Difficult to treat cancer entities such as sarcomas and peritoneal carcinosis challenged by suicide gene-armed virotherapeutic vector systems MeV and VACV

Virotherapy is one of the novel anti-cancer strategies currently being investigated in preclinical experiments and clinical trials to fight cancer. Virotherapy is based on attenuated, replication-competent oncolytic viruses which selectively infect, replicate in and kill tumor cells without significantly harming healthy tissue. To advance the inherited oncolytic effect of viruses, trans¬genes like anti-angiogenic, immuno-stimulatory or suicide genes were inserted into the viral genome. For our examinations we chose two genetically modified viral vector systems, MeV (MeV-SCD) and VACV (GLV-1h68/GLV-1h95), which hold an outstanding safety profile and recently have entered extensive clinical testing as state-of-the-art viro-therapeutics. Both vector systems encode for marker genes and were armed with the suicide gene SCD which converts the non-toxic prodrug 5-FC into the common chemotherapeutic 5-FU. MeV-SCD, GLV-1h68 and GLV-1h95 were investigated with regard to their ability of infection, replication behaviour and oncolysis in vitro as potential virotherapeutics in the fight against cancer. Summing up our findings we could demonstrate that MeV-SCD was able to kill primarily therapy-resistant sarcoma cell lines expressing high levels of CD46 but failed to kill the latter expressing low levels of CD46. GLV-1h68 however was able to kill primarily therapy-resistant sarcoma cell lines, the peritoneal carcinosis causing cell lines CC531s and SKOV3ip.1 and also all the cell lines called ‘in vivo non-responders’ by Worschech et al. (2009). The SCOS cells, which were highly resistant to MeV-SCD, also resisted GLV-1h68 treatment to a lower extent. The armed vector GLV-1h95 finally led to massive cell mass reduction of SCOS cells. The additional effect of the suicide gene therapy with GLV-1h95 and 5-FC especially became obvious in our experiments with low MOI 0.1. Healthy PHHs were infected by GLV-1h68 but stayed mostly unaffected at MOI 0.1. Therefore, our virotherapeutics should be short-listed to fight against peritoneal carcinosis and sarcomas in order to overcome current therapy resistances

Chemoresistance acquisition induces a global shift of expression of aniogenesis-associated genes and increased pro-angogenic activity in neuroblastoma cells

BACKGROUND: Chemoresistance acquisition may influence cancer cell biology. Here, bioinformatics analysis of gene expression data was used to identify chemoresistance-associated changes in neuroblastoma biology. RESULTS: Bioinformatics analysis of gene expression data revealed that expression of angiogenesis-associated genes significantly differs between chemosensitive and chemoresistant neuroblastoma cells. A subsequent systematic analysis of a panel of 14 chemosensitive and chemoresistant neuroblastoma cell lines in vitro and in animal experiments indicated a consistent shift to a more pro-angiogenic phenotype in chemoresistant neuroblastoma cells. The molecular mechanims underlying increased pro-angiogenic activity of neuroblastoma cells are individual and differ between the investigated chemoresistant cell lines. Treatment of animals carrying doxorubicin-resistant neuroblastoma xenografts with doxorubicin, a cytotoxic drug known to exert anti-angiogenic activity, resulted in decreased tumour vessel formation and growth indicating chemoresistance-associated enhanced pro-angiogenic activity to be relevant for tumour progression and to represent a potential therapeutic target. CONCLUSION: A bioinformatics approach allowed to identify a relevant chemoresistance-associated shift in neuroblastoma cell biology. The chemoresistance-associated enhanced pro-angiogenic activity observed in neuroblastoma cells is relevant for tumour progression and represents a potential therapeutic target

MDD4SOA: Model-Driven Service Orchestration

Service-Oriented Architectures (SOAs) have become an important cornerstone of the development of enterprise-scale software applications. Although a range of domain-specific languages and standards are available for dealing with such architectures, model-driven approaches starting from models written in an established modelling language like UML and including the ability for model transformation (in particular, for code generation) are still in their infancy. In this paper, we show (1) how our UML-based domain-specific language for working with SOA artefacts, UML4SOA, can be used for modelling service orchestrations, and (2) how to exploit so-designed models in the MDD4SOA approach to generate code in multiple languages, among them BPEL and WSDL, Java, and the formal language Jolie. We use a case study for illustrating this approach. Our main contributions are an easy-to-use, conservative extension to the UML2 for modelling service orchestrations on a high level of abstraction, and a fully automated, model-driven approach for transforming these orchestrations down to code. 1

Attenuation effects of prenatal stress by early postnatal stimulation in different research models

Prenatal stress alters the pattern of corticoid secretion and affects transplacentally the fetus hypothalamic-pituitary-adrenal axis (HPA) in different animal models. Early postnatal stimulation or handling results in an increase in maternal care to the offspring what reverts the effects of prenatal stress on the alterations produced in the HPA axis. In this revision article we describe and discuss the underlying mechanism present and discuss the mechanisms leading to causing imbalance produced by prenatal stress and how it is related to immune system disorders. The general effects that postnatal early stimulation have on the parameters altered by prenatal stress and the attenuation produced on prenatal stress immune system negative effects will also be discussed.Fil: Liaudat, Ana Cecilia. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Mayer, Nora I.. Universidad Nacional de Río Cuarto. Facultad de Agronomía y Veterinaria. Departamento de Anatomía Animal. Cátedra de Histología; ArgentinaFil: Vivas, Adriana Beatriz. Universidad Nacional de Río Cuarto. Facultad de Agronomía y Veterinaria. Departamento de Anatomía Animal. Laboratorio de Biología Cecular y Embriología; ArgentinaFil: Romanini, María Cristina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; ArgentinaFil: Bosch, Pablo. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Rodriguez, Nancy. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentin

IL-2 is involved in immune response of prenatally stressed rats exposed to postnatally stimulation

Environmental cues influence growth and development of mammals during prenatal and particularly early postnatal life and can exert long-lasting effects in adult life. High circulating concentration of glucocorticoids during pregnancy (prenatal stress) affects the activity of the hypothalamic-pituitary-adrenal axis (HPA) of offspring and has been linked to alter immune system responses. Early postnatal stimulation (handling) of prenatally stressed animals generates long-term beneficial effects on the reactiveness of the HPA axis and immune system function. The aim of this study was to further investigate the effect of handling on immune response in prenatally stressed male rats and to elucidate a possible relationship with the HPA axis activity. Control and prenatally stressed (PS) offspring by immobilization (IMO) were handled during the first week of life. Animals from both treatments were subjected to acute stress by IMO. Corticosterone (COR) plasma concentration was measured by RIA assay, T lymphocyte proliferation by [3H] thymidine assay and IL-2 levels by direct ELISA technique. Chronic IMO prenatal stress caused an increase in mother plasma COR basal levels. Furthermore, prenatally stressed rats subjected to an acute stress session had lower T cell proliferation and decreased IL-2 release. In addition, early postnatal stimulation reversed the negative effects of prenatal stress on proliferation of T lymphocytes and IL-2 release

Socially sensitive lactation: Exploring the social context of breastfeeding

Many women report difficulties with breastfeeding and do not maintain the practice for as long as intended. Although psychologists and other researchers have explored some of the difficulties they experience, fuller exploration of the relational contexts in which breastfeeding takes place is warranted to enable more in-depth analysis of the challenges these pose for breastfeeding women. The present paper is based on qualitative data collected from 22 first-time breastfeeding mothers through two phases of interviews and audio-diaries which explored how the participants experienced their relationships with significant others and the wider social context of breastfeeding in the first five weeks postpartum. Using a thematic analysis informed by symbolic interactionism, we develop the overarching theme of ‘Practising socially sensitive lactation’ which captures how participants felt the need to manage tensions between breastfeeding and their perceptions of the needs, expectations and comfort of others. We argue that breastfeeding remains a problematic social act, despite its agreed importance for child health. Whilst acknowledging the limitations of our sample and analytic approach, we suggest ways in which perinatal and public health interventions can take more effective account of the social challenges of breastfeeding in order to facilitate the health and psychological well-being of mothers and their infants

Non-functional properties in the model-driven development of service-oriented systems

Systems based on the service-oriented architecture (SOA) principles have become an important cornerstone of the development of enterprise-scale software applications. They are characterized by separating functions into distinct software units, called services, which can be published, requested and dynamically combined in the production of business applications. Service-oriented systems (SOSs) promise high flexibility, improved maintainability, and simple re-use of functionality. Achieving these properties requires an understanding not only of the individual artifacts of the system but also their integration. In this context, non-functional aspects play an important role and should be analyzed and modeled as early as possible in the development cycle. In this paper, we discuss modeling of non-functional aspects of service-oriented systems, and the use of these models for analysis and deployment. Our contribution in this paper is threefold. First, we show how services and service compositions may be modeled in UML by using a profile for SOA (UML4SOA) and how non-functional properties of service-oriented systems can be represented using the non-functional extension of UML4SOA (UML4SOA-NFP) and the MARTE profile. This enables modeling of performance, security and reliable messaging. Second, we discuss formal analysis of models which respect this design, in particular we consider performance estimates and reliability analysis using the stochastically timed process algebra PEPA as the underlying analytical engine. Last but not least, our models are the source for the application of deployment mechanisms which comprise model-to-model and model-to-text transformations implemented in the framework VIATRA. All techniques presented in this work are illustrated by a running example from an eUniversity case study

The Quest for Dual and Binary Supermassive Black Holes: A Multi-Messenger View

The quest for binary and dual supermassive black holes (SMBHs) at the dawn of the multi-messenger era is compelling. Detecting dual active galactic nuclei (AGN) – active SMBHs at projected separations larger than several parsecs – and binary AGN – probing the scale where SMBHs are bound in a Keplerian binary – is an observational challenge. The study of AGN pairs (either dual or binary) also represents an overarching theoretical problem in cosmology and astrophysics. The AGN triggering calls for detailed knowledge of the hydrodynamical conditions of gas in the imminent surroundings of the SMBHs and, at the same time, their duality calls for detailed knowledge on how galaxies assemble through major and minor mergers and grow fed by matter along the filaments of the cosmic web. This review describes the techniques used across the electromagnetic spectrum to detect dual and binary AGN candidates and proposes new avenues for their search. The current observational status is compared with the state-of-the-art numerical simulations and models for formation of dual and binary AGN. Binary SMBHs are among the loudest sources of gravitational waves (GWs) in the Universe. The search for a background of GWs at nHz frequencies from inspiralling SMBHs at low redshifts, and the direct detection of signals from their coalescence by the Laser Interferometer Space Antenna in the next decade, make this a theme of major interest for multi-messenger astrophysics. This review discusses the future facilities and observational strategies that are likely to significantly advance this fascinating field