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Abstract The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS.

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value

Background: Despite (neo) adjuvant chemotherapy with cisplatin, doxorubicin and methotrexate, some patients with primary osteosarcoma progress during first-line systemic treatment and have a poor prognosis. In this study, we investigated whether patients with early disease progression (EDP), are characterized by a distinctive pharmacogenetic profile.Methods and Findings: Germline DNA from 287 Dutch high-grade osteosarcoma patients was genotyped using the DMET Plus array (containing 1,936 genetic markers in 231 drug metabolism and transporter genes). Associations between genetic variants and EDP were assessed using logistic regression models and associated variants (p

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Thyroid cancer is the most common type of endocrine malignancy. Cornerstones of thyroid cancer treatment include surgery, radioactive iodine ablation, and thyroid stimulating hormone suppression. The National Comprehensive Cancer Network guidelines recommend two tyrosine kinase inhibitors for thyroid cancer patients who are non-responsive to iodine: sorafenib and lenvatinib. Another oral kinase inhibitor, regorafenib, is not considered standard of care treatment for differentiated thyroid cancer. The chemical structures of regorafenib and sorafenib differ by a single fluorine atom. Given the significant improvement in progression-free survival (PFS) of sorafenib compared to placebo demonstrated in the phase 3 DECISION trial, we report on a patient with iodine-refractory follicular thyroid cancer treated with regorafenib as part of a phase 1 clinical trial. A 75 year old woman was diagnosed with follicular thyroid carcinoma in 2006 and initiated on treatment with regorafenib in 2011. She has completed 76 cycles with stable disease and pulmonary metastases 34% smaller than baseline.

Antibiotics are used to control infectious diseases in both animals and humans. They can be life-saving compounds but excessive use in animal husbandry leads to the development of antibiotic resistance which can impact the public health. Since similar antibiotics are used in both animal and human healthcare, it is important to reduce the use of antibiotics in production animals. In the Netherlands policies have been developed aiming for a decrease of antibiotic usage in animals, and alternatives to antibiotics are investigated. Currently, a one-on-one relationship between farmer and veterinarian is successfully implemented and (national) registration of antibiotic usage is mandatory. Unfortunately, after a 70% decrease in antibiotic usage since 2009, this decrease is now stagnating in most sectors. Innovative strategies are required to facilitate a further reduction. One promising option is a focus on farm management and natural alternatives to antibiotics. The Dutch government has invested in the spread of knowledge of natural remedies and good animal management to support animal health via so called Barnbooks for farmers and veterinarians. Another option is the analysis of on-farm antibiotic use to prevent unregistered applications. New (bio)analytical strategies to monitor the correct and complete registration of antibiotic usage have been developed and trial-tested in the Netherlands. Such strategies support a risk-based monitoring and allow effective selection of high-risk (high antibiotic use or illegal antibiotic) users. Both effective monitoring and the availability and knowledge of alternatives is a prerequisite to achieve a further significant decrease in antibiotic veterinary usage.

Abstract Arboviruses represent a significant burden to public health and local economies due to their ability to cause unpredictable and widespread epidemics. To maximize early detection of arbovirus emergence in non-endemic areas, surveillance efforts should target areas where circulation is most likely. However, identifying such hotspots of potential emergence is a major challenge. The ecological conditions leading to arbovirus outbreaks are shaped by complex interactions between the virus, its vertebrate hosts, arthropod vector, and abiotic environment that are often poorly understood. Here, we systematically review the ecological risk factors associated with the circulation of six arboviruses that are of considerable concern to northwestern Europe. These include three mosquito-borne viruses (Japanese encephalitis virus, West Nile virus, Rift Valley fever virus) and three tick-borne viruses (Crimean-Congo hemorrhagic fever virus, tick-borne encephalitis virus, and louping-ill virus). We consider both intrinsic (e.g. vector and reservoir host competence) and extrinsic (e.g. temperature, precipitation, host densities, land use) risk factors, identify current knowledge gaps, and discuss future directions. Our systematic review provides baseline information for the identification of regions and habitats that have suitable ecological conditions for endemic circulation, and therefore may be used to target early warning surveillance programs aimed at detecting multi-virus and/or arbovirus emergence.

