Artus Krohn-Grimberghe

Dopamine gene predicts the brain's response to dopaminergic drug

Dopamine is critical for reward‐based decision making, yet dopaminergic drugs can have opposite effects in different individuals. This apparent discrepancy can be accounted for by hypothesizing an ‘inverted‐U’ relationship, whereby the effect of dopamine agents depends on baseline dopamine system functioning. Here, we used functional MRI to test the hypothesis that genetic variation in the expression of dopamine D2 receptors in the human brain predicts opposing dopaminergic drug effects during reversal learning. We scanned 22 subjects while they engaged in a feedback‐based reversal learning task. Ten subjects had an allele on the Taq1A DRD2 gene, which is associated with reduced dopamine receptor concentration and decreased neural responses to rewards (A1+ subjects). Subjects were scanned twice, once on placebo and once on cabergoline, a D2 receptor agonist. Consistent with an inverted‐U relationship between the DRD2 polymorphism and drug effects, cabergoline increased neural reward responses in the medial orbitofrontal cortex, cingulate cortex and striatum for A1+ subjects but decreased reward responses in these regions for A1– subjects. In contrast, cabergoline decreased task performance and fronto‐striatal connectivity in A1+ subjects but had the opposite effect in A1– subjects. Further, the drug effect on functional connectivity predicted the drug effect on feedback‐guided learning. Thus, individual variability in how dopaminergic drugs affect the brain reflects genetic disposition. These findings may help to explain the link between genetic disposition and risk for addictive disorders.

Deformation styles for spline-based skeletal animation

We present a novel skinned skeletal animation system based on spline-aligned deformations for providing high quality and fully designable deformations in real-time. Our ambition is to allow artists the easy creation of abstract, pose-dependent deformation behaviors that might directly be assigned to a large variety of target objects simultaneously. To achieve this goal, we introduce the usage of deformation styles and demonstrate their applicability by our animation system. We therefore enhance spline-skinned skeletal animation with two sweep-based free-form-deformation (FFD) variants. The two FFD variants are pose-dependent, driven by three textures and three curves, which can be designed by the artist. As the three textures are similar to height-maps, their creation is very intuitive. Once designed, the deformation styles can be directly applied to any number of targets for imitating material behaviors of cloth, metal or even muscles. Our GPU based implementation shows promising results for real-time usage, as about 30 Million vertices per second can be animated. The basic spline-skinning even reaches more than twice the speed and gets close to the performance of skeletal subspace deformation (SSD). Furthermore, our method can easily be combined along with other existing deformation techniques as pose space deformation or SSD.

Monitoring multiple myeloma by next-generation sequencing of V(D)J rearrangements from circulating myeloma cells and cell-free myeloma DNA.

Recent studies suggest that circulating tumor cells and cell-free DNA may represent powerful non-invasive tools for monitoring disease in patients with solid and hematologic malignancies. Here, we conducted a pilot study in 27 myeloma patients to explore the clonotypic V(D)J rearrangement for monitoring circulating myeloma cells and cell-free myeloma DNA. Next-generation sequencing was used to define the myeloma V(D)J rearrangement and for subsequent peripheral blood tracking after treatment initiation. Positivity for circulating myeloma cells/cell-free myeloma was associated with conventional remission status (P<0.001) and 91% of non-responders/progressors versus 41% of responders had evidence of persistent circulating myeloma cells/cell-free myeloma DNA (P<0.001). About half of the partial responders showed complete clearance of circulating myeloma cells/cell-free myeloma DNA despite persistent M-protein, suggesting that these markers are less inert than the M-protein, rely more on cell turnover and, therefore, decline more rapidly after initiation of effective treatment. Positivity for circulating myeloma cells and for cell-free myeloma DNA were associated with each other (P=0.042), but discordant in 30% of cases. This indicates that cell-free myeloma DNA may not be generated entirely by circulating myeloma cells and may reflect overall tumor burden. Prospective studies need to define the predictive potential of high-sensitivity determination of circulating myeloma cells and DNA in the monitoring of multiple myeloma.

Clinical response to ibrutinib is accompanied by normalization of the T-cell environment in CLL-related autoimmune cytopenia

Clinical response to ibrutinib is accompanied by normalization of the T-cell environment in CLL-related autoimmune cytopenia

T-cell diversification reflects antigen selection in the blood of patients on immune checkpoint inhibition and may be exploited as liquid biopsy biomarker.

