Proteomic profile determination of autosomal aneuploidies by mass spectrometry on amniotic fluids

<p>Abstract</p> <p>Background</p> <p>Prenatal diagnosis of chromosomal abnormalities by cytogenetic analysis is time-consuming, expensive, and requires highly qualified technicians. Rapid diagnosis of aneuploidies followed by reassurance of women with normal results can be performed by molecular analysis of uncultured foetal cells. In the present study, we developed a proteomic fingerprinting approach coupled with a statistical classification method to improve diagnosis of aneuploidies, including trisomies 13, 18, and 21, in amniotic fluid samples.</p> <p>Results</p> <p>The proteomic spectra obtained from 52 pregnant women were compiled, normalized, and mass peaks with mass-to-charge ratios between 2.5 and 50 kDa identified. Peak information was combined together and analysed using univariate statistics. Among the 208 expressed protein peaks, 40 differed significantly between aneuploid and non aneuploid samples, with AUC diagnostic values ranging from 0.71 to 0.91. Hierarchical clustering, principal component analysis and support vector machine (SVM) analysis were performed. Two class predictor models were defined from the training set, which resulted in a prediction accuracy of 92.3% and 96.43%, respectively. Using an external and independent validation set, diagnostic accuracies were maintained at 87.5% and 91.67%, respectively.</p> <p>Conclusion</p> <p>This pilot study demonstrates the potential interest of protein expression signature in the identification of new potential biological markers that might be helpful for the rapid clinical management of high-risk pregnancies.</p

Rôle de la densité membranaire en CCR5 dans la migration des lymphocytes T vers CCL5 (application à la polyarthrite rhumatoïde)

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUP (751062107) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

Les lymphocytes BUne cible prometteuse pour traiter l’athérosclérose ?

International audienceAtherosclerosis is a chronic inflammatory disease of the arterial wall. It is already well established that several immune cells (macrophages, T lymphocytes, etc.) modulate atherosclerosis progression whereas the role of the different subpopulations of B lymphocytes emerged only recently. B1 lymphocytes secrete protective IgM antibodies that act as scavenger of deleterious molecules whereas B2 lymphocytes probably worsen the disease by activating pro-inflammatory T lymphocytes. The outcome of these opposite functional properties of B lymphocytes on the evolution of arterial lesions may vary depending on their local environment during the different stages of the disease. In this review, we emphasize recent progresses in understanding the specific contribution of B lymphocytes to atherosclerosis and discuss the interest of targeting them to improve therapy.L’athérosclérose est une maladie inflammatoire chronique de la paroi artérielle. Il est bien établi que certaines cellules immunitaires (macrophages, lymphocytes T, etc.) interviennent dans la progression de l’athérosclérose. Cependant, le rôle des différentes sous-populations de lymphocytes B n’a été évoqué que récemment. Les lymphocytes B1 sécrètent des anticorps IgM protecteurs permettant l’élimination de molécules délétères, alors que les lymphocytes B2 aggravent probablement la maladie en activant des lymphocytes T pro-inflammatoires. La résultante de ces propriétés fonctionnelles opposées des lymphocytes B sur l’évolution des lésions artérielles peut varier selon leur environnement tissulaire au cours des différents stades de la maladie. Dans cette revue, nous mettons l’accent sur les progrès récents dans la compréhension de la contribution spécifique des lymphocytes B au processus athéromateux, permettant de considérer ces derniers comme des cibles potentielles d’une démarche thérapeutiqu

Étude de la réaction immunitaire humorale aux cancers par des approches protéomiques

International audienceDiscovery of new serum biomarkers exhibiting an increased sensitivity and specificity for cancer are of major importance for diagnosis improvement. There is considerable evidence for an immune response to cancer in humans, as demonstrated in part by the identification of autoantibodies against a number of tumour-associated antigens in sera from patients with different cancer types. Thus, identification of tumour-associated antigens and their associated antibodies is a promising strategy to find relevant biomarkers. Proteomic approaches such as SEREX and SERPA have allowed identification of great numbers of antigens and their cognate autoantibodies during these past few years. They show many advantages, and allowed identification of relevant autoantigens in different types of cancer. However, they are also time consuming, and lack sensibility and specificity. To circumvent these drawbacks, new proteomic techniques, based on protein or antibody arrays, allow high throughput analysis of multiple targets in a single experiment. Specific combinations of markers should thus be identified, theoretically being more efficient to detect a tumor compared to a single marker. In conclusion, these approaches promise great advances in the field of biomarkers for cancer. They also further need to be validated for clinical application on large populations

