Molecularly defined vaccines for cancer immunotherapy, and protective T cell immunity.

Malignant cells are frequently recognized and destroyed by T cells, hence the development of T cell vaccines against established tumors. The challenge is to induce protective type 1 immune responses, with efficient Th1 and CTL activation, and long-term immunological memory. These goals are similar as in many infectious diseases, where successful immune protection is ideally induced with live vaccines. However, large-scale development of live vaccines is prevented by their very limited availability and vector immunogenicity. Synthetic vaccines have multiple advantages. Each of their components (antigens, adjuvants, delivery systems) contributes specifically to induction and maintenance of T cell responses. Here we summarize current experience with vaccines based on proteins and peptide antigens, and discuss approaches for the molecular characterization of clonotypic T cell responses. With carefully designed step-by-step modifications of innovative vaccine formulations, T cell vaccination can be optimized towards the goal of inducing therapeutic immune responses in humans.

Sobriété volontaire : en quête de nouveaux modes de vie

Textes d'Aurélien Boutaud, Jean-Claude Galey, Sylvia Generoso, Susana Jourdan, Jacques Mirenowicz, René Nouailhat, Sylvain Piron, Cécile Renouard, Yvan Rytz et Marie-Christine Zélem.

Ètica interlineal: o alguna cosa més que matèria i creativitat

Treball de recerca realitzat per alumnes d’ensenyament secundari i guardonat amb un Premi CIRIT per fomentar l'esperit científic del Jovent l’any 2010. La idea de redactar aquest treball de recerca ha sorgit de l'interès per descobrir la relació entre l'ètica i l'estètica de les obres d'art.

Estudio Farmacogenético en Pacientes con Cáncer de Pulmón No Microcítico Avanzado tratados con Quimioterapia basada en Platino

a partir de ADN genómico obtenido de las células nucleadas de sangre periférica de 103 pacientes con Cáncer de Pulmón No Microcítico (CPNM) avanzado tratados con quimioterapia basada en platino, hemos analizado la asociación entre supervivencia y cinco SNPs (Single Nucleotide Polymorphism) pertenecientes a dos grupos de genes: i) de la via metabólica del ácido fólico (Timidilato Sintetasa (TS), Metil-tetrahidrofolato Reductasa (MTHFR) y, ii) de la vía de reparación del ADN (Excision repair cross-complemeting group 1 (ERCC1) y Xeroderma pigmentosum group D (XPD).

Lung microbiota promotes tolerance to allergens in neonates via PD-L1.

Epidemiological data point toward a critical period in early life during which environmental cues can set an individual on a trajectory toward respiratory health or disease. The neonatal immune system matures during this period, although little is known about the signals that lead to its maturation. Here we report that the formation of the lung microbiota is a key parameter in this process. Immediately following birth, neonatal mice were prone to develop exaggerated airway eosinophilia, release type 2 helper T cell cytokines and exhibit airway hyper-responsiveness following exposure to house dust mite allergens, even though their lungs harbored high numbers of natural CD4(+)Foxp3(+)CD25(+)Helios(+) regulatory T (Treg) cells. During the first 2 weeks after birth, the bacterial load in the lungs increased, and representation of the bacterial phyla shifts from a predominance of Gammaproteobacteria and Firmicutes towards Bacteroidetes. The changes in the microbiota were associated with decreased aeroallergen responsiveness and the emergence of a Helios(-) Treg cell subset that required interaction with programmed death ligand 1 (PD-L1) for development. Absence of microbial colonization(10) or blockade of PD-L1 during the first 2 weeks postpartum maintained exaggerated responsiveness to allergens through to adulthood. Adoptive transfer of Treg cells from adult mice to neonates before aeroallergen exposure ameliorated disease. Thus, formation of the airway microbiota induces regulatory cells early in life, which, when dysregulated, can lead to sustained susceptibility to allergic airway inflammation in adulthood.

Improved statistical evaluation of group differences in connectomes by screening-filtering strategy with application to study maturation of brain connections between childhood and adolescence.

