Effects of a national genomic preselection on the international genetic evaluations

AbstractGenomic preselection of young bulls is now widely implemented in dairy breeding schemes, especially in the Holstein breed. However, if this step is not accounted for in genetic evaluation models, the national breeding values of bulls retained by a genomic preselection and of their progeny are estimated with bias. It follows that countries participating in international genetic evaluations will provide a selected and possibly biased set of data to the Interbull Centre (Swedish University of Agricultural Sciences, Uppsala, Sweden). The objective of the study was to show evidence of bias at the international level due to a genomic preselection step in national breeding schemes. The consequence of a genomic preselection for the international evaluations (i.e., using selected and biased national estimated breeding values) was simulated using actual national estimated breeding values as a proxy for genomically enhanced breeding values. Data were provided for 3 countries with a large population of Holstein bulls. International breeding values from simulated scenarios were compared with international breeding values using all available data, assumed to be complete and unbiased. Bias was measured among young bulls retained by a genomic preselection and their contemporaries in other countries. The results were analyzed by traits measured within each country and by country of origin of the young bulls. It turned out that sending preselected data, though based on genomic information, created bias in international evaluations, penalizing young bulls from the country sending the incorrect data. It also had an effect on the young bulls from the other countries. Sending biased data further affected the quality of international evaluations. This study underlines the importance of accounting for genomic preselection at the national level first. Moreover, submitting all available data appeared essential to maintain the quality of the international genetic evaluations after implementation of a genomic preselection step

Endometrial cancer in elderly women: which disease, which surgical management? A systematic review of the literature

International audienceObjective: Endometrial cancer primarily affects elderly women. The aim of the present literature review is to define the population of elderly women with this disease and to define the characteristics of this cancer in elderly people as well as its surgical treatment. Materials and Methods: A systematic review of the English-language literature of the last 20 years indexed in the PubMed database. Results Endometrial cancer is more aggressive in elderly women. However, surgical staging performed in elderly patients is often not concomitant with the disease’s aggressiveness in this group. Mini-invasive surgery is performed less often, for no obvious reason. Of note, oncogeriatric evaluation was not usually ruled out to determine the most appropriate surgical modality. Conclusion: Studies are needed to evaluate surgical management of endometrial cancer in elderly women, notably with the aid of oncogeriatric scores to predict surgical morbidity

Synthesis and cellular uptake of superparamagnetic dextran-nanoparticles with porphyrinic motifs grafted by esterification

International audienceThis paper describes new superparamagnetic nanoparticles bearing dextran-grafted porphyrins with effective cellular uptake properties. They average 110 nm in diameter and are composed of a 5 nm iron oxide core coated with protoporphyrin grafted dextrans. These particles show good magnetic properties, are avidly incorporated into cultured cancer cell lines, and thus present a great potential for cellular imaging and photodynamic therapy applications

Molecular cloning and differential IgG responses to a histidine-rich antigen (OvL3.C1) of Onchocerca volvulus by selected residents of onchocerciasis endemic regions in Cameroon and Ecuador

In order to further investigate host-parasite interactions in onchocerciasis, a major Onchocerca volvulus histidine rich antigen termed OvL3.C1 was isolated from an O. volvulus cDNA library using antibodies from putatively immune subjects living in onchocerciasis endemic communities in Cameroon. Analysis of its sequences predicted the protein to be helix-rich with a single transmembrane region. Recombinant OvL3.C1 antigen induced from pBAD-TOPO/Thio vector in Escherichia coli was purified as inclusion bodies and further by a combination of Ni2+ chelate chromatography and electroelution. Anti-OvL3.C1 immunoglobulin G (IgG) subclass levels were assessed by ELISA in 15 pairs and 18 pairs of selected and cross-matched infected and putatively immune subjects from Cameroon and Ecuador, respectively. IgG3 and IgG4 levels were shown to be significantly higher in putatively immune (immune protected) subjects. A higher IgG3 level in endemic normal subjects is implicated in parasite killing and the development of the putative immune status while IgG4 has been shown to block onchocercal pathology. OvL3.C1 is a dominant antigen in onchocerciasis which elicits strong responses in subjects expose to both African and South American forms of onchocerciasis. It is therefore an important player in mechanisms of resistance or allergy attenuation in onchocerciasis.Keywords: Onchocerciasis, immunoglobulin G, putative immunit

Accounting for genomic pre-selection in national BLUP evaluations in dairy cattle

