CD40-stimulated B Lymphocytes Pulsed with Tumor Antigens Are Effective Antigen-presenting Cells That Can Generate Specific T Cells

Although they are considered as antigen presenting cells (APC), the role of antigen-unspecific B-lymphocytes in antigen presentation and T lymphocyte stimulation remains controversial. In this paper, we tested the capacity of normal human peripheral activated B cells to stimulate T cells using melanoma antigens or melanoma cell lysates. B lymphocytes activated through CD40 ligation and then pulsed with tumor antigens efficiently processed and presented MHC class II restricted peptides to specific CD4+ T cell clones. This suggests that CD40-activated B cells have the functional and molecular competence to present MHC class II epitopes when pulsed with exogenous antigens, thereby making them a relevant source of APC to generate T cells. To test this hypothesis, CD40-activated B cells were pulsed with a lysate prepared from melanoma cells and used to stimulate peripheral autologous T cells. Interestingly, T cells specific to melanoma antigens were generated. Further analysis of these T cell clones revealed that they recognized MHC class II restricted epitopes from tyrosinase, a known melanoma tumor antigen. The efficient antigen presentation by antigen-unspecific activated B cells was correlated with a down-regulation in the expression of HLA-DO, a B cell specific protein known to interfere with HLA-DM function. Because HLA-DM is important in MHC class II peptide loading, the observed decrease in HLA-DO may partially explain the enhanced antigen presentation following B-cell activation. Results globally suggest that when they are properly activated, antigen-unspecific B-lymphocytes can present exogenous antigens by MHC class II molecules and stimulate peripheral antigen-specific T cells. Antigen presentation by activated B cells could be exploited for immunotherapy by allowing the in vitro generation of T cells specific against antigens expressed by tumors or viruses.

Letters to the Editor: Correspondence re R. Lapointe et al., CD40-stimulated B Lymphocytes Pulsed with Tumor Antigens Are Effective Antigen-presenting Cells That Can Generate Specific T Cells. Cancer Res 2003;63:2836–43.

La réplique provient de Réjean Lapointe, Jacques Thibodeau et Patrick Hwu; Réjean Lapointe et Jacques Thibodeau sont affiliés à la faculté de médecine de l'Université de Montréal

Environnement alimentaire local et son association avec les habitudes alimentaires de personnes âgées

Contexte : Un accès adéquat aux aliments sains dans les environnements résidentiels peut contribuer aux saines habitudes alimentaires. Un tel accès est d’autant plus important pour les personnes âgées, où les changements associés au vieillissement peuvent accentuer leur dépendance aux ressources disponibles dans le voisinage. Cependant, cette relation n’a pas encore été établie chez les aînés. Objectifs : La présente thèse vise à quantifier les associations entre l’environnement alimentaire local et les habitudes alimentaires de personnes âgées vivant à domicile en milieu urbain. La thèse s’est insérée dans un projet plus large qui a apparié les données provenant d’une cohorte d’aînés québécois vivant dans la région métropolitaine montréalaise avec des données provenant d’un système d’information géographique. Trois études répondent aux objectifs spécifiques suivants : (1) développer des indices relatifs de mixité alimentaire pour qualifier l’offre d’aliments sains dans les magasins d’alimentation et l’offre de restaurants situés dans les quartiers faisant partie du territoire à l’étude et en examiner la validité; (2) quantifier les associations entre la disponibilité relative de magasins d’alimentation et de restaurants près du domicile et les habitudes alimentaires des aînés; (3) examiner l’influence des connaissances subjectives en nutrition dans la relation entre l’environnement alimentaire près du domicile et les habitudes alimentaires chez les hommes et les femmes âgés. Méthodes : Le devis consiste en une analyse secondaire de données transversales provenant de trois sources : les données du cycle 1 pour 848 participants de l’Étude longitudinale québécoise « La nutrition comme déterminant d’un vieillissement réussi » (2003-2008), le Recensement de 2001 de Statistique Canada et un registre privé de commerces et services (2005), ces derniers regroupés dans un système d’information géographique nommé Mégaphone. Des analyses bivariées non paramétriques ont été appliquées pour répondre à l’objectif 1. Les associations entre l’exposition aux commerces alimentaires dans le voisinage et les habitudes alimentaires (objectif 2), ainsi que l’influence des connaissances subjectives en nutrition dans cette relation (objectif 3), ont été vérifiées au moyen d’analyses de régression linéaires. Résultats : Les analyses ont révélé trois résultats importants. Premièrement, l’utilisation d’indices relatifs pour caractériser l’offre alimentaire s’avère pertinente pour l’étude des habitudes alimentaires, plus particulièrement pour l’offre de restaurants-minute. Deuxièmement, l’omniprésence d’aspects défavorables dans l’environnement, caractérisé par une offre relativement plus élevée de restaurants-minute, semble nuire davantage aux saines habitudes alimentaires que la présence d’opportunités d’achats d’aliments sains dans les magasins d’alimentation. Troisièmement, un environnement alimentaire plus favorable aux saines habitudes pourrait réduire les écarts quant à la qualité de l’alimentation chez les femmes ayant de plus faibles connaissances subjectives en nutrition par rapport aux femmes mieux informées. Conclusion : Ces résultats mettent en relief la complexité des liens entre l’environnement local et l’alimentation. Dans l’éventualité où ces résultats seraient reproduits dans des recherches futures, des stratégies populationnelles visant à résoudre un déséquilibre entre l’accès aux sources d’aliments sains par rapport aux aliments peu nutritifs semblent prometteuses.

