With the growing numbers of nanomaterials (NMs), there is a great demand for rapid and reliable ways of testing NM safety—preferably using in vitro approaches, to avoid the ethical dilemmas ...associated with animal research. Data are needed for developing intelligent testing strategies for risk assessment of NMs, based on grouping and read‐across approaches. The adoption of high throughput screening (HTS) and high content analysis (HCA) for NM toxicity testing allows the testing of numerous materials at different concentrations and on different types of cells, reduces the effect of inter‐experimental variation, and makes substantial savings in time and cost. HTS/HCA approaches facilitate the classification of key biological indicators of NM‐cell interactions. Validation of in vitro HTS tests is required, taking account of relevance to in vivo results. HTS/HCA approaches are needed to assess dose‐ and time‐dependent toxicity, allowing prediction of in vivo adverse effects. Several HTS/HCA methods are being validated and applied for NM testing in the FP7 project NANoREG, including Label‐free cellular screening of NM uptake, HCA, High throughput flow cytometry, Impedance‐based monitoring, Multiplex analysis of secreted products, and genotoxicity methods—namely High throughput comet assay, High throughput in vitro micronucleus assay, and γH2AX assay. There are several technical challenges with HTS/HCA for NM testing, as toxicity screening needs to be coupled with characterization of NMs in exposure medium prior to the test; possible interference of NMs with HTS/HCA techniques is another concern. Advantages and challenges of HTS/HCA approaches in NM safety are discussed. WIREs Nanomed Nanobiotechnol 2017, 9:e1413. doi: 10.1002/wnan.1413
This article is categorized under:
Therapeutic Approaches and Drug Discovery > Emerging Technologies
Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine
Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate ...loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects.
In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days+8 and+10 of each cycle, patients received intratumoral image-guided 0.25mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600mg/m2 was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease (SD) were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRβ sequencing.
Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-β and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1β concentrations, especially in patients presenting SD. IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD.
This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.
Expression of surface immunoglobulin appears critical for the growth and survival of B-cell lymphomas. In follicular lymphoma, we found previously that the Ig variable (V) regions in the B-cell ...receptor express a strikingly high incidence of N-glycosylation sequons, NX(S/T). These potential glycosylation sites are introduced by somatic mutation and are lymphoma-specific, pointing to their involvement in tumor pathogenesis. Analysis of the V region sugars from lymphoma-derived IgG/IgM reveals that they are mostly oligomannose and, remarkably, are located in the antigen-binding site, possibly precluding conventional antigen binding. The Fc region contains complex glycans, confirming that the normal glycan processing pathway is intact. Binding studies indicate that the oligomannose glycans occupying the V regions are accessible to mannose-binding lectin. These findings suggest a potential contribution to lymphoma pathogenesis involving antigen-independent interaction of surface immunoglobulin of the B-cell receptor with mannose-binding molecules of innate immunity in the germinal center.
Summary
Background Multiple questionnaires to screen for psoriatic arthritis (PsA) have been developed but the optimal screening questionnaire is unknown.
Objectives To compare three PsA screening ...questionnaires in a head‐to‐head study using CASPAR (the Classification Criteria for Psoriatic Arthritis) as the gold standard.
Methods This study recruited from 10 U.K. secondary care dermatology clinics. Patients with a diagnosis of psoriasis, not previously diagnosed with PsA, were given all three questionnaires. All patients who were positive on any questionnaire were invited for a rheumatological assessment. Receiver operating characteristic (ROC) curves were used to compare the sensitivity, specificity and area under the curve of the three questionnaires according to CASPAR criteria.
Results In total, 938 patients with psoriasis were invited to participate and 657 (70%) patients returned the questionnaires. One or more questionnaires were positive in 314 patients (48%) and 195 (62%) of these patients attended for assessment. Of these, 47 patients (24%) were diagnosed with PsA according to the CASPAR criteria. The proportion of patients with PsA increased with the number of positive questionnaires (one questionnaire, 19·1%; two, 34·0%; three, 46·8%). Sensitivities and specificities for the three questionnaires, and areas under the ROC curve were, respectively: Psoriatic Arthritis Screening Evaluation (PASE), 74·5%, 38·5%, 0·594; Psoriasis Epidemiology Screening Tool (PEST), 76·6%, 37·2%, 0·610; Toronto Psoriatic Arthritis Screen (ToPAS), 76·6%, 29·7%, 0·554. The majority of patients with a false positive response had degenerative or osteoarthritis.
Conclusion Although the PEST and ToPAS questionnaires performed slightly better than the PASE questionnaire at identifying PsA, there is little difference between these instruments. These screening tools identify many cases of musculoskeletal disease other than PsA.
What’s already known about this topic?
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A number of screening questionnaires have been developed to detect psoriatic arthritis in people with psoriasis.
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Each questionnaire has shown good and largely equivalent performance, in terms of specificity and sensitivity, in the development cohorts.
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What is needed is a head‐to‐head study in a new cohort of patients with psoriasis.
