level that does not increase in the presence of bafilomycin A1 in primary effusion lymphoma (PEL) cells induced to enter the lytic cycle, either by TPA/sodium butyrate (BC3 and BCBL1) or by doxycycline (TRExBCBL1-Rta). The autophagic block correlates with the downregulation of RAB7, whose silencing with specific siRNA results in an autophagic block in the same cells. Finally, by electron microscopy analysis, we observed viral particles inside autophagic vesicles in the cytoplasm of PEL cells undergoing viral replication, suggesting that they may be involved in viral transpor

Architectus-Sculpere: Objetos al límite entre la Arquitectura y la Escultura

Exposición oral presentada en la sesión dedicada a Formación,Doctorado y Posgrado en las IV Jornadas Internacionales sobre Investigación en Arquitectura y Urbanismo.Al observar la historia de la arquitectura y la escultura como actividades de creación de objetos tridimensionales vinculadas al espacio y al espectador es necesario detenerse en ciertos proyectos que guardan una número de características, enlazando estrechamente una (la escultura) con la otra (la arquitectura), objetos arquitectónicos y/o escultóricos que desbordan un cierto placer visual, pero que no están inscritos específicamente en alguna categoría, objetos penetrables que en ciertos casos podrían considerarse hasta extravagantes, cargados de una búsqueda estética insaciable. Esta investigación se centra en la documentación, análisis y experimentación de estos objetos tridimensionales ubicados en el límite entre la arquitectura y la escultura, para posteriormente desarrollar una terminología propia para dichos elementos y crear así un nuevo género en la creación humana en el ámbito de la tridimensionalidad.Zapata Gonnella, MF. (2012). Architectus-Sculpere: Objetos al límite entre la Arquitectura y la Escultura. http://hdl.handle.net/10251/1491

Biodiversity of vegetable crops, a living heritage

Biodiversity is the natural heritage of the planet and is one of the key factors of sustainable development, due to its importance not only for the environmental aspects of sustainability but also for the social and economic ones. The purpose of this Special Issue is to publish high-quality research papers addressing recent progress and perspectives while focusing on different aspects related to the biodiversity of vegetable crops. Original, high-quality contributions that have not yet been published, or that are not currently under review by other journals, have been gathered. A broad range of aspects such as genetic, crop production, environments, customs and traditions were covered. All contributions are of significant relevance and could stimulate further research in this area

Increasing appropriateness of hospital admissions in the Emilia-Romagna region of Italy.

OBJECTIVES: The Emilia-Romagna region of Italy has reduced the number of available hospital beds and introduced financial incentives to curb hospital use. The goal of this study was to assess the impact of these policies on changes over time in the number of acute hospital admissions classified in diagnosis related groups (DRGs) that could be treated safely and effectively in alternative, less costly settings. METHODS: The assessment of the appropriate site of care was based on analysis of hospital discharge data for all hospitals for the selected diagnosis related groups in the Emilia-Romagna region for 2001 to 2005. The necessity for acute hospital admission was based on the severity of a patient\u27s principal diagnosis, co-morbid diseases and, for surgical admissions, procedure performed. RESULTS: From 2001 to 2005, potentially inappropriate medical admissions of more than one day decreased from 20,076 to 11,580, a 42% decrease. Inappropriate admissions decreased in both public and private hospitals but there remained a higher rate of inappropriate admissions to private hospitals. Potentially inappropriate medical admissions accounted for 128,319 bed-days in 2001 and 68,968 bed-days in 2005, a reduction of 59,351 bed-days. Potentially inappropriate surgical admissions decreased from 7383 in 2001 to 4349 in 2005, a 41% decrease. Bed-days consumed by inappropriate surgical admissions decreased from 23,181 in 2001 to 13,660 in 2005. CONCLUSIONS: The Emilia-Romagna region has succeeded in reducing the use of acute hospital beds for patients in selected diagnosis related groups. However, there are still substantial numbers of admissions that could potentially be treated in less costly settings

