Identification of PVR (CD155) and Nectin-2 (CD112) as Cell Surface Ligands for the Human DNAM-1 (CD226) Activating Molecule

Human natural killer (NK) cells express a series of activating receptors and coreceptors that are involved in recognition and killing of target cells. In this study, in an attempt to identify the cellular ligands for such triggering surface molecules, mice were immunized with NK-susceptible target cells. On the basis of a functional screening, four mAbs were selected that induced a partial down-regulation of the NK-mediated cytotoxicity against the immunizing target cells. As revealed by biochemical analysis, three of such mAbs recognized molecules of ∼70 kD. The other mAb reacted with two distinct molecules of ∼65 and 60 kD, respectively. Protein purification followed by tryptic digestion and mass spectra analysis, allowed the identification of the 70 kD and the 65/60 kD molecules as PVR (CD155) and Nectin-2 δ/α (CD112), respectively. PVR-Fc and Nectin-2-Fc soluble hybrid molecules brightly stained COS-7 cells transfected with the DNAM-1 (CD226) construct, thus providing direct evidence that both PVR and Nectin-2 represent specific ligands for the DNAM-1 triggering receptor. Finally, the surface expression of PVR or Nectin-2 in cell transfectants resulted in DNAM-1–dependent enhancement of NK-mediated lysis of these target cells. This lysis was inhibited or even virtually abrogated upon mAb-mediated masking of DNAM-1 (on NK cells) or PVR or Nectin-2 ligands (on cell transfectants)

'Less is more': validation with Rasch analysis of five short-forms for the Brain Injury Rehabilitation Trust Personality Questionnaires (BIRT-PQs).

Background: Previous analyses demonstrated a lack of unidimensionality, item redundancy, and substantial administrative burden for the Brain Injury Rehabilitation Trust Personality Questionnaires (BIRT-PQs). Objective: To use Rasch Analysis to calibrate five short-forms of the BIRT-PQs, satisfying the Rasch model requirements. Methods: BIRT-PQs data from 154 patients with severe Acquired Brain Injury (s-ABI) and their caregivers (total sample = 308) underwent Rasch analysis to examine their internal construct validity and reliability according to the Rasch model. Results: The base Rasch analyses did not show sufficient internal construct validity according to the Rasch model for all five BIRT-PQs. After rescoring 18 items, and deleting 75 of 150 items, adequate internal construct validity was achieved for all five BIRT-PQs short forms (model chi-square p-values ranging from 0.0053 to 0.6675), with reliability values compatible with individual measurements. Conclusions: After extensive modifications, including a 48% reduction of the item load, we obtained five short forms of the BIRT-PQs satisfying the strict measurement requirements of the Rasch model. The ordinal-to-interval measurement conversion tables allow measuring on the same metric the perception of the neurobehavioral disability for both patients with s-ABI and their caregivers

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

International audienceBACKGROUND:Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.METHODS:Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.RESULTS:For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).CONCLUSIONS:These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers

Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)

The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer‐reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state‐of‐the‐art handbook for basic and clinical researchers.DFG, 389687267, Kompartimentalisierung, Aufrechterhaltung und Reaktivierung humaner Gedächtnis-T-Lymphozyten aus Knochenmark und peripherem BlutDFG, 80750187, SFB 841: Leberentzündungen: Infektion, Immunregulation und KonsequenzenEC/H2020/800924/EU/International Cancer Research Fellowships - 2/iCARE-2DFG, 252623821, Die Rolle von follikulären T-Helferzellen in T-Helferzell-Differenzierung, Funktion und PlastizitätDFG, 390873048, EXC 2151: ImmunoSensation2 - the immune sensory syste

Medical encounter for breast cancer screening, breast risk factors to disclose

Who should undergo breast cancer screening and its timing rely on breast cancer risk factors. This article describes the logic at stake and offers a grid to analyse which factors should be disclosed and discussed. (C) 2018 Elsevier Masson SAS. All rights reserved

Les femmes à haut risque de cancer du sein : quelle attitude ?

