Luxembourg Institute of Health LIH

Esch-sur-Alzette, Luxembourg

Luxembourg Institute of Health LIH

Esch-sur-Alzette, Luxembourg
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Du Four S.,Vrije Universiteit Brussel | Maenhout S.K.,Vrije Universiteit Brussel | De Pierre K.,UZ Brussel | Renmans D.,Vrije Universiteit Brussel | And 4 more authors.
OncoImmunology | Year: 2015

Melanoma patients are at a high risk of developing brain metastases, which are strongly vascularized and therefore have a significant risk of spontaneous bleeding. VEGF not only plays a role in neo-angiogenesis but also in the antitumor immune response. VEGFR-targeted therapy might not only have an impact on the tumor vascularization but also on tumor-infiltrating immune cells. In this study, we investigated the effect of axitinib, a small molecule TKI of VEGFR-1, -2, and -3, on tumor growth and on the composition of tumor-infiltrating immune cells in subcutaneous and intracranial mouse melanoma models. In vivotreatment with axitinib induced a strong inhibition of tumor growth and significantly improved survival in both tumor models. Characterization of the immune cells within the spleen and tumor of tumor-bearing mice respectively showed a significant increase in the number of CD3+CD8+ T cells and CD11b+ cells of axitinib-treated mice. More specifically, we observed a significant increase of intratumoral monocytic myeloid-derived suppressor cells (moMDSCs; CD11b+Ly6ChighLy6G-). Interestingly, in vitro proliferation assays showed that moMDSCs isolated from spleen or tumor of axitinib-treated mice had a reduced suppressive capacity on a per cell basis as compared to those isolated from vehicle-treated mice. Moreover, MDSCs from axitinib-treated animals displayed the capacity to stimulate allogeneic T cells. Thus, treatment with axitinib induces differentiation of moMDSC toward an antigen-presenting phenotype. Based on these observations, we conclude that the impact of axitinib on tumor growth and survival is most likely not restricted to direct anti-angiogenic effects but also involves important effects on tumor immunity. © 2015 Taylor & Francis Group, LLC.

PubMed | University of East London, University of Zürich, Medical University of Graz, National and Kapodistrian University of Athens and 22 more.
Type: | Journal: Allergy | Year: 2017

The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines on Allergen Immunotherapy (AIT) for the management of insect venom allergy. To inform this process, we sought to assess the effectiveness, cost-effectiveness and safety of AIT in the management of insect venom allergy.We undertook a systematic review, which involved searching 15 international biomedical databases for published and unpublished evidence. Studies were independently screened and critically appraised using established instruments. Data were descriptively summarized and, where possible, meta-analysed.Our searches identified a total of 16 950 potentially eligible studies; of which, 17 satisfied our inclusion criteria. The available evidence was limited both in volume and in quality, but suggested that venom immunotherapy (VIT) could substantially reduce the risk of subsequent severe systemic sting reactions (OR = 0.08, 95% CI 0.03-0.26); meta-analysis showed that it also improved disease-specific quality of life (risk difference = 1.41, 95% CI 1.04-1.79). Adverse effects were experienced in both the build-up and maintenance phases, but most were mild with no fatalities being reported. The very limited evidence found on modelling cost-effectiveness suggested that VIT was likely to be cost-effective in those at high risk of repeated systemic sting reactions and/or impaired quality of life.The limited available evidence suggested that VIT is effective in reducing severe subsequent systemic sting reactions and in improving disease-specific quality of life. VIT proved to be safe and no fatalities were recorded in the studies included in this review. The cost-effectiveness of VIT needs to be established.

Ollert M.,Luxembourg Institute of Health LIH | Ollert M.,University of Southern Denmark | Blank S.,Helmholtz Center Munich
Current Allergy and Asthma Reports | Year: 2015

Anaphylaxis due to Hymenoptera stings is one of the most severe consequences of IgE-mediated hypersensitivity reactions. Although allergic reactions to Hymenoptera stings are often considered as a general model for the underlying principles of allergic disease, diagnostic tests are still hampered by a lack of specificity and venom immunotherapy by severe side effects and incomplete protection. In recent years, the knowledge about the molecular composition of Hymenoptera venoms has significantly increased and more and more recombinant venom allergens with advanced characteristics have become available for diagnostic measurement of specific IgE in venom-allergic patients. These recombinant venom allergens offer several promising possibilities for an improved diagnostic algorithm. Reviewed here are the current status, recent developments, and future perspectives of molecular diagnostics of venom allergy. Already to date, it is foreseeable that component-resolution already has now or will in the future have the potential to discriminate between clinically significant and irrelevant sensitization, to increase the specificity and sensitivity of diagnostics, to monitor immunotherapeutic intervention, and to contribute to the understanding of the immunological mechanisms elicited by insect venoms. © The Author(s) 2015.