KSHV dysregulates bulk macroautophagy, mitophagy and UPR to promote endothelial to mesenchymal transition and CCL2 release, key events in viral-driven sarcomagenesis

Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the causative agent of KS, an aggressive neoplasm that mainly occurs in immune-compromised patients. Spindle cells represent the main feature of this aggressive malignancy and arise from KSHV-infected endothelial cells undergoing endothelial to mesenchymal transition (EndMT), which changes their cytoskeletal composition and organization. As in epithelial to mesenchymal transition (EMT), EndMT is driven by transcription factors such as SNAI1 and ZEB1 and implies a cellular reprogramming mechanism regulated by several molecular pathways, particularly PI3K/AKT/MTOR. Here we found that KSHV activated MTOR and its targets 4EBP1 and ULK1 and reduced bulk macroautophagy and mitophagy to promote EndMT, activate ER stress/ Unfolded Protein Response (UPR), and increase the release of the pro-angiogenic and pro-inflammatory chemokine CCL2 by HUVEC cells. This study suggests that the manipulation of macroautophagy, mitophagy, and UPR and the interplay between the three could be a promising strategy to counteract EndMT, angiogenesis, and inflammation, the key events of KSHV-driven sarcomagenesis

Influence of soil and soilless agricultural growing system on postharvest quality of three ready-to-use multi-leaf lettuce cultivars

In this study the influence of soil and soilless growing systems (substrate 3:1 v/v perlite:peat) on quality and microbial traits of three multi-leaf lettuce cultivars (two green, ‘Eztoril’ and ‘Ezabel’, and one red, ‘Ezra’) was evaluated at harvest and after 7 and 13 days of storage at 8°C. At harvest, ‘Ezra’ showed a respiration activity and a total phenol content respectively 2-fold and 25% significantly higher than the green cultivars. Soil lettuces resulted more stressed than those grown in soilless, as indicated by their initial content in antioxidants. As for nitrate content, soilless grown lettuces at harvest showed an average concentration higher than soil-grown ones, although values are generally lower than limits imposed by the EU Regulation (No. 1258/2011). During storage, soilless lettuces showed no ammonium accumulation, differently from those cultivated in soil. In addition, lettuce cultivars grown in soilless condition showed unchanged content in the antioxidant activity and total phenols, and lower microbial counts than soil lettuces. Results of the present study showed that soilless growing system can positively affect qualitative and microbiological parameter of lettuces studied, and it can be considered a good soilless growing technique in order to obtain high quality multi-leaf lettuces for ready-to-use industry

Quanto, come e perché si cade in ospedale? Indagine in un'ASL piemontese

RIASSUNTO Introduzione. Secondo l'Organizzazione Mondiale della Sanití  (OMS) le cadute e i danni ad esse correlati sono una problematica prioritaria per i sistemi sanitari e sociali in Europa e nel mondo, soprattutto tenendo conto del rapido accrescersi dell'aspettativa di vita. Scopo: Obiettivo del presente studio è descrivere incidenza, cause e modalití  di caduta nell'Azienda Sanitaria Locale Cuneo 1 (ASL CN1) in seguito all'accorpamento del 2008. Metodo: L'indagine si articola in due fasi: 1. definizione dell'atteso sulla base di letteratura ed altre realtí  comparabili; 2. analisi del contesto realizzata attraverso esame delle schede di segnalazione delle cadute compilate tra 1 Luglio 2010 - 30 Giugno 2011. Risultati: L'incidenza delle cadute nel periodo in esame è dello 0.8% e nel 69% dei casi la causa è rappresentata dai fattori intrinseci, seguiti da quelli estrinseci (7.4%), organizzativi (5.4%) e quelli legati a difficoltí  comunicative interprofessionali (3.1%). Conclusioni: Data l'eziologia multifattoriale delle cadute, l'approccio più efficace per ridurne l'incidenza è quello multidimensionale; si comprende quindi l'importanza di un'azione simultanea su tre livelli: organizzativo, staff/comunicazione e paziente.Parole chiave: Cadute accidentali/economia, Cadute accidentali/mortalití , Cadute accidentali/prevenzione e controllo, Cadute accidentali/statistiche e datiAbstractIntroduction.According to the World Health Organization (WHO), falls and falls related-injuries are a main issue for health and social systems in Europe and all over the world, particularly considering that life is lengthening. Objective: To describe incidence, causes and falls modalities in a Northern Italian Hospital following the organizational changes set up in 2008. Methods: The survey consists of two steps: 1. definition of expected situation according to the literature and other similar contexts; 2. examination of the fall report forms between July 1, 2010 and June 30, 2011. Results: In this period the incidence of falls has been 0.8% and in 69% of cases patients' intrinsic factors have been identified to be the cause, followed by extrinsic factors (7.4%), organizational factors (5.4%) and inter-professional communication difficulties (3.1%). Conclusion: Falls have a multi-factorial etiology, therefore the most effective approach should be multidimensional. A simultaneous action on three levels, organizational, staff/communication and patient, would be needed.Keywords: Accidental Falls/economics, Accidental Falls/mortality, Accidental Falls/prevention and control, Accidental Falls/statistics and numerical dat