International audienceIn France, breast cancer is the most common cancer among women and the leading cause of cancer deaths. Identifying women with a “high” or “very high” breast cancer risk, according the terminology of the Haute Autorité de Santé 2014 guidelines, is essential to offer them special cares in term of screening and prevention.Women genetically predisposed have a very high risk of breast cancer. During the oncogenetic specialist consultation, familial and personal history of cancer is taken into account to evaluate the risk of hereditary Breast/Ovarian syndrome and thus the need of a genetic screening. In 2017, a list of 13 genes involved in hereditary ovarian or breast cancer has been established in France (Genetic and Cancer Group – Unicancer).Women carrying a BRCA1, BRCA2, PALB2, TP53, CDH1, PTEN mutation have a higher risk of breast cancer and are considered as “high risk”. Therefore, medical breast surveillance similar to carriers of BRCA1/BRCA2 mutation is recommended for these patients (INCa guidelines 2017).However a mutation in one of those genes is only identified in approximatively 10 % of the screened families. The oncogenetic specialist's assessment distinguishes families in which women remain at a “high” risk of breast cancer (HAS 2014 for screening) from those where women have a “very high” risk (INCa guidelines 2017 for screening and prevention).Le cancer du sein est, en France, le plus fréquent des cancers chez la femme et la première cause de décès par cancer. L’identification des femmes, dont le niveau de risque de cancer du sein est « élevé » ou « très élevé » selon la terminologie de la Haute Autorité de Santé en 2014, est essentielle puisque leur prise en charge, en termes de dépistage et de prévention, pourra ainsi être adaptée.Les femmes prédisposées génétiquement sont à risque très élevé de cancer du sein. La consultation d’oncogénétique a pour but d’étudier l’histoire personnelle et familiale de cancers de la patiente afin d’identifier les situations évocatrices d’une prédisposition héréditaire aux cancers du sein et/ou des ovaires et leur proposer des analyses de biologie moléculaire. Une liste de 13 gènes devant être étudiés face à ce risque héréditaire a été établie en France en 2017 (Groupe Génétique et Cancer – Unicancer).La mise en évidence d’une mutation constitutionnelle délétère des gènes BRCA1, BRCA2, PALB2, TP53, CDH1, PTEN confère un niveau de risque de cancer du sein considéré comme « très élevé » chez les femmes porteuses. Elles se voient recommander une surveillance mammaire similaire aux femmes porteuses d’une mutation d’un des deux gènes BRCA1/BRCA2 (Référentiel INCa 2017).Une mutation délétère sur un gène d’intérêt est identifiée dans environ 10 % des familles testées. Lorsque l’analyse est négative, l’évaluation faite par l’onco-généticien permet de distinguer les familles où les femmes restent à un risque « élevé » de cancer du sein (Référentiel HAS 2014 pour le dépistage) de celles où les femmes sont à un risque « très élevé » (Référentiel INCa 2017 pour le dépistage et la prévention)

Médecine personnalisée et cancer du sein : médecine anticipatoire, évaluation pronostique et ciblage thérapeutique

International audienc

Avoir un enfant et accéder au DPN/DPI pour des femmes porteuses d’une mutation BRCA ? Malades et indemnes appréhendent la question différemment

International audienceGenetic tests in families with a mutation related to breast and ovarian cancers (BRCA1/2) are now offered to the persons before completion of their reproductive project. The aim of this qualitative study was to descriptively explore how the issues of reproduction are faced in women belonging to these families, and how the possible use of prenatal diagnostic (PND) and preimplantation genetic diagnosis (PGD) would be faced in a theoretical context. We conducted in-depth interviews, face to face, according to the so-called Grounded Theory approach. Twenty women with a BRCA genetic mutation participated in the study (age range: 31-57 years); 12 have had a breast and/or ovarian cancer. The knowledge of having the mutation did not modify the parental project; however prophylactic anexectomy was likely to alter it in some women. If the majority of women were in favor of PGD (n = 14), medical termination of pregnancy was a constraint towards the position in relation to PND. Besides ethical and moral arguments, the women's attitudes were constructed differently according to their own personal or familial experience of the disease. The women's perceptions of the cancer severity, risk and cure were organized according to this experience.Les tests génétiques dans les familles ayant une mutation prédisposant aux cancers sein/ovaire (BRCA1/2) sont maintenant accessibles à des personnes n’ayant pas encore accompli leur projet parental. L’objectif de cette étude qualitative était d’explorer de manière descriptive comment se posent les questions de reproduction pour des femmes appartenant à ces familles, et comment s’argumentent dans un contexte théorique les attitudes par rapport au diagnostic prénatal (DPN) et/ou préimplantatoire (DPI). Nous avons utilisé une méthodologie par entretiens de recherche approfondis, menés en face-à-face, selon l’approche dite grounded theory. Vingt femmes porteuses d’une mutation BRCA1/2ont été incluses (31-57ans); 12ayant eu un cancer du sein et/ou de l’ovaire. La connaissance de la mutation n’a pas modifié fondamentalement le projet parental mais l’annexectomie prophylactique en a fait varier sa dynamique pour certaines. Si la majoritédes femmes étaient favorables au DPI (n = 14) la position par rapport au DPN était freinée par l’interruption médicale de grossesse. À côté des argumentations éthiques et morales, les positions des femmes s’élaborent différemment en fonction de leur expérience de la maladie, personnelle ou familiale. Cette expérience organise les perceptions que les femmes ont de la gravité, du risque et de la curabilité de cette maladie