Kandala N.-B.,Luxembourg Institute of Health LIH | Kandala N.-B.,Northumbria University | Emina J.B.O.,University of Kinshasa
Journal of Biosocial Science | Year: 2016

Summary In sub-Saharan Africa, nutrition research has primarily focused on under-nutrition, particularly among vulnerable children. However, there is increasing evidence of an emerging nutrition transition with extremely high rates of obesity, and malnutrition in women may be a problem that is insufficiently recognized and inadequately documented. This analysis was based on the 2008 Nigerian Demographic and Health Survey (NDHS), which included 27,967 women aged 15-49 years. Individual-level data were collected for socio-demographic characteristics and aggregated to the country's 37 states. A Bayesian geo-Additive mixed model was used to map the geographic distribution of under-nutrition at the state level, accounting for individual-level risk factors. The results reveal that 12.0% of the population were underweight, while 20.9% were either overweight or obese, based on BMI. The northern states of Sokoto and Yobe/Borno and the southern state of Delta had the highest prevalence of underweight, while states in the centre had the lowest underweight prevalence. Underweight women were more likely to be from poorer households compared with their counterparts from the richest wealth index, which were consistently associated with lower odds of being underweight (posterior odds ratio (POR) and 95% credible region (CR): 0.56 [0.46, 0.70]). On the other hand Muslim women (1.61 [1.10, 2.23]), those of traditional religion (2.12 [1.44, 3.00]), those from the Fulani ethnic group (2.90 [1.64, 5.55]) and those living in Yobe state were all consistently associated with higher odds of being underweight. This study demonstrates that underweight is a major public health problem in Nigeria affecting adult females in the northern states of Nigeria. Identifying risk factors and the need to account for sex, spatial and socio-cultural issues are crucial to develop and implement evidence-informed strategies and interventions for lifestyle health promotion. Copyright © Cambridge University Press, 2015.

Blank S.,Helmholtz Center Munich | Schiener M.,Helmholtz Center Munich | Ollert M.,Luxembourg Institute of Health LIH | Ollert M.,University of Southern Denmark
Allergologie | Year: 2016

Allergic reactions due to stings of Hymenoptera species, such as honeybees or yellow jackets, are well known as severe allergies with potentially fatal outcome. Much less common is that also bites of blood-sucking insects (mosquitos, horseflies, flies, bugs, lice and fleas) and arachnids (ticks) represent relevant elicitors of allergy. Although, local cutaneous hypersensitivity reactions are more common, also severe systemic reactions can occur. In the last decades the molecular knowledge of the allergen composition of hymenoptera venoms has led to considerable improvements of diagnostic and therapeutic options. Even though bloodsucking insects might be the most common elicitors of allergy overall, surprisingly little is known about their relevant allergens and possible cross-reactivities. The lack of diagnostic tools in this area results in the fact that these allergies remain underdiagnosed and-treated. © 2016 Dustri-Verlag Dr. Karl Feistle.

Gallien S.,Luxembourg Institute of Health LiH | Domon B.,Luxembourg Institute of Health LiH
Methods | Year: 2015

Quantitative proteomics has benefited from the recent development of mass spectrometers capable of high-resolution and accurate-mass (HR/AM) measurements. While targeted experiments are routinely performed on triple quadrupole instruments in selected reaction monitoring (SRM; often referred as multiple reaction monitoring, MRM) mode, the quadrupole-orbitrap mass spectrometers allow quantification in MS/MS mode, also known as parallel reaction monitoring (PRM). This technique is characterized by higher selectivity and better confidence in the assignment of the precursor and fragment ions, and thus translates into an improved analytical performance. More fundamentally, PRM introduces a change of the overall paradigm of targeted experiments, by the decoupling of the acquisition and data processing. They rely on two distinct steps, with a simplified acquisition method in conjunction with a flexible, iterative, post-acquisition data processing.This account describes in detail the different steps of a PRM experiment, which include the design of the acquisition method, the confirmation of the identity of the analytes founded upon a full MS/MS fragmentation pattern, and the quantification based on the extraction of specific fragment ions (selected post-acquisition) using tight mass tolerance. The different types of PRM experiments, defined as large-scale screening or precise targeted quantification using calibrated internal standards, together with the considerations on the selection of experimental parameters are discussed. © 2015 Elsevier Inc.

