T-cell activation by treatment of cancer patients with EMD 521873 (Selectikine), an IL-2/anti-DNA fusion protein.

ABSTRACT: BACKGROUND: EMD 521873 (Selectikine or NHS-IL2LT) is a fusion protein consisting of modified human IL-2 which binds specifically to the high-affinity IL-2 receptor, and an antibody specific for both single- and double-stranded DNA, designed to facilitate the enrichment of IL-2 in tumor tissue. METHODS: An extensive analysis of pharmacodynamic (PD) markers associated with target modulation was assessed during a first-in-human phase I dose-escalation trial of Selectikine. RESULTS: Thirty-nine patients with metastatic or locally advanced tumors refractory to standard treatments were treated with increasing doses of Selectikine, and nine further patients received additional cyclophosphamide. PD analysis, assessed during the first two treatment cycles, revealed strong activation of both CD4+ and CD8+ T-cells and only weak NK cell activation. No dose response was observed. As expected, Treg cells responded actively to Selectikine but remained at lower frequency than effector CD4+ T-cells. Interestingly, patient survival correlated positively with both high lymphocyte counts and low levels of activated CD8+ T-cells at baseline, the latter of which was associated with enhanced T-cell responses to the treatment. CONCLUSIONS: The results confirm the selectivity of Selectikine with predominant T-cell and low NK cell activation, supporting follow-up studies assessing the clinical efficacy of Selectikine for cancer patients.

Low dose endoluminal photodynamic therapy improves murine T cell-mediated colitis.

BACKGROUND AND STUDY AIMS: Low dose photodynamic therapy (LDPDT) may modify the mucosal immune response and may thus provide a therapy for Crohn's disease. We evaluated the efficacy and safety of this technique in a murine T cell-mediated colitis model. METHODS: The safety of LDPDT was first tested in BALB/c mice. Naïve T cells were used to induce colitis in mice with severe combined immunodeficiency, which were followed up endoscopically, and a murine endoscopic index of colitis (MEIC) was developed. The efficacy of LDPDT (10 J/cm (2); delta-aminolevulinic acid, 15 mg/kg bodyweight) was then tested on mice with moderate colitis, while a disease control group received no treatment. The MEIC, weight, length, and histology of the colon, cytokine expression indices, number of mucosal CD4 (+) T cells, percentage of apoptotic CD4 (+) T cells, body weight, and systemic side effects were evaluated. RESULTS: LDPDT improved the MEIC ( P = 0.011) and the histological score ( P = 0.025), diminished the expression indices of the proinflammatory cytokines, interleukin-6 ( P = 0.042), interleukin-17 ( P = 0.029), and interferon-gamma ( P = 0.014), decreased the number of mucosal CD4 (+) T cells, and increased the percentage of apoptotic CD4 (+) T cells compared with the disease control group. No local or systemic side effects occurred. CONCLUSION: LDPDT improves murine T cell-mediated colitis, decreases the proinflammatory cytokines interleukin-6, interleukin-17, and interferon-gamma, and decreases the number of CD4 (+) T cells. No adverse events were observed. Therefore, this technique is now being evaluated in patients with inflammatory bowel disease.

Un ancrage familial et social fort. Le cas de Dole

L'enquête menée à Dole (Franche-Comté), définie selon les modalités du projet KASS, permet de distinguer entre les liens intergénérationnels dont la solidarité entre les membres est vécue comme « naturelle », et ceux entre parents de même génération, dont le soutien est plus électif. Elle révèle surtout l'importance de la matérialisation du réseau familial dans des lieux. D'une manière générale, les ménages enquêtés valorisent la proximité géographique de la parenté, un attachement local et l'ancrage familial dans une maison de famille. Dans cette logique, ils font peu appel aux ressources publiques quand ils ont besoin d'aide, car leur choix s'exerce d'abord au sein du réseau familial.

Perspectives et défis de la gestion durable du sous-sol en Suisse : analyse des droits de propriété et d'usages relatifs à l'espace souterrain et aux éléments physiques du sous-sol

La présente publication s'intéresse à un nouveau domaine de recherche des politiques environnementales. Elle se propose de théoriser et d'analyser le sous-sol comme une ressource naturelle potentiellement menacée. Le sous-sol suisse est depuis quelques années l'objet d'une forte intensification des demandes d'utilisation. Une pression démographique croissante s'exerce sur le Plateau, entrainant une augmentation du nombre d'infrastructures. Parallèlement, l'accroissement général de la valeur des terrains dans les villes pousse à une utilisation accrue de l'espace souterrain. Les progrès techniques rendent possible l'implantation d'infrastructures dans presque tous les contextes géologique. Enfin, la volonté politique et sociale de voir certains ouvrages ou substances, comme les déchets nucléaires, enterrés peut s'avérer déterminante. L'approche théorique privilégiée dans cette étude pour aborder le thème de la gestion durable de l'exploitation du sous-sol est celle, développée à l'IDHEAP, des « Régimes institutionnels de ressources » (RIR). Cette démarche se caractérise par sa volonté d'aborder la gestion d'une ressource de manière globale, en faisant fi des découpages territoriaux et institutionnels. Les résultats de l'analyse des juridictions cantonales et fédérales indiquent un risque clair de surexploitation de la ressource. En cause, le flou qui règne autour de la définition des droits de propriété du sous-sol et la faible coordination des politiques publiques concernées. L'étude se conclut sur une mise en perspective des possibilités de régulation qui s'offrent aux décideurs politiques, s'ils décident de prendre en charge le risque de surexploitation du sous-sol.

