Sustained activation and tumor targeting of NKT cells using a CD1d-anti-HER2-scFv fusion protein induce antitumor effects in mice

Invariant NKT (iNKT) cells are potent activators of DCs, NK cells, and T cells, and their antitumor activity has been well demonstrated. A single injection of the high-affinity CD1d ligand alpha-galactosylceramide (alphaGalCer) leads to short-lived iNKT cell activation followed, however, by long-term anergy, limiting its therapeutic use. In contrast, we demonstrated here that when alphaGalCer was loaded on a recombinant soluble CD1d molecule (alphaGalCer/sCD1d), repeated injections led to sustained iNKT and NK cell activation associated with IFN-gamma secretion as well as DC maturation in mice. Most importantly, when alphaGalCer/sCD1d was fused to a HER2-specific scFv antibody fragment, potent inhibition of experimental lung metastasis and established s.c. tumors was obtained when systemic treatment was started 2-7 days after the injection of HER2-expressing B16 melanoma cells. In contrast, administration of free alphaGalCer at this time had no effect. The antitumor activity of the CD1d-anti-HER2 fusion protein was associated with HER2-specific tumor localization and accumulation of iNKT, NK, and T cells at the tumor site. Targeting iNKT cells to the tumor site thus may activate a combined innate and adaptive immune response that may prove to be effective in cancer immunotherapy

Decision fusion for the classification of hyperspectral data: Outcome of the 2008 GRS-S data fusion contest

The 2008 Data Fusion Contest organized by the IEEE Geoscience and Remote Sensing Data Fusion Technical Committee deals with the classification of high-resolution hyperspectral data from an urban area. Unlike in the previous issues of the contest, the goal was not only to identify the best algorithm but also to provide a collaborative effort: The decision fusion of the best individual algorithms was aiming at further improving the classification performances, and the best algorithms were ranked according to their relative contribution to the decision fusion. This paper presents the five awarded algorithms and the conclusions of the contest, stressing the importance of decision fusion, dimension reduction, and supervised classification methods, such as neural networks and support vector machines.

Sequential analysis of trans-SNARE formation in intracellular membrane fusion.

SNARE complexes are required for membrane fusion in the endomembrane system. They contain coiled-coil bundles of four helices, three (Q(a), Q(b), and Q(c)) from target (t)-SNAREs and one (R) from the vesicular (v)-SNARE. NSF/Sec18 disrupts these cis-SNARE complexes, allowing reassembly of their subunits into trans-SNARE complexes and subsequent fusion. Studying these reactions in native yeast vacuoles, we found that NSF/Sec18 activates the vacuolar cis-SNARE complex by selectively displacing the vacuolar Q(a) SNARE, leaving behind a Q(bc)R subcomplex. This subcomplex serves as an acceptor for a Q(a) SNARE from the opposite membrane, leading to Q(a)-Q(bc)R trans-complexes. Activity tests of vacuoles with diagnostic distributions of inactivating mutations over the two fusion partners confirm that this distribution accounts for a major share of the fusion activity. The persistence of the Q(bc)R cis-complex and the formation of the Q(a)-Q(bc)R trans-complex are both sensitive to the Rab-GTPase inhibitor, GDI, and to mutations in the vacuolar tether complex, HOPS (HOmotypic fusion and vacuolar Protein Sorting complex). This suggests that the vacuolar Rab-GTPase, Ypt7, and HOPS restrict cis-SNARE disassembly and thereby bias trans-SNARE assembly into a preferred topology.

Multi-modal Change Detection, Application to the Detection of Flooded Areas: Outcome of the 2009-2010 data fusion contest

The 2009-2010 Data Fusion Contest organized by the Data Fusion Technical Committee of the IEEE Geoscience and Remote Sensing Society was focused on the detection of flooded areas using multi-temporal and multi-modal images. Both high spatial resolution optical and synthetic aperture radar data were provided. The goal was not only to identify the best algorithms (in terms of accuracy), but also to investigate the further improvement derived from decision fusion. This paper presents the four awarded algorithms and the conclusions of the contest, investigating both supervised and unsupervised methods and the use of multi-modal data for flood detection. Interestingly, a simple unsupervised change detection method provided similar accuracy as supervised approaches, and a digital elevation model-based predictive method yielded a comparable projected change detection map without using post-event data.