Detecting local differences between groups of connectomes is a great challenge in neuroimaging, because the large number of tests that have to be performed and the impact on multiplicity correction. Any available information should be exploited to increase the power of detecting true between-group effects. We present an adaptive strategy that exploits the data structure and the prior information concerning positive dependence between nodes and connections, without relying on strong assumptions. As a first step, we decompose the brain network, i.e., the connectome, into subnetworks and we apply a screening at the subnetwork level. The subnetworks are defined either according to prior knowledge or by applying a data driven algorithm. Given the results of the screening step, a filtering is performed to seek real differences at the node/connection level. The proposed strategy could be used to strongly control either the family-wise error rate or the false discovery rate. We show by means of different simulations the benefit of the proposed strategy, and we present a real application of comparing connectomes of preschool children and adolescents.

Pretargeted radioimmunotherapy using genetically engineered antibody-streptavidin fusion proteins for treatment of non-hodgkin lymphoma.

Purpose: Pretargeted radioimmunotherapy (PRIT) using streptavidin (SAv)-biotin technology can deliver higher therapeutic doses of radioactivity to tumors than conventional RIT. However, "endogenous" biotin can interfere with the effectiveness of this approach by blocking binding of radiolabeled biotin to SAv. We engineered a series of SAv FPs that downmodulate the affinity of SAv for biotin, while retaining high avidity for divalent DOTA-bis-biotin to circumvent this problem.Experimental Design: The single-chain variable region gene of the murine 1F5 anti-CD20 antibody was fused to the wild-type (WT) SAv gene and to mutant SAv genes, Y43A-SAv and S45A-SAv. FPs were expressed, purified, and compared in studies using athymic mice bearing Ramos lymphoma xenografts.Results: Biodistribution studies showed delivery of more radioactivity to tumors of mice pretargeted with mutant SAv FPs followed by (111)In-DOTA-bis-biotin [6.2 +/- 1.7% of the injected dose per gram (%ID/gm) of tumor 24 hours after Y43A-SAv FP and 5.6 +/- 2.2%ID/g with S45A-SAv FP] than in mice on normal diets pretargeted with WT-SAv FP (2.5 +/- 1.6%ID/g; P = 0.01). These superior biodistributions translated into superior antitumor efficacy in mice treated with mutant FPs and (90)Y-DOTA-bis-biotin [tumor volumes after 11 days: 237 +/- 66 mm(3) with Y43A-SAv, 543 +/- 320 mm(3) with S45A-SAv, 1129 +/- 322 mm(3) with WT-SAv, and 1435 +/- 212 mm(3) with control FP (P < 0.0001)].Conclusions: Genetically engineered mutant-SAv FPs and bis-biotin reagents provide an attractive alternative to current SAv-biotin PRIT methods in settings where endogenous biotin levels are high. Clin Cancer Res; 17(23); 7373-82. (C)2011 AACR.

Validation of the Mini Nutritional Assessment short-form (MNA-SF): a practical tool for identification of nutritional status.

OBJECTIVE: To validate a revision of the Mini Nutritional Assessment short-form (MNA(R)-SF) against the full MNA, a standard tool for nutritional evaluation. METHODS: A literature search identified studies that used the MNA for nutritional screening in geriatric patients. The contacted authors submitted original datasets that were merged into a single database. Various combinations of the questions on the current MNA-SF were tested using this database through combination analysis and ROC based derivation of classification thresholds. RESULTS: Twenty-seven datasets (n=6257 participants) were initially processed from which twelve were used in the current analysis on a sample of 2032 study participants (mean age 82.3y) with complete information on all MNA items. The original MNA-SF was a combination of six questions from the full MNA. A revised MNA-SF included calf circumference (CC) substituted for BMI performed equally well. A revised three-category scoring classification for this revised MNA-SF, using BMI and/or CC, had good sensitivity compared to the full MNA. CONCLUSION: The newly revised MNA-SF is a valid nutritional screening tool applicable to geriatric health care professionals with the option of using CC when BMI cannot be calculated. This revised MNA-SF increases the applicability of this rapid screening tool in clinical practice through the inclusion of a "malnourished" category.