Association entre les affections buccodentaires et le cancer colorectal : une revue et synthèse de la littérature

Position du problème: La parodontite chronique et l’édentement sont des affections buccodentaires chroniques qui, depuis quelques décennies, sont incriminées dans la survenue de différents types de cancers. Cette revue de littérature avait pour but d’examiner l’association entre le cancer colorectal et ces affections buccodentaires. Résultats: Les études épidémiologiques évaluant une association potentielle entre la parodontite, l’édentement et le cancer colorectal sont peu nombreuses. Cependant, plusieurs mécanismes plaident en faveur de cette association, notamment l’inflammation, la nutrition et possiblement l’infection par certains pathogènes, comme le suggère cette revue de la littérature.

Efficient mining of association rules based on formal concept analysis

Association rules are a popular knowledge discovery technique for warehouse basket analysis. They indicate which items of the warehouse are frequently bought together. The problem of association rule mining has first been stated in 1993. Five years later, several research groups discovered that this problem has a strong connection to Formal Concept Analysis (FCA). In this survey, we will first introduce some basic ideas of this connection along a specific algorithm, TITANIC, and show how FCA helps in reducing the number of resulting rules without loss of information, before giving a general overview over the history and state of the art of applying FCA for association rule mining.

Compositional hypotheses of subcompositional stability and specific perturbation change and their testing

In standard multivariate statistical analysis common hypotheses of interest concern changes in mean vectors and subvectors. In compositional data analysis it is now well established that compositional change is most readily described in terms of the simplicial operation of perturbation and that subcompositions replace the marginal concept of subvectors. To motivate the statistical developments of this paper we present two challenging compositional problems from food production processes. Against this background the relevance of perturbations and subcompositions can be clearly seen. Moreover we can identify a number of hypotheses of interest involving the specification of particular perturbations or differences between perturbations and also hypotheses of subcompositional stability. We identify the two problems as being the counterpart of the analysis of paired comparison or split plot experiments and of separate sample comparative experiments in the jargon of standard multivariate analysis. We then develop appropriate estimation and testing procedures for a complete lattice of relevant compositional hypotheses

PTPN22 Association in Systemic Lupus Erythematosus (SLE) with Respect to Individual Ancestry and Clinical Sub-Phenotypes

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a negative regulator of T-cell activation associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). Missense rs2476601 is associated with SLE in individuals with European ancestry. Since the rs2476601 risk allele frequency differs dramatically across ethnicities, we assessed robustness of PTPN22 association with SLE and its clinical subphenotypes across four ethnically diverse populations. Ten SNPs were genotyped in 8220 SLE cases and 7369 controls from in European-Americans (EA), African-Americans (AA), Asians (AS), and Hispanics (HS). We performed imputation-based association followed by conditional analysis to identify independent associations. Significantly associated SNPs were tested for association with SLE clinical sub-phenotypes, including autoantibody profiles. Multiple testing was accounted for by using false discovery rate. We successfully imputed and tested allelic association for 107 SNPs within the PTPN22 region and detected evidence of ethnic-specific associations from EA and HS. In EA, the strongest association was at rs2476601 (P = 4.761029, OR = 1.40 (95% CI = 1.25–1.56)). Independent association with rs1217414 was also observed in EA, and both SNPs are correlated with increased European ancestry. For HS imputed intronic SNP, rs3765598, predicted to be a cis-eQTL, was associated (P = 0.007, OR = 0.79 and 95% CI = 0.67–0.94). No significant associations were observed in AA or AS. Case-only analysis using lupus-related clinical criteria revealed differences between EA SLE patients positive for moderate to high titers of IgG anti-cardiolipin (aCL IgG .20) versus negative aCL IgG at rs2476601 (P = 0.012, OR = 1.65). Association was reinforced when these cases were compared to controls (P = 2.761025, OR = 2.11). Our results validate that rs2476601 is the most significantly associated SNP in individuals with European ancestry. Additionally, rs1217414 and rs3765598 may be associated with SLE. Further studies are required to confirm the involvement of rs2476601 with aCL IgG.