Differential proteoglycan expression in two spinal cord regions after dorsal root injury.

Dorsal root injury leads to reactive gliosis in the spinal cord dorsal root entry zone and dorsal column, two regions that undergo Wallerian degeneration, but have distinct growth-inhibitory properties. This disparity could in part be due to differences in the number of degenerating sensory fibers, differences in glial cell activation, and/or to differential expression of growth-inhibitory molecules such as chondroitin sulfate proteoglycans. Laser capture microdissection of these two spinal cord white matter regions, followed by quantitative analysis of mRNA expression by real-time PCR, revealed that glial marker transcripts were differentially expressed post-injury and that the chondroitin sulfate proteoglycans Brevican and Versican V1 and V2 were preferentially up-regulated in the dorsal root entry zone, but not the dorsal column. These results indicate that reactive gliosis differs between these two regions and that Brevican and Versican are potential key molecules participating in the highly inhibitory properties of the dorsal root entry zone.

Line bisection by eye and by hand reveal opposite biases

The vision-for-action literature favours the idea that the motor output of an action - whether manual or oculomotor - leads to similar results regarding object handling. Findings on line bisection performance challenge this idea: healthy individuals bisect lines manually to the left of centre, and to the right of centre when using eye fixation. In case that these opposite biases for manual and oculomotor action reflect more universal compensatory mechanisms that cancel each other out to enhance overall accuracy, one would like to observe comparable opposite biases for other material. In the present study, we report on three independent experiments in which we tested line bisection (by hand, by eye fixation) not only for solid lines, but also for letter lines; the latter, when bisected manually, is known to result in a rightward bias. Accordingly, we expected a leftward bias for letter lines when bisected via eye fixation. Analysis of bisection biases provided evidence for this idea: manual bisection was more rightward for letter as compared to solid lines, while bisection by eye fixation was more leftward for letter as compared to solid lines. Support for the eye fixation observation was particularly obvious in two of the three studies, for which comparability between eye and hand action was increasingly adjusted (paper-pencil versus touch screen for manual action). These findings question the assumption that ocular motor and manual output are always inter-changeable, but rather suggest that at least for some situations ocular motor and manual output biases are orthogonal to each other, possibly balancing each other out.

Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis.

Background Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era. Methods 1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy. Findings 40.0% (299/747) of the tumours harboured a KRAS mutation, 14.5% (108/743) harboured a PIK3CA mutation (of which 68.5% [74/108] were located in exon 9 and 20.4% [22/108] in exon 20), 4.7% (36/761) harboured a BRAF mutation, and 2.6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6.7% (17/253) versus 35.8% (126/352; odds ratio [OR] 0.13, 95% CI 0.07-0.22; p<0.0001), a median PFS of 12. weeks versus 24 weeks (hazard ratio [HR] 1 98, 1.66-2.36; p<0.0001), and a median overall survival of 32 weeks versus 50 weeks (1.75, 1.47-2.09; p<0.0001). In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types, with a response rate of 8.3% (2/24) in carriers of BRAF mutations versus 38.0% in BRAF wild types (124/326; OR 0.15, 95% CI 0.02-0.51; p=0.0012); and 7.7% (1/13) in carriers of NRAS mutations versus 38.1% in NRAS wild types (110/289; OR 0.14, 0.007-0.70; p=0.013). PIK3CA exon 9 mutations had no effect, whereas exon 20 mutations were associated with a worse outcome compared with wild types, with a response rate of 0.0% (0/9) versus 36.8% (121/329; OR 0.00,0.00-0.89; p=0.029), a median PFS of 11.5 weeks versus 24 weeks (HR 2.52, 1.33-4.78; p=0.013), and a median overall survival of 34 weeks versus 51 weeks (3.29, 1.60-6.74; p=0.0057). Multivariate analysis and conditional inference trees confirmed that, if KRAS is not mutated, assessing BRAF, NRAS, and PIK3CA exon 20 mutations (in that order) gives additional information about outcome. Objective response rates in our series were 24.4% in the unselected population, 36.3% in the KRAS wild-type selected population, and 41.2% in the KRAS, BRAF, NRAS, and PIK3CA exon 20 wild-type population. Interpretation While confirming the negative effect of KRAS mutations on outcome after cetuximab, we show that BRAF, NRAS, and PIK3CA,exon 20 mutations are significantly associated with a low response rate. Objective response rates could be improved by additional genotyping of BRAF, NRAS, and PIK3CA exon 20 mutations in a KRAS wild-type population.

