Melphalan is an efficient chemotherapeutic agent that is currently used to treat retinoblastoma (Rb); however, the inherent risk of immunogenicity and the hazardous integration of this drug in ...healthy cells is inevitable. MicroRNAs are short non-coding single-stranded RNAs that affect a vast range of biological processes. Previously, we focused on the regulatory role of miR-181a during cancer development and progression. In this manuscript, 171 nm switchable lipid nanoparticles (LNP) co-delivered melphalan and miR-181a with encapsulation efficiencies of 93%. Encapsulation of melphalan in LNP significantly improved its therapeutic efficiency. Gene analysis shows that miR-181a decreases the expression of anti-proliferative gene MAPK1 and anti-apoptotic gene Bcl-2, but significantly increased the expression of pro-apoptotic gene BAX. Our results suggest that the two agents have a complementary effect in reducing the viability of cultured Rb cells (primary and cell line) and decreasing Rb cell counts in an in-vivo xenograft Rb model in rats. Our results suggest that the proposed co-delivery technique significantly increases the therapeutic impact, allows for lower administration of melphalan, and consequently, could minimize the cytotoxic side-effects of this drug.
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The European Commission asked EFSA for a scientific opinion on the risks for animal and human health related to the presence of glycoalkaloids (GAs) in feed and food. This risk assessment covers ...edible parts of potato plants and other food plants containing GAs, in particular, tomato and aubergine. In humans, acute toxic effects of potato GAs (α‐solanine and α‐chaconine) include gastrointestinal symptoms such as nausea, vomiting and diarrhoea. For these effects, the CONTAM Panel identified a lowest‐observed‐adverse‐effect level of 1 mg total potato GAs/kg body weight (bw) per day as a reference point for the risk characterisation following acute exposure. In humans, no evidence of health problems associated with repeated or long‐term intake of GAs via potatoes has been identified. No reference point for chronic exposure could be identified from the experimental animal studies. Occurrence data were available only for α‐solanine and α‐chaconine, mostly for potatoes. The acute dietary exposure to potato GAs was estimated using a probabilistic approach and applying processing factors for food. Due to the limited data available, a margin of exposure (MOE) approach was applied. The MOEs for the younger age groups indicate a health concern for the food consumption surveys with the highest mean exposure, as well as for the P95 exposure in all surveys. For adult age groups, the MOEs indicate a health concern only for the food consumption surveys with the highest P95 exposures. For tomato and aubergine GAs, the risk to human health could not be characterised due to the lack of occurrence data and the limited toxicity data. For horses, farm and companion animals, no risk characterisation for potato GAs could be performed due to insufficient data on occurrence in feed and on potential adverse effects of GAs in these species.
This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2020.EN-1905/full
Performance Impacts through Intelligent Transport Systems An Assessment of how to Measure and Evaluate Hofmeister Patrick , Internationella Handelshögskolan, Högskolan i Jönköping, IHH, Centre of Logistics and Supply Chain Management; Kadner Matthias , Internationella Handelshögskolan, Högskolan i Jönköping, IHH, Centre of Logistics and Supply Chain Management; Hofmeister Patrick, International School of Business, University of Jönköping, IHH, Centre of Logistics and Supply Chain Management ...
2011
Web Resource
This study assesses how to measure and evaluate performance impacts of IntelligentTransport Systems (ITS) in the transport chain.The importance of transportation in global trade has increased ...significantly in the lastdecades. Cost pressure, rising customer demand for sophisticated logistics services, sustainabilityand security as well as safety issues have boosted the need for more efficient,effective and differentiated transport operations. Intelligent Transport Systems werefound to have the potential to address these challenges in the transport chain. However,due to the novelty of the technology both ITS developers and users face huge uncertaintyabout the performance impacts of ITS. Evaluating ITS in the transport chain beforethe rollout based on concrete measures is likely to reduce the uncertainty involvedin ITS developments and enhance the adoption rate of the new technology. The increasingnumber of ITS projects, like the Secure Intermodal Transport Systems at VolvoTechnology, create a need for a structured approach to measure and evaluate ITS.A literature review concerning the characteristics of the transport industry, technologyadoption, ITS and performance measurements served as a basis for the empirical studyin which 8 semi-structured interviews with different stakeholders in the transport industrywere conducted in order to find out how the performance impacts of ITS are perceivedin the industry and how they could possibly be assessed. The focus groupmethod was used to validate and apply the findings from the interview study to a GeofencingITS-service.The study has confirmed that the concept of ITS is still an emerging phenomenon in thetransportation industry. There is no common understanding of ITS among researchersand practitioners in the transport industry and still a lack of knowledge regarding theperformance impacts of ITS. Even though it could be found that ITS leverages mainlythe service level that can be offered to the customer and that they increase the efficiencyin the back office, the great variety of ITS-services calls for an individual assessment.Structuring the assessment into the phases of measurement design, implementation anduse of the measures facilitates this process. For the different phases a set of activitiescritical for a successful assessment of ITS have been identified. Despite its usefulnessfor mitigating the uncertainty related to the new technology, the focus group validationuncovered that a comprehensive measurement for ITS is not appropriate from the outset,but should be assessed based on the cost of the measurement, the ITS project priority,the customer relations as well as the hierarchical structure in the provider firm.