Extraits de divers CARTULAIRES.

Contient : Cartulaire de Saint-Just-en-Beauvaisis[Stein, n° 3463], avec cette note de Baluze : « J'ay copié cecy sur une copie, n'ayant pas veu l'original. » ; Cartulaire [A] de l'église de Grenoble [Stein, n° 1619] ; Cartulaire de l'abbaye de Fécamp [ibid., n° 1309] ; Cartulaire de Saint-Flour, table et extraits [ibid., n° 3412], et pièces (1362-1368) concernant la même église (f. 73-79) ; Cartulaire de Saint-Cybard d'Angoulême [Stein, p. 20] ; Cartulaire de l'église d'Angoulême [ibid., n° 150] ; Cartulaire de l'abbaye d'Yères [ibid., n° 4153] ; Cartulaire de Saint-Etienne de Dreux [ibid, n° 1231], extraits faits en 1683 ; Cartulaire du prieuré de Domène [ibid., n° 1212] ; Cartulaire de la Chapelle-Aude [ibid., n° 1789] ; en tête copie de l'acte de fondation, de la main d'André Duchesne ; Cartulaire de Saint-Denis [ms. lat. 5415 ; Stein, n° 3362] ; Cartulaire de Saint-Crépin-en-Chaye [ibid., n° 3350] ; Cartulaire de Conques [ibid., n° 1043] ; Echange entre la dite abbaye et un nommé Autbertus (947), d'après l'original ; Extraits d'une chronique manuscrite du même monastère ; « Ex tabulario Compendiensi. »

Erosividade das chuvas e sua distribuição entre 1989 e 1998 no município de Lages (SC)

A erosão hídrica resulta da erosividade das chuvas e da erodibilidade dos solos. O conhecimento da erosividade, portanto, torna-se um guia valioso na recomendação de práticas de manejo e conservação do solo que visem à redução da erosão hídrica. O objetivo do trabalho foi identificar e quantificar o fator de erosividade das chuvas naturais de Lages (SC), bem como conhecer sua distribuição temporal. A pesquisa foi realizada em 2000, utilizando dados de chuvas e perdas de solo do período entre 1989 e 1998, no Centro de Ciências Agroveterinárias de Lages (SC), situado a 27º 49' de latitude Sul e 50º 20' de longitude Oeste, a 937 m de altitude média, na região do Planalto Sul Catarinense. Foram estudados diversos fatores de erosividade, utilizando os métodos de Wischmeier & Smith e de Wagner & Massambani, de 437 chuvas erosivas, num total de 966 chuvas, compreendendo um volume médio anual de 1.301 mm de chuvas erosivas, num total médio anual de 1.549 mm de chuvas. O EI30 é o fator de erosividade (fator R da Equação Universal de Perda de Solo - EUPS) recomendado para Lages, cujo valor médio anual é de 5.790 MJ mm ha-1 h-1; 63 % do qual ocorre na primavera-verão; 76 % no período de setembro a março e, no período crítico, outubro, janeiro e fevereiro, 41 % do referido fator. Considerando o número e o volume das chuvas, 45 e 84 %, respectivamente, são erosivas.

HLA-C cell surface expression and control of HIV/AIDS correlate with a variant upstream of HLA-C.

A variant 35 kb upstream of the HLA-C gene (-35C/T) was previously shown to associate with HLA-C mRNA expression level and steady-state plasma HIV RNA levels. We genotyped this variant in 1,698 patients of European ancestry with HIV. Individuals with known seroconversion dates were used for disease progression analysis and those with longitudinal viral load data were used for viral load analysis. We further tested cell surface expression of HLA-C in normal donors using an HLA-C-specific antibody. We show that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high-expressing HLA-C alleles progress more slowly to AIDS and control viremia significantly better than individuals with low HLA-C expressing alleles. These data strongly implicate high HLA-C expression levels in more effective control of HIV-1, potentially through better antigen presentation to cytotoxic T lymphocytes or recognition and killing of infected cells by natural killer cells.