<p>Abstract</p> <p>Background</p> <p>In future Best Linear Unbiased Prediction (BLUP) evaluations of dairy cattle, genomic selection of young sires will cause evaluation biases and loss of accuracy once the selected ones get progeny.</p> <p>Methods</p> <p>To avoid such bias in the estimation of breeding values, we propose to include information on all genotyped bulls, including the culled ones, in BLUP evaluations. Estimated breeding values based on genomic information were converted into genomic pseudo-performances and then analyzed simultaneously with actual performances. Using simulations based on actual data from the French Holstein population, bias and accuracy of BLUP evaluations were computed for young sires undergoing progeny testing or genomic pre-selection. For bulls pre-selected based on their genomic profile, three different types of information can be included in the BLUP evaluations: (1) data from pre-selected genotyped candidate bulls with actual performances on their daughters, (2) data from bulls with both actual and genomic pseudo-performances, or (3) data from all the genotyped candidates with genomic pseudo-performances. The effects of different levels of heritability, genomic pre-selection intensity and accuracy of genomic evaluation were considered.</p> <p>Results</p> <p>Including information from all the genotyped candidates, i.e. genomic pseudo-performances for both selected and culled candidates, removed bias from genetic evaluation and increased accuracy. This approach was effective regardless of the magnitude of the initial bias and as long as the accuracy of the genomic evaluations was sufficiently high.</p> <p>Conclusions</p> <p>The proposed method can be easily and quickly implemented in BLUP evaluations at the national level, although some improvement is necessary to more accurately propagate genomic information from genotyped to non-genotyped animals. In addition, it is a convenient method to combine direct genomic, phenotypic and pedigree-based information in a multiple-step procedure.</p

HDAC Inhibition with Valproate Improves Direct Cytotoxicity of Monocytes against Mesothelioma Tumor Cells

peer reviewedThe composition of the tumor microenvironment (TME) mediates the outcome of chemo- and immunotherapies in malignant pleural mesothelioma (MPM). Tumor-associated macrophages (TAMs) and monocyte myeloid-derived immunosuppressive cells (M-MDSCs) constitute a major fraction of the TME. As central cells of the innate immune system, monocytes exert well-characterized functions of phagocytosis, cytokine production, and antibody-dependent cell-mediated cytotoxicity (ADCC). The objective of this study was to evaluate the ability of monocytes to exert a direct cytotoxicity by cell-to-cell contact with MPM cells. The experimental model is based on cocultures between human blood-derived monocytes sorted by negative selection and mesothelioma cell lines. Data show (i) that blood-derived human monocytes induce tumor cell death by direct cell-to-cell contact, (ii) that VPA is a pharmacological enhancer of this cytotoxic activity, (iii) that VPA increases monocyte migration and their aggregation with MPM cells, and (iv) that the molecular mechanisms behind VPA modulation of monocytes involve a downregulation of the membrane receptors associated with the M2 phenotype, i.e., CD163, CD206, and CD209. These conclusions, thus, broaden our understanding about the molecular mechanisms involved in immunosurveillance of the tumor microenvironment and open new prospects for further improvement of still unsatisfactory MPM therapies

Contribution of lysine deacetylases to the therapy of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare cancer arising from mesothelial cells from the pleura. The first line chemotherapy of the epithelioid subtype of MPM is based on a combined regimen of cisplatin and an antifolate (pemetrexed). Recently, immunotherapy with two checkpoint inhibitors (PD-1, nivolumab and CTLA-4, ipilimumab) showed promising results for the sarcomatoid subtype. Despite this major breakthrough, the median overall survival of patients only reached 18.1 months, compared to 14 months in standard chemotherapy. With an objective response rate of 40%, only a subset of patients benefits from immunotherapy. Therefore, options for second line treatment are still mandatory. We previously proposed a therapy based on the combination of a topoisomerase inhibitor (doxorubicin) and a lysine deacetylase inhibitor (valproate, VPA) (Scherpereel et al, European Respiratory Journal 37:129-135). We identified one of the key determinants that modulates the chemoresistance (Staumont et al, Cancers 12:1484). In this study, we aimed to further investigate the mechanisms involved by analyzing the effect of VPA on the tumor microenvironment and more particularly on the interactions between monocytes and tumor cells. We showed that VPA affects the viability of doxorubicin-treated mesothelioma cells and promotes their apoptosis. The use of caspase and calpeptin inhibitors demonstrated that apoptosis occurs through a caspase-dependent mechanism involving both intrinsic and extrinsic pathway. Western blot analysis revealed that the combination of VPA and doxorubicin increases the expression of clived-Bid, Bax and cytochrome c while decreasing the expression of Bcl-2 and Bcl-XL. Transcriptomic analysis unveiled that epithelioid mesothelioma cells express more p21, Fas, Bbc3 and TP53INP1 upon treatment compared to the sarcomatoid subtype. To investigate the role of the microenvironment, we designed two models to study the influence of tumor-associated monocytes. Mesothelioma cells were co-cultured with THP-1 monocytes differentiated in presence of PMA. Flow cytometry, confocal microscopy and live imaging demonstrated that THP-1-derived monocytes are able to interact and kill tumor cells. Furthermore, VPA promotes the interaction between monocytes and tumor cells and fosters the cytotoxic activity of monocytes. In contrast to PMA, VPA does not affect the motility of THP-1 monocytes. These observations were validated and extended to primary monocytes isolated from peripheral blood. Increased cytotoxicity of primary monocytes is correlated with a reduced frequency of CD16+ cells. In this model, VPA augments the average speed of primary monocytes. Finally, RNA sequencing highlighted the key mechanisms involved in monocyte antitumor activity. In conclusion, we demonstrate that VPA directly affects the survival of tumor cells and indirectly modulates the cytotoxic activity of monocytes in the microenvironment