Le filtre invisible : l'obstacle du Sujet (conflits implicites dans les transferts culturels de France en Russie en philosophie)

Cette thèse est un travail de comparaison qui essaie de s'affranchir des dogmes ambiants afin de trouver une nouvelle voie, une autre façon de comprendre la culture intellectuelle en Russie. La présente recherche s'inscrit dans le cadre de l'épistémologie comparée dont l'objectif principal est d'éviter un travail par oppositions et de mettre en évidence les différences et les ressemblances des systèmes de connaissances dans deux mondes intellectuels : la Russie et le monde francophone.La question posée dans ce travail concerne le Sujet en philosophie en Russie, plus précisément la façon dominante de le voir et de le théoriser, qui joue un rôle important dans la formation de l'horizon d'attente intellectuelle. On trouve l'impact de cette attente intellectuelle particulière lors des transferts « culturels » des théories et des idées quand certaines de ces dernières passent et d'autres provoquent des résistances. Qu'est-ce qui définit alors le seuil de passage et quel obstacle [invisible ?) est la cause des malentendus ?La réponse trouvée est simple dans sa complexité : le dispositif de la *personne intégrale. Il s'agit d'un ensemble de discours et de pratiques qui valorise et rend possible certains comportements mettant en avant les idées de fusion et de collectivisme à différents niveaux de la vie sociale, par rapport à l'homme et à ses relations dans la société, et décourageant les idées d'individualisme au sens large du terme.Le dispositif de la *personne intégrale nous a permis de constater et d'expliquer une certaine continuité des valeurs et de la doxa dans les théories du Sujet au XIXe siècle en Russie, à l'époque soviétique et après la dissolution de l'URSS, ce qui, à première vue, pouvait paraître paradoxal. Les ruptures idéologiques importantes qu'a connues la Russie auraient dû susciter des changements dans la vision du Sujet. Or, d'une façon étonnante, aussi bien les slavophiles, les anarchistes que les marxistes soviétiques cherchaient à construire une théorie du Sujet fondée sur les principes d'organicisme, d'intégralité et d'ontologisme. Autrement dit, la conception matérialiste du Sujet à l'époque soviétique n'était pas fondamentalement distincte de celle que le XIXe siècle lui avait léguée. C'est la raison pour laquelle la période postsoviétique manifeste autant d'intérêt pour les valeurs d'intégralité, d'organisme vivant et d'ontologisme, qui trouvent leur place dans une grande partie des critiques adressées aux idées « postmodernes » proclamant une tout autre façon de voir les choses : le décentrement, la déconstruction, le multiple et l'hétérogène, ce qui ne peut que provoquer un grave conflit de valeurs.Il y avait une énigme à résoudre : qu'est-ce qui fait obstacle à la réception des théories du Sujet divisé ? Cette énigme, nous avons essayé de l'élucider en rassemblant patiemment les bribes entrelacées d'un gigantesque tissu, en tentant d'en montrer la paradoxale cohérence. Un autre travail reste à faire, qui consisterait à construire une hypothèse autrement hardie, celle qui saurait expliquer pourquoi un tel dispositif s'est mis en place en Russie à cette époque et pas ailleurs.

Fusion telomérique de deux chromosomes X par leurs bras courts chez une patiente présentant un syndrome de Turner atypique. [Telomeric fusion of the short arms of both X chromosomes in a patient presenting an atypical Turner syndrome.]

A case of atypical Turner's syndrome with unusual karyotype is reported. The chromosome complements of the patient, studied with different banding techniques, is 45,XO/46,X,dic(X)(Xqter leads to p22::p22 leads to qter). In the literature 8 similar cases have been reported. Short stature and amenorrhea are the most constant findings. The mechanisms by which the observed chromosomal "rearrangement" can be produced are briefly discussed.

Weighted Shape-based Averaging with Neighborhood Prior Model for Multiple Atlas Fusion-based Medical Image Segmentation

In medical imaging, merging automated segmentations obtained from multiple atlases has become a standard practice for improving the accuracy. In this letter, we propose two new fusion methods: "Global Weighted Shape-Based Averaging" (GWSBA) and "Local Weighted Shape-Based Averaging" (LWSBA). These methods extend the well known Shape-Based Averaging (SBA) by additionally incorporating the similarity information between the reference (i.e., atlas) images and the target image to be segmented. We also propose a new spatially-varying similarity-weighted neighborhood prior model, and an edge-preserving smoothness term that can be used with many of the existing fusion methods. We first present our new Markov Random Field (MRF) based fusion framework that models the above mentioned information. The proposed methods are evaluated in the context of segmentation of lymph nodes in the head and neck 3D CT images, and they resulted in more accurate segmentations compared to the existing SBA.