Azuaje F.,Luxembourg Institute of Health LIH | Tiemann K.,Luxembourg Institute of Health LIH | Niclou S.P.,Luxembourg Institute of Health LIH
Cell Communication and Signaling | Year: 2015

The alteration of the epidermal growth factor receptor (EGFR)-driven signaling network is a characteristic feature of glioblastomas (GBM), and its inhibition represents a treatment strategy. However, EGFR-targeted interventions have been largely ineffective. Complex perturbations in this system are likely to be central to tumor cells with high adaptive capacity and resistance to therapies. We review key concepts and mechanisms relevant to EGFR-targeted treatment resistance at a systems level. Our understanding of treatment resistance as a systems-level phenomenon is necessary to develop effective therapeutic options for GBM patients. This is allowing us to go beyond the notion of therapeutic targets as single molecular components, into strategies that can weaken cancer signaling robustness and boost inherent network-level vulnerabilities. © 2015 Azuaje et al.; licensee BioMed Central.

Gallien S.,Luxembourg Institute of Health LIH | Domon B.,Luxembourg Institute of Health LIH
Expert Review of Proteomics | Year: 2015

The advances in high-resolution mass spectrometry instrumentation, capable of accurate mass measurement and fast acquisition, have enabled new approaches for targeted quantitative proteomics. More specifically, analyses performed on quadrupole-orbitrap mass spectrometers operated in parallel reaction monitoring (PRM) mode leverage the intrinsic high resolving power and trapping capabilities. The PRM technique offers unmatched degrees of selectivity and analytical sensitivity, typically required to analyze peptides in complex samples, such as those encountered in biomedical research or clinical studies. The features of PRM have provoked a paradigm change in targeted experiments, by decoupling acquisition and data processing. It has resulted in a new analytical workflow comprising distinct methods for each step, thus enabling much larger flexibility. The PRM technique was further enhanced by a new data acquisition scheme, allowing dynamic parameter settings. The potential of the technique may radically impact future quantitative proteomics studies. © 2015 Informa UK, Ltd.

Gallien S.,Luxembourg Institute of Health LIH | Kim S.Y.,Luxembourg Institute of Health LIH | Domon B.,Luxembourg Institute of Health LIH
Molecular and Cellular Proteomics | Year: 2015

Targeted high-resolution and accurate mass analyses performed on fast sequencing mass spectrometers have opened new avenues for quantitative proteomics. More specifically, parallel reaction monitoring (PRM) implemented on quadrupole-orbitrap instruments exhibits exquisite selectivity to discriminate interferences from analytes. Furthermore, the instrument trapping capability enhances the sensitivity of the measurements. The PRM technique, applied to the analysis of limited peptide sets (typically 50 peptides or less) in a complex matrix, resulted in an improved detection and quantification performance as compared with the reference method of selected reaction monitoring performed on triple quadrupole instruments. However, the implementation of PRM for the analysis of large peptide numbers requires the adjustment of mass spectrometry acquisition parameters, which affects dramatically the quality of the generated data, and thus the overall output of an experiment. A newly designed data acquisition scheme enabled the analysis of moderate- to-large peptide numbers while retaining a high performance level. This new method, called internal standard triggered-parallel reaction monitoring (IS-PRM), relies on added internal standards and the on-the-fly adjustment of acquisition parameters to drive in real-time measurement of endogenous peptides. The acquisition time management was designed to maximize the effective time devoted to measure the analytes in a time-scheduled targeted experiment. The data acquisition scheme alternates between two PRM modes: a fast low-resolution "watch mode" and a "quantitative mode" using optimized parameters ensuring data quality. The IS-PRM method exhibited a highly effective use of the instrument time. Applied to the analysis of large peptide sets (up to 600) in complex samples, the method showed an unprecedented combination of scale and analytical performance, with limits of quantification in the low amol range. The successful analysis of various types of biological samples augurs a broad applicability of the method, which is likely to benefit a wide range of proteomics experiments. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Erasimus H.,Luxembourg Institute of Health LIH | Gobin M.,Luxembourg Institute of Health LIH | Niclou S.,Luxembourg Institute of Health LIH | Van Dyck E.,Luxembourg Institute of Health LIH
Mutation Research - Reviews in Mutation Research | Year: 2016

Despite surgical resection and genotoxic treatment with ionizing radiation and the DNA alkylating agent temozolomide, glioblastoma remains one of the most lethal cancers, due in great part to the action of DNA repair mechanisms that drive resistance and tumor relapse. Understanding the molecular details of these mechanisms and identifying potential pharmacological targets have emerged as vital tasks to improve treatment. In this review, we introduce the various cellular systems and animal models that are used in studies of DNA repair in glioblastoma. We summarize recent progress in our knowledge of the pathways and factors involved in the removal of DNA lesions induced by ionizing radiation and temozolomide. We introduce the therapeutic strategies relying on DNA repair inhibitors that are currently being tested in vitro or in clinical trials, and present the challenges raised by drug delivery across the blood brain barrier as well as new opportunities in this field. Finally, we review the genetic and epigenetic alterations that help shape the DNA repair makeup of glioblastoma cells, and discuss their potential therapeutic impact and implications for personalized therapy. © 2016 The Authors.

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