Age-specific survival of male Golden-cheeked Warblers on the Fort Hood Military Reservation, Texas

Population models are essential components of large-scale conservation and management plans for the federally endangered Golden-cheeked Warbler (Setophaga chrysoparia; hereafter GCWA). However, existing models are based on vital rate estimates calculated using relatively small data sets that are now more than a decade old. We estimated more current, precise adult and juvenile apparent survival (Φ) probabilities and their associated variances for male GCWAs. In addition to providing estimates for use in population modeling, we tested hypotheses about spatial and temporal variation in Φ. We assessed whether a linear trend in Φ or a change in the overall mean Φ corresponded to an observed increase in GCWA abundance during 1992-2000 and if Φ varied among study plots. To accomplish these objectives, we analyzed long-term GCWA capture-resight data from 1992 through 2011, collected across seven study plots on the Fort Hood Military Reservation using a Cormack-Jolly-Seber model structure within program MARK. We also estimated Φ process and sampling variances using a variance-components approach. Our results did not provide evidence of site-specific variation in adult Φ on the installation. Because of a lack of data, we could not assess whether juvenile Φ varied spatially. We did not detect a strong temporal association between GCWA abundance and Φ. Mean estimates of Φ for adult and juvenile male GCWAs for all years analyzed were 0.47 with a process variance of 0.0120 and a sampling variance of 0.0113 and 0.28 with a process variance of 0.0076 and a sampling variance of 0.0149, respectively. Although juvenile Φ did not differ greatly from previous estimates, our adult Φ estimate suggests previous GCWA population models were overly optimistic with respect to adult survival. These updated Φ probabilities and their associated variances will be incorporated into new population models to assist with GCWA conservation decision making.

AtTRB1, a telomeric DNA-binding protein from Arabidopsis, is concentrated in the nucleolus and shows highly dynamic association with chromatin

AtTRB1, 2 and 3 are members of the SMH (single Myb histone) protein family, which comprises double-stranded DNA-binding proteins that are specific to higher plants. They are structurally conserved, containing a Myb domain at the N-terminus, a central H1/H5-like domain and a C-terminally located coiled-coil domain. AtTRB1, 2 and 3 interact through their Myb domain specifically with telomeric double-stranded DNA in vitro, while the central H1/H5-like domain interacts non-specifically with DNA sequences and mediates protein–protein interactions. Here we show that AtTRB1, 2 and 3 preferentially localize to the nucleus and nucleolus during interphase. Both the central H1/H5-like domain and the Myb domain from AtTRB1 can direct a GFP fusion protein to the nucleus and nucleolus. AtTRB1–GFP localization is cell cycle-regulated, as the level of nuclear-associated GFP diminishes during mitotic entry and GFP progressively re-associates with chromatin during anaphase/telophase. Using fluorescence recovery after photobleaching and fluorescence loss in photobleaching, we determined the dynamics of AtTRB1 interactions in vivo. The results reveal that AtTRB1 interaction with chromatin is regulated at two levels at least, one of which is coupled with cell-cycle progression, with the other involving rapid exchange.

Family-based association analysis with ordered categorical phenotypes, covariates and interactions

Genetic association analyses of family-based studies with ordered categorical phenotypes are often conducted using methods either for quantitative or for binary traits, which can lead to suboptimal analyses. Here we present an alternative likelihood-based method of analysis for single nucleotide polymorphism (SNP) genotypes and ordered categorical phenotypes in nuclear families of any size. Our approach, which extends our previous work for binary phenotypes, permits straightforward inclusion of covariate, gene-gene and gene-covariate interaction terms in the likelihood, incorporates a simple model for ascertainment and allows for family-specific effects in the hypothesis test. Additionally, our method produces interpretable parameter estimates and valid confidence intervals. We assess the proposed method using simulated data, and apply it to a polymorphism in the c-reactive protein (CRP) gene typed in families collected to investigate human systemic lupus erythematosus. By including sex interactions in the analysis, we show that the polymorphism is associated with anti-nuclear autoantibody (ANA) production in females, while there appears to be no effect in males.