Autoanticorps et diagnostic précoce des cancers

Il est clairement établi que le système immunitaire réagit très précocement à l’apparition et au développement d’une masse tumorale. Cette réaction fait intervenir une réponse cellulaire (activation des lymphocytes T) mais aussi une réponse humorale (production d’anticorps) contre des autoantigènes tumoraux devenus fortement immunogènes. Durant ces dix dernières années, des méthodes de protéomique ont été développées afin d’identifier les autoanticorps circulants et les antigènes qui leur correspondent dans différents types de cancer. La détection dans le sérum des patients d’un panel d’autoanticorps dirigés contre des protéines tumorales a ainsi été proposée comme nouvelle stratégie diagnostique en cancérologie. Cette signature humorale semble tout particulièrement adaptée à la détection précoce des cancers, notamment ceux du sein et du poumon. Elle présente un grand intérêt pour les patients qui ont un risque élevé de développer des cancers comme par exemple les sujets tabagiques chroniques, et pour lesquels il y a un déficit d’examens complémentaires

Sodium restriction modulates innate immunity and prevents cardiac remodeling in a rat model of metabolic syndrome

International audienc

Identification of a New Panel of Serum Autoantibodies Associated with the Presence of In situ Carcinoma of the Breast in Younger Women

International audienceWe examined the feasibility of using a panel of autoantibodies to multiple tumor-associated proteins as a method for early detection of breast cancer and, more particularly, carcinoma in situ (CIS)

Characterization of Resident B Cells of Vascular Walls in Human Atherosclerotic Patients

International audienceAnimal models of atherosclerosis suggest that B cells have contradictory protective or proatherogenic effects that are also subset and context dependent. To further understand the pathophysiology of human atheroma, we characterized local Ig production and functional properties of resident B cells in human arterial lesions. Ig repertoires were analyzed by RT-PCR in carotid endarterectomy samples. Cytokine, differentiation marker and transcription factor mRNA expression was studied on arterial wall lymphocytes isolated by laser capture microdissection. Ig sequence analysis revealed that individual samples each contained a limited number of B cell clones. Functional α and γ mRNAs made up the majority of H chain mRNAs in the adventitia. Clonal evolution of Ig V regions, expression of activation-induced cytidine deaminase, clonal H chain switch, and an inverted λ/κ ratio of Ig L chain usage indicated that a local differentiation process was taking place in arterial walls. Clonotypic markers revealed different plaque and adventitia Ig repertoires and a B cell recirculation between adventitia and draining lymph nodes. Microdissected mononuclear cells had an activated phenotype expressing IL-6, GM-CSF, and TNF-α, whereas IL-2, IL-4, IL-10, M-CSF, and IFN-γ were not detected. Adventitial oligoclonal resident B cells of atherosclerotic patients are mainly mature B2 (conventional) CD20⁻ plasmablasts lacking markers of terminal differentiation to plasma cell (CD138 and Blimp-1). They present hallmarks of Ag-driven maturation and could act on inflammation and disease progression directly or by promoting polarization of other immune cells

FKBP4 connects mTORC2 and PI3K to activate the PDK1/Akt-dependent cell proliferation signaling in breast cancer

International audiencePurpose: Among the FKBP family members, FKBP4 has been described to have a potential role in tumorigenesis, and as a putative tissue marker. We previously showed that FKBP4, an HSP90-associated co-chaperone, can elicit immune response as a tumor-specific antigen, and are overexpressed in breast cancer. Experimental design: In this study, we examined how loss of FKBP4 affect breast cancer progression and exploited protein interactomics to gain mechanistic insight into this process. Results: We found that FKBP4 expression is associated with breast cancer progression and prognosis, especially of ER-negative breast cancer. Furthermore, FKBP4 depletion specifically reduces cell growth and proliferation of triple negative breast cancer cell model and xenograft tumor model. Using specific protein interactome strategy by BirA proximity-dependent biotin identification, we demonstrated that FKBP4 is a novel PI3K-Akt-mTOR proximal interacting protein. Conclusion: Our results suggest that FKBP4 interacts with PI3K and can enhance Akt activation through PDK1 and mTORC2