EPMA position paper in cancer:current overview and future perspectives

At present, a radical shift in cancer treatment is occurring in terms of predictive, preventive, and personalized medicine (PPPM). Individual patients will participate in more aspects of their healthcare. During the development of PPPM, many rapid, specific, and sensitive new methods for earlier detection of cancer will result in more efficient management of the patient and hence a better quality of life. Coordination of the various activities among different healthcare professionals in primary, secondary, and tertiary care requires well-defined competencies, implementation of training and educational programs, sharing of data, and harmonized guidelines. In this position paper, the current knowledge to understand cancer predisposition and risk factors, the cellular biology of cancer, predictive markers and treatment outcome, the improvement in technologies in screening and diagnosis, and provision of better drug development solutions are discussed in the context of a better implementation of personalized medicine. Recognition of the major risk factors for cancer initiation is the key for preventive strategies (EPMA J. 4(1):6, 2013). Of interest, cancer predisposing syndromes in particular the monogenic subtypes that lead to cancer progression are well defined and one should focus on implementation strategies to identify individuals at risk to allow preventive measures and early screening/diagnosis. Implementation of such measures is disturbed by improper use of the data, with breach of data protection as one of the risks to be heavily controlled. Population screening requires in depth cost-benefit analysis to justify healthcare costs, and the parameters screened should provide information that allow an actionable and deliverable solution, for better healthcare provision

Contributions à la segmentation d'image : phase locale et modèles statistiques

Ce document presente une synthèse de mes travaux apres these, principalement sur la problematique de la segmentation d’images

Mesh adaptation for pseudospectral ultrasound simulations

High-intensity focussed ultrasound (HIFU) is an emerging cancer therapy that holds great promise, as it is minimially invasive, requires no ionising radiation, and can treat small volumes precisely. However, currently therapies are hindered by an inadequate capacity for treatment planning, as the interactions between the sound waves and tissue are complex and difficult to simulate. The Fourier pseudospectral method is one way of efficiently performing these simulations, as it can provide high accuracies with low computational costs. However, it is typically used with uniform computational meshes, wasting resolution in regions of the simulation where only low frequencies are present, and typically under-resolving the acoustic field in the focal region. This thesis addresses this problem in two ways: First, a bandwidth-based measure of the spatial resolution requirements for a model solution is developed and integrated into a moving mesh method. This allows spatially and temporally-varying resolution requirements to be met. Bandwidth-based meshes are shown to perform very well when compared with current mesh adaptation approaches. Second, a technique is presented for discretising arbitrary acoustic source distributions that does not rely on the source's region of support coinciding with the mesh. This not only allows sources to be represented with adaptive meshes, but greatly improves the accuracy of source discretisations for uniform meshes as well. These two contributions are of vital importance in the context of HIFU simulation, and can easily be applied to the many other problems for which the Fourier pseudospectral method is used

3D head motion, point-of-regard and encoded gaze fixations in real scenes: next-generation portable video-based monocular eye tracking

Portable eye trackers allow us to see where a subject is looking when performing a natural task with free head and body movements. These eye trackers include headgear containing a camera directed at one of the subject\u27s eyes (the eye camera) and another camera (the scene camera) positioned above the same eye directed along the subject\u27s line-of-sight. The output video includes the scene video with a crosshair depicting where the subject is looking -- the point-of-regard (POR) -- that is updated for each frame. This video may be the desired final result or it may be further analyzed to obtain more specific information about the subject\u27s visual strategies. A list of the calculated POR positions in the scene video can also be analyzed. The goals of this project are to expand the information that we can obtain from a portable video-based monocular eye tracker and to minimize the amount of user interaction required to obtain and analyze this information. This work includes offline processing of both the eye and scene videos to obtain robust 2D PORs in scene video frames, identify gaze fixations from these PORs, obtain 3D head motion and ray trace fixations through volumes-of-interest (VOIs) to determine what is being fixated, when and where (3D POR). To avoid the redundancy of ray tracing a 2D POR in every video frame and to group these POR data meaningfully, a fixation-identification algorithm is employed to simplify the long list of 2D POR data into gaze fixations. In order to ray trace these fixations, the 3D motion -- position and orientation over time -- of the scene camera is computed. This camera motion is determined via an iterative structure and motion recovery algorithm that requires a calibrated camera and knowledge of the 3D location of at least four points in the scene (that can be selected from premeasured VOI vertices). The subjects 3D head motion is obtained directly from this camera motion. For the final stage of the algorithm, the 3D locations and dimensions of VOIs in the scene are required. This VOI information in world coordinates is converted to camera coordinates for ray tracing. A representative 2D POR position for each fixation is converted from image coordinates to the same camera coordinate system. Then, a ray is traced from the camera center through this position to determine which (if any) VOI is being fixated and where it is being fixated -- the 3D POR in the world. Results are presented for various real scenes. Novel visualizations of portable eye tracker data created using the results of our algorithm are also presented

From Underactuation to Quasi‐Full Actuation: A Unifying Control Framework for Rigid and Elastic Joint Robot