Peptides generated ex vivo from serum proteins by tumor-specific exopeptidases are not useful biomarkers in ovarian cancer

BACKGROUND: The serum peptidome may be a valuable source of diagnostic cancer biomarkers. Previous mass spectrometry (MS) studies have suggested that groups of related peptides discriminatory for different cancer types are generated ex vivo from abundant serum proteins by tumor-specific exopeptidases. We tested 2 complementary serum profiling strategies to see if similar peptides could be found that discriminate ovarian cancer from benign cases and healthy controls. METHODS: We subjected identically collected and processed serum samples from healthy volunteers and patients to automated polypeptide extraction on octadecylsilane-coated magnetic beads and separately on ZipTips before MALDI-TOF MS profiling at 2 centers. The 2 platforms were compared and case control profiling data analyzed to find altered MS peak intensities. We tested models built from training datasets for both methods for their ability to classify a blinded test set. RESULTS: Both profiling platforms had CVs of approximately 15% and could be applied for high-throughput analysis of clinical samples. The 2 methods generated overlapping peptide profiles, with some differences in peak intensity in different mass regions. In cross-validation, models from training data gave diagnostic accuracies up to 87% for discriminating malignant ovarian cancer from healthy controls and up to 81% for discriminating malignant from benign samples. Diagnostic accuracies up to 71% (malignant vs healthy) and up to 65% (malignant vs benign) were obtained when the models were validated on the blinded test set. CONCLUSIONS: For ovarian cancer, altered MALDI-TOF MS peptide profiles alone cannot be used for accurate diagnoses.

The roles of feature-specific task set and bottom-up salience in attentional capture: An ERP study

We investigated the roles of top-down task set and bottom-up stimulus salience for feature-specific attentional capture. Spatially nonpredictive cues preceded search arrays that included a color-defined target. For target-color singleton cues, behavioral spatial cueing effects were accompanied by cueinduced N2pc components, indicative of attentional capture. These effects were only minimally attenuated for nonsingleton target-color cues, underlining the dominance of top-down task set over salience in attentional capture. Nontarget-color singleton cues triggered no N2pc, but instead an anterior N2 component indicative of top-down inhibition. In Experiment 2, inverted behavioral cueing effects of these cues were accompanied by a delayed N2pc to targets at cued locations, suggesting that perceptually salient but task-irrelevant visual events trigger location-specific inhibition mechanisms that can delay subsequent target selection.

Corticotropin-releasing factor binding protein dimerizes after association with ligand.

We have suggested recently that the fall in plasma CRF-binding protein (BP) during the last few weeks of pregnancy is a direct effect of association with its ligand because of the rapid decrease in plasma BP concentration seen in normal males reaching a nadir some 15 min after a bolus injection of synthetic CRF. In the present study, we have investigated the physicochemical properties of both natural and recombinant BP by gel filtration under physiological conditions and have shown that association of human CRF to this BP results in an increase in molecular weight consistent with the formation of a dimer form of the BP ligand complex. The dimer is more stable when the interaction occurs in the presence of serum or if a peptide with a higher affinity for the BP is substituted as ligand. Experimental evidence would also suggest that the dimer BP has a higher affinity for ligand than the monomeric form. We suggest that this dimerization occurs in vivo when CRF is released into the bloodstream and provides the trigger that causes the uptake of the complex at specific receptor sites.

Multi-target out-of-sequence data association: tracking using graphical models

When performing data fusion, one often measures where targets were and then wishes to deduce where targets currently are. There has been recent research on the processing of such out-of-sequence data. This research has culminated in the development of a number of algorithms for solving the associated tracking problem. This paper reviews these different approaches in a common Bayesian framework and proposes an architecture that orthogonalises the data association and out-of-sequence problems such that any combination of solutions to these two problems can be used together. The emphasis is not on advocating one approach over another on the basis of computational expense, but rather on understanding the relationships among the algorithms so that any approximations made are explicit. Results for a multi-sensor scenario involving out-of-sequence data association are used to illustrate the utility of this approach in a specific context.

Fimbriae- and flagella-mediated association with and invasion of cultured epithelial cells by Salmonella enteritidis

Salmonella enteritidis expresses flagella and several finely regulated fimbriae, including SEF14, SEF17 and SEF21 (type 1). A panel of mutants was prepared in three strains of S. enteritidis to elucidate the role of these surface appendages in the association with and invasion of cultured epithelial cells. In all assays, the naturally occurring regulatory-defective strain 27655R associated with tissue culture cells significantly more than wild-type progenitor strains LA5 and S1400/94. Compared with wild-type strains, SEF14 mutants had no effect on association and invasion, whereas SEF17, SEF21 and aflagellate mutants showed significant reductions in both processes. Histological examination suggested a role for SEF17 in localized, aggregative adherence, which could be specifically blocked by anti-SEF17 sera and purified SEF17 fimbriae. SEF21-mediated association was neutralized by mannose and a specific monoclonal antibody, although to observe enhanced association it was necessary for the bacteria to be in fimbriate phase prior to infection. Additionally, aflagellate mutants associated and invaded less than motile bacteria. This study demonstrated the potential for multifactorial association and invasion of epithelial cells which involved SEF17 and SEF21 fimbriae, and flagella-mediated motility.