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This study assesses how to measure and evaluate performance impacts of IntelligentTransport Systems (ITS) in the transport chain.The importance of transportation in global trade has increased significantly in the lastdecades. Cost pressure, rising customer demand for sophisticated logistics services, sustainabilityand security as well as safety issues have boosted the need for more efficient,effective and differentiated transport operations. Intelligent Transport Systems werefound to have the potential to address these challenges in the transport chain. However,due to the novelty of the technology both ITS developers and users face huge uncertaintyabout the performance impacts of ITS. Evaluating ITS in the transport chain beforethe rollout based on concrete measures is likely to reduce the uncertainty involvedin ITS developments and enhance the adoption rate of the new technology. The increasingnumber of ITS projects, like the Secure Intermodal Transport Systems at VolvoTechnology, create a need for a structured approach to measure and evaluate ITS.A literature review concerning the characteristics of the transport industry, technologyadoption, ITS and performance measurements served as a basis for the empirical studyin which 8 semi-structured interviews with different stakeholders in the transport industrywere conducted in order to find out how the performance impacts of ITS are perceivedin the industry and how they could possibly be assessed. The focus groupmethod was used to validate and apply the findings from the interview study to a GeofencingITS-service.The study has confirmed that the concept of ITS is still an emerging phenomenon in thetransportation industry. There is no common understanding of ITS among researchersand practitioners in the transport industry and still a lack of knowledge regarding theperformance impacts of ITS. Even though it could be found that ITS leverages mainlythe service level that can be offered to the customer and that they increase the efficiencyin the back office, the great variety of ITS-services calls for an individual assessment.Structuring the assessment into the phases of measurement design, implementation anduse of the measures facilitates this process. For the different phases a set of activitiescritical for a successful assessment of ITS have been identified. Despite its usefulnessfor mitigating the uncertainty related to the new technology, the focus group validationuncovered that a comprehensive measurement for ITS is not appropriate from the outset,but should be assessed based on the cost of the measurement, the ITS project priority,the customer relations as well as the hierarchical structure in the provider firm.
The liver is bathed in bacterial products, including lipopolysaccharide transported from the intestinal portal vasculature, but maintains a state of tolerance that is exploited by persistent ...pathogens and tumours
. The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8
T cells compartmentalized in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins and are enriched in close proximity to CD14
myeloid cells in hepatic zone 2. CD14
CD8
T cells preferentially accumulate within the donor pool in liver allografts, among hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14
CD8
T cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10 and IL-2 production ex vivo, and enhanced antiviral/anti-tumour effector function after TCR engagement. This CD14
CD8
T cell profile can be recapitulated by the acquisition of membrane proteins-including the lipopolysaccharide receptor complex-from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T cells in vitro. CD14
CD8
T cells express integrins and chemokine receptors that favour interactions with the local stroma, which can promote their induction through CXCL12. Lipopolysaccharide can also increase the frequency of CD14
CD8
T cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut-liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8
T cells with immunomodulatory ability.