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.

Landmark detection for fusion of fundus and MRI toward a patient-specific multimodal eye model.

Ophthalmologists typically acquire different image modalities to diagnose eye pathologies. They comprise, e.g., Fundus photography, optical coherence tomography, computed tomography, and magnetic resonance imaging (MRI). Yet, these images are often complementary and do express the same pathologies in a different way. Some pathologies are only visible in a particular modality. Thus, it is beneficial for the ophthalmologist to have these modalities fused into a single patient-specific model. The goal of this paper is a fusion of Fundus photography with segmented MRI volumes. This adds information to MRI that was not visible before like vessels and the macula. This paper contributions include automatic detection of the optic disc, the fovea, the optic axis, and an automatic segmentation of the vitreous humor of the eye.

Use of an empty, Plasmapore-covered titanium cage for interbody fusion after anterior cervical microdiscectomy.

The use of cages of different material and shapes for cervical discectomy with fusion (ACDF) has increased during the last few years. The use of additional osteogenic material is controversial. We prospectively evaluated an empty, Plasmapore-covered titanium cage (PCTC) in 45 patients undergoing 58 ACDFs. Patients were evaluated using standard clinical and radiological criteria. Good to excellent outcome was achieved in 93%, 78% and 75% after 3, 12 and 48 months, respectively. Sixty-five percent of patients could resume their prior work after 48 months. Disc space height and lordosis could be preserved in all cases. Two percent of the treated levels showed subsidence and 2% increased segmental motion. There were no procedure-related complications. Implantation of an empty PCTC after microsurgical anterior cervical discectomy is a safe procedure with good results and low incidence of complications. Disc height and lordosis can be preserved with low incidence of subsidence and good fusion rates.

The SM protein Vps33 and the t-SNARE H(abc) domain promote fusion pore opening.

Intracellular membrane fusion proceeds via distinct stages of membrane docking, hemifusion and fusion pore opening and depends on interacting families of Rab, SNARE and SM proteins. Trans-SNARE complexes dock the membranes in close apposition. Efficient fusion requires further SNARE-associated proteins. They might increase the number of trans-SNARE complexes or the fusogenic potential of a single SNARE complex. We investigated the contributions of the SM protein Vps33 to hemifusion and pore opening between yeast vacuoles. Mutations in Vps33 that weaken its interactions with the SNARE complex allowed normal trans-SNARE pairing and lipid mixing but retarded content mixing. Deleting the H(abc) domain of the vacuolar t-SNARE Vam3, which interacts with Vps33, had the same effect. This suggests that SM proteins promote fusion pore opening by enhancing the fusogenic activity of a SNARE complex. They should thus be considered integral parts of the fusion machinery.

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.

Model-based Segmentation and Fusion of 3D Computed Tomography and 3D Ultrasound of the Eye for Radiotherapy Planning

Computed Tomography (CT) represents the standard imaging modality for tumor volume delineation for radiotherapy treatment planning of retinoblastoma despite some inherent limitations. CT scan is very useful in providing information on physical density for dose calculation and morphological volumetric information but presents a low sensitivity in assessing the tumor viability. On the other hand, 3D ultrasound (US) allows a highly accurate definition of the tumor volume thanks to its high spatial resolution but it is not currently integrated in the treatment planning but used only for diagnosis and follow-up. Our ultimate goal is an automatic segmentation of gross tumor volume (GTV) in the 3D US, the segmentation of the organs at risk (OAR) in the CT and the registration of both modalities. In this paper, we present some preliminary results in this direction. We present 3D active contour-based segmentation of the eye ball and the lens in CT images; the presented approach incorporates the prior knowledge of the anatomy by using a 3D geometrical eye model. The automated segmentation results are validated by comparing with manual segmentations. Then, we present two approaches for the fusion of 3D CT and US images: (i) landmark-based transformation, and (ii) object-based transformation that makes use of eye ball contour information on CT and US images.