Psychiatrie de l'enfant et de l'adolescent : une approche basée sur les preuves

L'approche basée sur les preuves, dérivée de I'evidence based medicine anglo-saxonne, offre une vision élargie de la pédopsychiatrie en permettant aux thérapeutes de s'extraire de la stricte soumission aux conclusions de la recherche pour donner à la pratique, dans une certaine mesure, la possibilité de valider des choix de prise en charge pluridisciplinaires. Alors que l'evidence based médecine s'est imposée dans la plupart des spécialités médicales, elle tarde à s'implanter en psychiatrie de l'enfant et de l'adolescent. Cet ouvrage fait donc le point sur les connaissances actuelles et propose une approche plus globale fondée sur les preuves. Les 13 chapitres qui le composent couvrent une grande partie des troubles pédopsychiatriques en y intégrant des sujets d'ouverture comme l'alliance thérapeutique, les soins sous contrainte ou les équipes mobiles. Un chapitre consacré aux médicaments psychotropes utilisés chez l'enfant et l'adolescent permet d'offrir un aperçu complet des moyens thérapeutiques à disposition pour chacun de ces troubles.

Photoaffinity labeling of the T cell receptor on cloned cytotoxic T lymphocytes by covalent photoreactive ligand.

The interaction of the T cell antigen receptor with a photoreactive antigenic peptide derivative bound covalently to the H-2Kd (Kd) molecule was studied by photoaffinity labeling on cloned, CD8 positive cytotoxic T lymphocytes. The Kd-restricted Plasmodium berghei circumsporozoite peptide 253-260 (YIPS-AEKI) was conjugated with iodo-4-azidosalicylic acid at the N terminus and with 4-azidobenzoic acid at the T cell receptor residue Lys-259. Cell-associated or soluble Kd molecules were photoaffinity-labeled with the peptide derivative by selective photoactivation of the N-terminal photoreactive group. Incubation of cell-associated or soluble covalent Kd-peptide derivative complexes (ligands) with cytotoxic T lymphocytes that recognized this peptide derivative and activation of the orthogonal photoreactive group resulted in specific photoaffinity labeling of the T cell receptor. The labeling was inhibitable by an anti-Kd antibody and was absent on Kd-restricted cytotoxic T lymphocytes of different specificity. The binding of the soluble ligand reached a maximum after 2-4 min at 37 degrees C, after 30 min at 18 degrees C, and after 3 h at 4 degrees C. In contrast, binding of the cell-associated ligand reached a transient maxima after 50 and 110 min at 37 and 18 degrees C, respectively. The degree of binding at 37 degrees C was approximately 30% lower than that at 18 degrees C. No binding took place at 4 degrees C. Inhibition studies with antibodies and drugs indicated that the binding of the cell-associated, but not the soluble ligand, was highly dependent on T cell-target cell conjugate formation, whereas the binding of the soluble ligand was greatly dependent on CD8.

On fast-decodable space-time block codes

We focus on full-rate, fast-decodable space–time block codes (STBCs) for 2 x 2 and 4 x 2 multiple-input multiple-output (MIMO) transmission. We first derive conditions and design criteria for reduced-complexity maximum-likelihood (ML) decodable 2 x 2 STBCs, and we apply them to two families of codes that were recently discovered. Next, we derive a novel reduced-complexity 4 x 2 STBC, and show that it outperforms all previously known codes with certain constellations.

Sequential estimation of multipath MIMO-OFDM channels

Wireless “MIMO” systems, employing multiple transmit and receive antennas, promise a significant increase of channel capacity, while orthogonal frequency-division multiplexing (OFDM) is attracting a good deal of attention due to its robustness to multipath fading. Thus, the combination of both techniques is an attractive proposition for radio transmission. The goal of this paper is the description and analysis of a new and novel pilot-aided estimator of multipath block-fading channels. Typical models leading to estimation algorithms assume the number of multipath components and delays to be constant (and often known), while their amplitudes are allowed to vary with time. Our estimator is focused instead on the more realistic assumption that the number of channel taps is also unknown and varies with time following a known probabilistic model. The estimation problem arising from these assumptions is solved using Random-Set Theory (RST), whereby one regards the multipath-channel response as a single set-valued random entity.Within this framework, Bayesian recursive equations determine the evolution with time of the channel estimator. Due to the lack of a closed form for the solution of Bayesian equations, a (Rao–Blackwellized) particle filter (RBPF) implementation ofthe channel estimator is advocated. Since the resulting estimator exhibits a complexity which grows exponentially with the number of multipath components, a simplified version is also introduced. Simulation results describing the performance of our channel estimator demonstrate its effectiveness.

Sequential estimation of time-varying multipath channel for MIMO-OFDM systems

In this paper, we introduce a pilot-aided multipath channel estimator for Multiple-Input Multiple-Output (MIMO) Orthogonal Frequency Division Multiplexing (OFDM) systems. Typical estimation algorithms assume the number of multipath components and delays to be known and constant, while theiramplitudes may vary in time. In this work, we focus on the more realistic assumption that also the number of channel taps is unknown and time-varying. The estimation problem arising from this assumption is solved using Random Set Theory (RST), which is a probability theory of finite sets. Due to the lack of a closed form of the optimal filter, a Rao-Blackwellized Particle Filter (RBPF) implementation of the channel estimator is derived. Simulation results demonstrate the estimator effectiveness.