What does this study add?
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Each of the questionnaires performed worse in this new cohort of patients in secondary care, with no significant differences between them.
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Both sensitivity and specificity were worse, although the study design was likely to underestimate the specificity and overestimate the sensitivity.
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Screening questionnaires such as these will detect other musculoskeletal diseases in addition to psoriatic arthritis and additional information may be needed to enhance their specificity.
Tumours lacking argininosuccinate synthetase-1 (ASS1) are auxotrophic for arginine and sensitive to amino-acid deprivation. Here, we investigated the role of ASS1 as a biomarker of response to the ...arginine-lowering agent, pegylated arginine deiminase (ADI-PEG20), in lymphoid malignancies. Although ASS1 protein was largely undetectable in normal and malignant lymphoid tissues, frequent hypermethylation of the ASS1 promoter was observed specifically in the latter. A good correlation was observed between ASS1 methylation, low ASS1 mRNA, absence of ASS1 protein expression and sensitivity to ADI-PEG20 in malignant lymphoid cell lines. We confirmed that the demethylating agent 5-Aza-dC reactivated ASS1 expression and rescued lymphoma cell lines from ADI-PEG20 cytotoxicity. ASS1-methylated cell lines exhibited autophagy and caspase-dependent apoptosis following treatment with ADI-PEG20. In addition, the autophagy inhibitor chloroquine triggered an accumulation of light chain 3-II protein and potentiated the apoptotic effect of ADI-PEG20 in malignant lymphoid cells and patient-derived tumour cells. Finally, a patient with an ASS1-methylated cutaneous T-cell lymphoma responded to compassionate-use ADI-PEG20. In summary, ASS1 promoter methylation contributes to arginine auxotrophy and represents a novel biomarker for evaluating the efficacy of arginine deprivation in patients with lymphoma.
In our case, The Robert Wood Johnson Foundation approved a grant opportunity with the National Association of County and City Health Officials (NACCHO) for an initiative called the Turning Point ...Program, which was a community involvement partnership, linking a health/faith work group with the University of South Carolina, the AME Church, and others. In Florida, Governor Jeb Bush signed an Executive Order in November 2004 which created a faith-based and community advisory board with a mission to help state government coordinate efforts to utilize and expand opportunities for faith-based and community-based organizations to address social needs in Florida's communities. The major hurdles for creating and implementing an effective partnership between government and faith-based organizations include: (1) Helping vendors learn what funds are available and how to access those funds; (2) Ensuring vendors have the necessary understanding to traverse the separation of religious activities and convictions from the implementation of the government-funded program; (3) Ensuring an awareness and understanding of the various rules, regulations and laws that govern the funding: and, (4) Ensuring that government staff understand the day-to-day challenges for these vendors, and that they provide technical assistance that allows providers to meet contract requirements.
Marine ecosystems, ranging from coastal seas and wetlands to the open ocean, accommodate a wealth of biological diversity from small microorganisms to large mammals. This biodiversity and its ...associated ecosystem function occurs across complex spatial and temporal scales and is not yet fully understood. Given the wide range of external pressures on the marine environment, this knowledge is crucial for enabling effective conservation measures and defining the limits of sustainable use. The development and application of omics-based approaches to biodiversity research has helped overcome hurdles, such as allowing the previously hidden community of microbial life to be identified, thereby enabling a holistic view of an entire ecosystem’s biodiversity and functioning. The potential of omics-based approaches for marine ecosystems observation is enormous and their added value to ecosystem monitoring, management, and conservation is widely acknowledged. Despite these encouraging prospects, most omics-based studies are short-termed and typically cover only small spatial scales which therefore fail to include the full spatio-temporal complexity and dynamics of the system. To date, few attempts have been made to establish standardised, coordinated, broad scaled, and long-term omics observation networks. Here we outline the creation of an omics-based marine observation network at the European scale, the European Marine Omics Biodiversity Observation Network (EMO BON). We illustrate how linking multiple existing individual observation efforts increases the observational power in large-scale assessments of status and change in biodiversity in the oceans. Such large-scale observation efforts have the added value of cross-border cooperation, are characterised by shared costs through economies of scale, and produce structured, comparable data. The key components required to compile reference environmental datasets and how these should be linked are major challenges that we address.
The literature on the concept and measurement of poverty has significantly improved from the traditional unidimensional (income/expenditure) analysis to the multidimensional concept of poverty and ...well-being. Following the Multidimensional Poverty Assessment Tool (MPAT), the study explored the potential of combining counting and participatory approaches in determining levels of deprivations and well-being in an upland farming community in the Philippines. Data from a random sample of 153 farming households and analyzed following Alkire and the Foster's methodology revealed that 3 out of 4 households are multidimensionally poor. Results of the study also show that farming households' ability to generate farm- and non-farm income in addition to the high degree of exposure to idiosyncratic and covariate shocks contribute to the high multidimensional poverty index. Further, the study presents implications of these results for antipoverty policy in the rural context.
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