NFE2L2 and STAT3 converge on common targets to promote survival of primary lymphoma cells

NFE2L2 and STAT3 are key pro-survival molecules, and thus, their targeting may represent a promising anti-cancer strategy. In this study, we found that a positive feedback loop occurred between them and provided evidence that their concomitant inhibition efficiently impaired the survival of PEL cells, a rare, aggressive B cell lymphoma associated with the gammaherpesvirus KSHV and often also EBV. At the molecular level, we found that NFE2L2 and STAT3 converged in the regulation of several pro-survival molecules and in the activation of processes essential for the adaption of lymphoma cells to stress. Among those, STAT3 and NFE2L2 promoted the activation of pathways such as MAPK3/1 and MTOR that positively regulate protein synthesis, sustained the antioxidant response, expression of molecules such as MYC, BIRC5, CCND1, and HSP, and allowed DDR execution. The findings of this study suggest that the concomitant inhibition of NFE2L2 and STAT3 may be considered a therapeutic option for the treatment of this lymphoma that poorly responds to chemotherapies

The inhibition of IRE1alpha/XBP1 axis prevents EBV-driven lymphomagenesis in NSG mice

Post-transplant lymphoproliferative disorders (PTLD) are a group of heterogeneous diseases originating in conditions of immune deficiency, whose main driver is considered to be Epstein-Barr virus (EBV). Here, we explored the role of IRE1alpha/XBP1s axis in EBV-driven lymphomagenesis in an NOD SCID gamma mouse model, as these animals develop malignancies that closely resemble PTLD when engrafted with EBV-positive peripheral blood momonuclear cells (PBMC). This study evidences for the first time that 4μ8C IRE1 alpha endoribonuclease inhibitor prevented lymphomagenesis in vivo and B-cell immortalization in vitro driven by the virus. At the molecular level, 4μ8C reduced the expression of EBV antigens such as ZEBRA and LMP1, downregulated c-Myc and cyclin D1, and prevented the activation of STAT3, molecules known to be involved in viral lymphomagenesis. The results obtained in this study suggest that the inhibition of IRE1 alpha endoribonuclease may represent a promising therapeutic strategy to prevent EBV-associated PTLD that arise in immune-deficient patients.IMPORTANCEThe novelty of this study lies in the fact that it shows that IRE1 alpha endoribonuclease inhibition by 4μ8C was able to counteract Epstein-Barr virus-driven lymphomagenesis in NOD SCID gamma mice and prevent B-cell immortalization in vitro, unveiling that this drug may be a promising therapeutic approach to reduce the risk of post-transplant lymphoproliferative disorders (PTLD) onset in immune-deficient patients. This hypothesis is further supported by the fact that 4μ8C impaired the survival of PTLD-like cells derived from mice, meaning that it could be helpful also in the case in which there is the possibility that these malignancies have begun to arise