The European Commission asked EFSA for a scientific opinion on the risks for animal and human health related to the presence of quinolizidine alkaloids (QAs) in feed and food. This risk assessment is ...limited to QAs occurring in Lupinus species/varieties relevant for animal and human consumption in Europe (i.e. Lupinus albus L., Lupinus angustifolius L., Lupinus luteus L. and Lupinus mutabilis Sweet). Information on the toxicity of QAs in animals and humans is limited. Following acute exposure to sparteine (reference compound), anticholinergic effects and changes in cardiac electric conductivity are considered to be critical for human hazard characterisation. The CONTAM Panel used a margin of exposure (MOE) approach identifying a lowest single oral effective dose of 0.16 mg sparteine/kg body weight as reference point to characterise the risk following acute exposure. No reference point could be identified to characterise the risk of chronic exposure. Because of similar modes of action for QAs, the CONTAM Panel used a group approach assuming dose additivity. For food, the highest mean concentration of Total QAs (TotQAs) (i.e. the 6 most abundant QAs) was found in lupin seed samples classified as ‘Lupins (dry) and similar‐’. Due to the limited data on occurrence and consumption, dietary exposure was calculated for some specific scenarios and no full human health risk characterisation was possible. The calculated margin of exposures (MOEs) may indicate a risk for some consumers. For example, when lupin seeds are consumed without a debittering step, or as debittered lupin seeds high in QA content and when ‘lupin‐based meat imitates’ are consumed. For horses, companion and farm animals, other than salmonids, the available database on adverse effects was too limited to identify no‐observed‐adverse‐effect levels and/or lowest‐observed‐adverse‐effect levels and no risk characterisation was possible. For salmonids, the CONTAM Panel considers the risk for adverse effects to be low.
This publication is linked to the following EFSA Supporting Publications articles: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2019.EN-1348/full, http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2019.EN-1717/full
SARS‐CoV‐2 infection results in different outcomes ranging from asymptomatic infection to mild or severe disease and death. Reasons for this diversity of outcome include differences in challenge ...dose, age, gender, comorbidity and host genomic variation. Human leukocyte antigen (HLA) polymorphisms may influence immune response and disease outcome. We investigated the association of HLAII alleles with case definition symptomatic COVID‐19, virus‐specific antibody and T‐cell immunity. A total of 1364 UK healthcare workers (HCWs) were recruited during the first UK SARS‐CoV‐2 wave and analysed longitudinally, encompassing regular PCR screening for infection, symptom reporting, imputation of HLAII genotype and analysis for antibody and T‐cell responses to nucleoprotein (N) and spike (S). Of 272 (20%) HCW who seroconverted, the presence of HLA‐DRB1*13:02 was associated with a 6·7‐fold increased risk of case definition symptomatic COVID‐19. In terms of immune responsiveness, HLA‐DRB1*15:02 was associated with lower nucleocapsid T‐cell responses. There was no association between DRB1 alleles and anti‐spike antibody titres after two COVID vaccine doses. However, HLA DRB1*15:01 was associated with increased spike T‐cell responses following both first and second dose vaccination. Trial registration: NCT04318314 and ISRCTN15677965.
SARS‐CoV‐2 infection results in different outcomes ranging from asymptomatic infection, to mild or severe disease and death. We investigated the association of HLAII alleles with case definition symptomatic COVID‐19, virus‐specific antibody and T cell immunity. Presence of HLA‐DRB1*13:02 was associated with increased risk of symptomatic COVID‐19, while, after vaccination, HLA DRB1*15:01 was associated with increased spike T cell responses.
•4 viability and 3 functionality bacterial markers measured after 3 drying processes.•Cell functionality is not directly linked to cell survival.•Drying process and species dependent effects on the ...different markers.•Use of PCA helps to show how drying process impact the different bacterial markers.
Probiotic formulations are widely used and are proposed to have a variety of beneficial effects, depending on the probiotic strains present in the product. The impact of drying processes on the viability of probiotics is well documented. However, the impact of these processes on probiotics functionality remains unclear. In this work, we investigated variations in seven different bacterial markers after various desiccation processes. Markers were composed of four different viability evaluation (combining two growth abilities and two cytometric measurements) and in three in vitro functionalities: stimulation of IL-10 and IL-12 production by PBMCs (immunomodulation) and bacterial adhesion to hexadecane. We measured the impact of three drying processes (air-drying, freeze-drying and spray-drying), without the use of protective agents, on three types of probiotic bacteria: Bifidobacterium bifidum, Lactobacillus plantarum and Lactobacillus zeae. Our results show that the bacteria respond differently to the three different drying processes, in terms of viability and functionality. Drying methods produce important variations in bacterial immunomodulation and hydrophobicity, which are correlated. We also show that adherence can be stimulated (air-drying) or inhibited (spray-drying) by drying processes. Results of a multivariate analysis show no direct correlation between bacterial survival and functionality, but do show a correlation between probiotic responses to desiccation–rewetting and the process used to dry the bacteria.