Bovine parainfluenza type 3 (BPIV3) and bovine respiratory syncytial virus (BRSV) may cause bovine respiratory disease (BRD) in very young calves, and therefore vaccination should induce protection at the youngest age and as quickly as possible. This can be achieved by intranasal vaccination with a vaccine containing live attenuated BRSV and BPIV3 virus strains. The objective of this study was to measure gene expression levels by means of RT-qPCR of proteins involved in the innate and adaptive immune response in the nasopharyngeal mucosae after administration of the above-mentioned vaccine and after challenge with BPIV3. Gene expression profiles were different between (i) vaccinated, (ii) nonvaccinated-challenged, and (iii) vaccinated-challenged animals. In nonvaccinated-challenged animals, expression of genes involved in development of disease symptoms and pathology were increased, however, this was not the case after vaccination. Moreover, gene expression patterns of vaccinated animals reflected induction of the antiviral and innate immune pathways as well as an initial Th1 (cytotoxic) cellular response. After challenge with BPIV3, the vaccinated animals were protected against nasal shedding of the challenge virus and clinical symptoms, and in parallel the expression levels of the investigated genes had returned to values that were found before vaccination. In conclusion, in comparison to the virulent wild-type field isolates, the two virus strains in the vaccine have lost their capacity to evade the immune response, resulting in the induction of an antiviral state followed by a very early activation of innate immune and antiviral responses as well as induction of specific cellular immune pathways, resulting in protection. The exact changes in the genomes of these vaccine strains leading to attenuation have not been identified. These data represent the real-life situation and can serve as a basis for further detailed research. This is the first report describing the effects on immune gene expression profiles in the nasal mucosae induced by intranasal vaccination with a bivalent, live BRSV-BPI3V vaccine formulation in comparison to wild-type infection with a virulent BPI3V strain.

Chondrosarcomas are malignant cartilage tumors that are relatively resistant towards conventional therapeutic approaches. Kinase inhibitors have been investigated and shown successful for several different cancer types. In this study we aimed at identifying kinase inhibitors that inhibit the survival of chondrosarcoma cells and thereby serve as new potential therapeutic strategies to treat chondrosarcoma patients.An siRNA screen targeting 779 different kinases was conducted in JJ012 chondrosarcoma cells in parallel with a compound screen consisting of 273 kinase inhibitors in JJ012, SW1353 and CH2879 chondrosarcoma cell lines. AURKA, CHK1 and PLK1 were identified as most promising targets and validated further in a more comprehensive panel of chondrosarcoma cell lines. Dose response curves were performed using tyrosine kinase inhibitors: MK-5108 (AURKA), LY2603618 (CHK1) and Volasertib (PLK1) using viability assays and cell cycle analysis. Apoptosis was measured at 24 h after treatment using a caspase 3/7 assay. Finally, chondrosarcoma patient samples (N = =34) were used to examine the correlation between AURKA, CHK1 and PLK1 RNA expression and documented patient survival.Dose dependent decreases in viability were observed in chondrosarcoma cell lines after treatment with MK-5108, LY2603618 and volasertib, with cell lines showing highest sensitivity to PLK1 inhibition. In addition increased sensitivity to conventional chemotherapy was observed after CHK1 inhibition in a subset of the cell lines. Interestingly, whereas AURKA and CHK1 were both expressed in chondrosarcoma patient samples, PLK1 expression was found to be low compared to normal cartilage. Analysis of patient samples revealed that high CHK1 RNA expression correlated with a worse overall survival.AURKA, CHK1 and PLK1 are identified as important survival genes in chondrosarcoma cell lines. Although further research is needed to validate these findings, inhibiting CHK1 seems to be the most promising potential therapeutic target for patients with chondrosarcoma. Keywords: Chondrosarcoma, AURKA, PLK1, CHK1, Screen

This article presents a reflection on the analytical value of intersectionality for scholars who seek to critically interrogate migration governance in Europe – of which integration measures are an integral part. While there is a growing interest in using gender and feminist theory to investigate the policies and practices that sustain migration governance, there has been little dedicated reflection on the analytical significance of intersectionality for scholarly knowledge production. Building upon work conducted within the field of feminist policy studies, we argue that intersectionality crucially points to the broad systems of inequality and domination that are implicated in the governance of migration, which materialize in the ways in which the latter categorizes and constructs immigrant identities along intersecting axes of inequality. Analytically disentangling how such migration-related difference is created and upheld through such structures of domination and discrimination, deconstructs the apparent naturalness of the state and its hegemonic classification power. [ABSTRACT FROM AUTHOR]

For osteosarcoma (OS), the most common primary malignant bone tumor, overall survival has hardly improved over the last four decades. Especially for metastatic OS, novel therapeutic targets are urgently needed. A hallmark of cancer is aberrant metabolism, which justifies targeting metabolic pathways as a promising therapeutic strategy. One of these metabolic pathways, the NAD+ synthesis pathway, can be considered as a potential target for OS treatment. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the classical salvage pathway for NAD+ synthesis, and NAMPT is overexpressed in OS. In this study, five OS cell lines were treated with the NAMPT inhibitor FK866, which was shown to decrease nuclei count in a 2D in vitro model without inducing caspase-driven apoptosis. The reduction in cell viability by FK866 was confirmed in a 3D model of OS cell lines (n = 3). Interestingly, only OS cells with low nicotinic acid phosphoribosyltransferase domain containing 1 (NAPRT1) RNA expression were sensitive to NAMPT inhibition. Using a publicly available (Therapeutically Applicable Research to Generate Effective Treatments (TARGET)) and a previously published dataset, it was shown that in OS cell lines and primary tumors, low NAPRT1 RNA expression correlated with NAPRT1 methylation around the transcription start site. These results suggest that targeting NAMPT in osteosarcoma could be considered as a novel therapeutic strategy, where low NAPRT expression can serve as a biomarker for the selection of eligible patients.