The quest for animal-like performance in robots has driven the integration of elastic elements in their drive trains, sparking a revolution in robot design. Elastic robots can store and release potential energy, providing distinct advantages over traditional robots, such as enhanced safety in human-robot interaction, resilience to mechanical shocks, improved energy efficiency in cyclic tasks, and dynamic motion capabilities. Exploiting their full potential, however, necessitates novel control methods. This thesis advances the field of nonlinear control for underactuated systems and utilizes the results to push the boundaries of motion and interaction performance of elastic robots. Through real-life experiments and applications, the proposed controllers demonstrate that compliant robots hold promise as groundbreaking robotic technology. To achieve these objectives, we first derive a simultaneous phase space and input transformation that enables a specific class of underactuated Lagrangian systems to be treated as if fully actuated. These systems can be represented as the interconnection of actuated and underactuated subsystems, with the kinetic energy of each subsystem depending only on its own velocity. Elastic robots are typical representatives. We refer to the transformed system as quasi-fully actuated due to weak constraints on the new inputs. Fundamental aspects of the transforming equations are 1) the same Lagrangian function characterizes both the original and transformed systems, 2) the transformed system establishes a passive mapping between inputs and outputs, and 3) the solutions of both systems are in a one-to-one correspondence, describing the same physical reality. This correspondence allows us to study and control the behavior of the quasi-fully actuated system instead of the underactuated one. Thus, this approach unifies the control design for rigid and elastic joint robots, enabling the direct application of control results inherited from the fully-actuated case while ensuring closed-loop system stability and passivity. Unlike existing methods, the quasi-full actuation concept does not rely on inner control loops or the neglect and cancellation of dynamics. Notably, as joint stiffness values approach infinity, the control equivalent of a rigid robot is recovered. Building upon the quasi-full actuation concept, we extend energy-based control schemes such as energy shaping and damping injection, Euler-Lagrange controllers, and impedance control. Moreover, we introduce Elastic Structure Preserving (ESP) control, a passivity-based control scheme designed for robots with elastic or viscoelastic joints, guided by the principle of ``do as little as possible''. The underlying hope is that reducing the system shaping, i.e., having a closed-loop dynamics match in some way the robot's intrinsic structure, will award high performance with little control effort. By minimizing the system shaping, we obtain low-gain designs, which are favorable concerning robustness and facilitate the emergence of natural motions. A comparison with state-of-the-art controllers highlights the minimalistic nature of ESP control. Additionally, we present a synthesis method, based on purely geometric arguments, for achieving time-optimal rest-to-rest motions of an elastic joint with bounded input. Finally, we showcase the remarkable performance and robustness of the proposed ESP controllers on DLR David, an anthropomorphic robot implemented with variable impedance actuators. Experimental evidence reveals that ESP designs enable safe and compliant interaction with the environment and rigid-robot-level accuracy in free motion. Additionally, we introduce a control framework that allows DLR David to perform commercially relevant tasks, such as pick and place, teleoperation, hammer drilling into a concrete block, and unloading a dishwasher. The successful execution of these tasks provides compelling evidence that compliant robots have a promising future in commercial applications

The Role of Mutations in Protein Structural Dynamics and Function: A Multi-scale Computational Approach

abstract: Proteins are a fundamental unit in biology. Although proteins have been extensively studied, there is still much to investigate. The mechanism by which proteins fold into their native state, how evolution shapes structural dynamics, and the dynamic mechanisms of many diseases are not well understood. In this thesis, protein folding is explored using a multi-scale modeling method including (i) geometric constraint based simulations that efficiently search for native like topologies and (ii) reservoir replica exchange molecular dynamics, which identify the low free energy structures and refines these structures toward the native conformation. A test set of eight proteins and three ancestral steroid receptor proteins are folded to 2.7Å all-atom RMSD from their experimental crystal structures. Protein evolution and disease associated mutations (DAMs) are most commonly studied by in silico multiple sequence alignment methods. Here, however, the structural dynamics are incorporated to give insight into the evolution of three ancestral proteins and the mechanism of several diseases in human ferritin protein. The differences in conformational dynamics of these evolutionary related, functionally diverged ancestral steroid receptor proteins are investigated by obtaining the most collective motion through essential dynamics. Strikingly, this analysis shows that evolutionary diverged proteins of the same family do not share the same dynamic subspace. Rather, those sharing the same function are simultaneously clustered together and distant from those functionally diverged homologs. This dynamics analysis also identifies 77% of mutations (functional and permissive) necessary to evolve new function. In silico methods for prediction of DAMs rely on differences in evolution rate due to purifying selection and therefore the accuracy of DAM prediction decreases at fast and slow evolvable sites. Here, we investigate structural dynamics through computing the contribution of each residue to the biologically relevant fluctuations and from this define a metric: the dynamic stability index (DSI). Using DSI we study the mechanism for three diseases observed in the human ferritin protein. The T30I and R40G DAMs show a loss of dynamic stability at the C-terminus helix and nearby regulatory loop, agreeing with experimental results implicating the same regulatory loop as a cause in cataracts syndrome.Dissertation/ThesisPh.D. Physics 201