Poppy seeds are obtained from the opium poppy (Papaver somniferum L.). They are used as food and to produce edible oil. The opium poppy plant contains narcotic alkaloids such as morphine and codeine. ...Poppy seeds do not contain the opium alkaloids, but can become contaminated with alkaloids as a result of pest damage and during harvesting. The European Commission asked EFSA to provide an update of the Scientific Opinion on opium alkaloids in poppy seeds. The assessment is based on data on morphine, codeine, thebaine, oripavine, noscapine and papaverine in poppy seed samples. The CONTAM Panel confirms the acute reference dose (ARfD) of 10 μg morphine/kg body weight (bw) and concluded that the concentration of codeine in the poppy seed samples should be taken into account by converting codeine to morphine equivalents, using a factor of 0.2. The ARfD is therefore a group ARfD for morphine and codeine, expressed in morphine equivalents. Mean and high levels of dietary exposure to morphine equivalents from poppy seeds considered to have high levels of opium alkaloids (i.e. poppy seeds from varieties primarily grown for pharmaceutical use) exceed the ARfD in most age groups. For poppy seeds considered to have relatively low concentrations of opium alkaloids (i.e. primarily varieties for food use), some exceedance of the ARfD is also seen at high levels of dietary exposure in most surveys. For noscapine and papaverine, the available data do not allow making a hazard characterisation. However, comparison of the dietary exposure to the recommended therapeutical doses does not suggest a health concern for these alkaloids. For thebaine and oripavine, no risk characterisation was done due to insufficient data. However, for thebaine, limited evidence indicates a higher acute lethality than for morphine and the estimated exposure could present a health risk.
The limitations of classical diagnostic methods for invasive fungal infections (IFIs) have led to the development of molecular techniques to aid in the detection of IFIs. Despite good published ...performance, interlaboratory reproduction of these assays is variable, and no consensus has been reached for an optimal method. This publication describes the first multicenter study of polymerase chain reaction methods, for the detection of Aspergillus and Candida species, currently used in the UK and Ireland by distribution and analysis of multiple specimen control panels. All three Candida methods were comparable, achieving a satisfactory level of detection (10 cfu), and the method of preference was dependent on the requirements of the particular laboratory. The results for the five Aspergillus assays were more variable, but two methods (2Asp and 4Asp) were superior (10(1) conidia). Formally, the overall performances of the two Aspergillus assays were comparable (kappa statistic = 0.77). However, on the Roche LightCycler, there was a clear sample-type effect that greatly reduced the detection limit of the 4Asp method when testing whole blood samples. Therefore, the preferred Aspergillus method relied on the amplification platform available to the user. This study represents the initial process to achieve a consensus method for the diagnosis of IFIs.
The European Commission requested EFSA to provide an update of the 2012 Scientific Opinion of the Panel on Contaminants in the Food Chain (CONTAM) on the risks for animal health related to the ...presence of ergot alkaloids (EAs) in feed. EAs are produced by several fungi of the Claviceps and Epichloë genera. This Opinion focussed on the 14 EAs produced by C. purpurea (ergocristine, ergotamine, ergocornine, α‐ and β‐ergocryptine, ergometrine, ergosine and their corresponding ‘inine’ epimers). Effects observed with EAs from C. africana (mainly dihydroergosine) and Epichloë (ergovaline/−inine) were also evaluated. There is limited information on toxicokinetics in food and non‐food producing animals. However, transfer from feed to food of animal origin is negligible. The major effects of EAs are related to vasoconstriction and are exaggerated during extreme temperatures. In addition, EAs cause a decrease in prolactin, resulting in a reduced milk production. Based on the sum of the EAs, the Panel considered the following as Reference Points (RPs) in complete feed for adverse animal health effects: for pigs and piglets 0.6 mg/kg, for chickens for fattening and hens 2.1 and 3.7 mg/kg, respectively, for ducks 0.2 mg/kg, bovines 0.1 mg/kg and sheep 0.3 mg/kg. A total of 19,023 analytical results on EAs (only from C. purpurea) in feed materials and compound feeds were available for the exposure assessment (1580 samples). Dietary exposure was assessed using two feeding scenarios (model diets and compound feeds). Risk characterisation was done for the animals for which an RP could be identified. The CONTAM Panel considers that, based on exposure from model diets, the presence of EAs in feed raises a health concern in piglets, pigs for fattening, sows and bovines, while for chickens for fattening, laying hens, ducks, ovines and caprines, the health concern related to EAs in feed is low.
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