Cancer immunotherapy with antibodies targeting immune checkpoints, such as programmed cell death protein 1 (PD‐1), shows encouraging results, but reliable biomarkers predicting response to this costly and potentially toxic treatment approach are still lacking. To explore an immune signature predictive for response, we performed liquid biopsy immunoprofiling in 18 cancer patients undergoing PD‐1 inhibition before and shortly after initiation of treatment by multicolor flow cytometry and next‐generation T‐ and B‐cell immunosequencing (TCRß/IGH). Findings were correlated with clinical outcomes. We found almost complete saturation of surface PD‐1 on all T‐cell subsets after the first dose of the antibody. Both T‐ and B‐cell compartments quantitatively expanded during treatment. These expansions were mainly driven by an increase in the activated T‐cell compartments, as well as of naïve B‐ and plasma cells. Deep immunosequencing revealed a clear diversification pattern of the clonal T‐cell space indicative of antigenic selection in 47% of patients, while the remaining patients showed stable repertoires. 43% of the patients with a diversification pattern showed disease control in response to the PD‐1 inhibitor. No disease stabilizations were observed without clonal T‐cell space diversification. Our data show for the first time a clear impact of PD‐1 targeting not only on circulating T‐cells, but also on B‐lineage cells, shedding light on the complexity of the anti‐tumor immune response. Liquid biopsy T‐cell next‐generation immunosequencing should be prospectively evaluated as part of a composite response prediction biomarker panel in the context of clinical studies.

Active learning for technology enhanced learning

Suggesting tasks and learning resources of appropriate difficulty to learners is challenging. Neither should they be too difficult and nor too easy. Well-chosen tasks would enable a quick assessment of the learner, well-chosen learning resources would speed up the learning curve most. We connect active learning to classical pedagogical theory and propose the uncertainty sampling framework as a means to the challenge of selecting optimal tasks and learning resources to learners. To assess the efficiency of this strategy, we compared different exercise selection strategies and evaluated their effect on different datasets. We consistently find that uncertainty sampling significantly outperforms several alternative exercise selection approaches and thus leads to a faster convergence to the true assessment. These findings demonstrate that active (machine) learning is consistent with classic learning theory. It is a valuable instrument for choosing appropriate exercises as well as learning resources both from a teachers and from a learners perspective.

Bitcoin: Eine erste Einordnung

ZusammenfassungBitcoins bewegen seit Anfang 2009 die Gemüter: Wie ist das System zu bewerten? Welche Risiken birgt die Nutzung als Zahlungssystem — und was steckt technisch dahinter? Die Autoren stellen das Bitcoin-Verfahren vor und wagen eine erste Einschätzung.

Computer Vision for Head Pose Estimation: Review of a Competition

This paper studies the prediction of head pose from still images, and summarizes the outcome of a recently organized competition, where the task was to predict the yaw and pitch angles of an image dataset with 2790 samples with known angles. The competition received 292 entries from 52 participants, the best ones clearly exceeding the state-of-the-art accuracy. In this paper, we present the key methodologies behind selected top methods, summarize their prediction accuracy and compare with the current state of the art.

Integrating OLAP and recommender systems: an evaluation perspective

The integration of OLAP with web-search technologies is a promising research topic. Recommender systems are popular web-search mechanisms, because they can address information overload and provide personalization of results. Nevertheless, the evaluation of recommender systems is a challenging task. In this paper, we propose a novel framework for evaluating recommender systems, which is multidimensional and takes into account for the multiple facets of the recommendation algorithms, data sets and performance measures. Emphasis is placed on supporting business applications of recommender systems, notably e-commerce, by allowing analysts to perform ad-hoc analysis and use popular online analytical processing (OLAP) operations. Combined with support for visual analysis, action such as drill-down or slice/dice allow assessment of the performance of recommendations in terms of business objectives. We describe a detailed methodology for designing and developing the proposed multidimensional framework, and provide insights about its applications. Our experimental results, using a research prototype, demonstrate the ability of the proposed framework to comprise an effective way for evaluating recommender systems.

Dynamic changes of the normal B lymphocyte repertoire in CLL in response to ibrutinib or FCR chemo-immunotherapy

ABSTRACT Using next-generation immunoglobulin (IGH) sequencing and flow cytometry, we characterized the composition, diversity and dynamics of non-malignant B cells in patients undergoing treatment with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib or chemo-immunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR). During ibrutinib therapy, non-malignant B cell numbers declined, but patients maintained stable IGH diversity and constant fractions of IGH-mutated B cells. This indicates partial preservation of antigen-experienced B cells during ibrutinib therapy, but impaired replenishment of the normal B cell pool with naïve B cells. In contrast, after FCR we noted a recovery of normal B cells with a marked predominance of B cells with unmutated IGH. This pattern is compatible with a deletion of pre-existing antigen-experienced B cells followed by repertoire renewal with antigen-naïve B cells. These opposite patterns in B cell dynamics may result in different responses towards neoantigens versus recall antigens, which need to be further defined.