Identification of Methylated Genes Associated with Aggressive Clinicopathological Features in Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is genetically characterized by the t(11;14)(q13;q32) translocation and a high number of secondary chromosomal alterations. The contribution of DNA methylation to MCL lymphomagenesis is not well known. We sought to identify epigenetically silenced genes in these tumours that might have clinical relevance. Methodology/Principal Findings: To identify potential methylated genes in MCL we initially investigated seven MCL cell lines treated with epigenetic drugs and gene expression microarray profiling. The methylation status of selected candidate genes was validated by a quantitative assay and subsequently analyzed in a series of primary MCL (n=38). After pharmacological reversion we identified 252 potentially methylated genes. The methylation analysis of a subset of these genes (n=25) in the MCL cell lines and normal B lymphocytes confirmed that 80% of them were methylated in the cell lines but not in normal lymphocytes. The subsequent analysis in primary MCL identified five genes (SOX9,HOXA9,AHR,NR2F2 ,and ROBO1) frequently methylated in these tumours. The gene methylation events tended to occur in the same primary neoplasms and correlated with higher proliferation, increased number of chromosomal abnormalities, and shorter survival of the patients. Conclusions: We have identified a set of genes whose methylation degree and gene expression levels correlate with aggressive clinicopathological features of MCL. Our findings also suggest that a subset of MCL might show a CpG island methylator phenotype (CIMP) that may influence the behaviour of the tumours.

Beaming into the rat world: enabling real-time intereaction between rat and human each at their own scale

Immersive virtual reality (IVR) typically generates the illusion in participants that they are in the displayed virtual scene where they can experience and interact in events as if they were really happening. Teleoperator (TO) systems place people at a remote physical destination embodied as a robotic device, and where typically participants have the sensation of being at the destination, with the ability to interact with entities there. In this paper, we show how to combine IVR and TO to allow a new class of application. The participant in the IVR is represented in the destination by a physical robot (TO) and simultaneously the remote place and entities within it are represented to the participant in the IVR. Hence, the IVR participant has a normal virtual reality experience, but where his or her actions and behaviour control the remote robot and can therefore have physical consequences. Here, we show how such a system can be deployed to allow a human and a rat to operate together, but the human interacting with the rat on a human scale, and the rat interacting with the human on the rat scale. The human is represented in a rat arena by a small robot that is slaved to the human"s movements, whereas the tracked rat is represented to the human in the virtual reality by a humanoid avatar. We describe the system and also a study that was designed to test whether humans can successfully play a game with the rat. The results show that the system functioned well and that the humans were able to interact with the rat to fulfil the tasks of the game. This system opens up the possibility of new applications in the life sciences involving participant observation of and interaction with animals but at human scale.

Identification and prospective validation of clinically relevant chronic obstructive pulmonary disease (COPD) subtypes.

Background Chronic obstructive pulmonary disease (COPD) is increasingly considered a heterogeneous condition. It was hypothesised that COPD, as currently defined, includes different clinically relevant subtypes. Methods To identify and validate COPD subtypes, 342 subjects hospitalised for the first time because of a COPD exacerbation were recruited. Three months after discharge, when clinically stable, symptoms and quality of life, lung function, exercise capacity, nutritional status, biomarkers of systemic and bronchial inflammation, sputum microbiology, CT of the thorax and echocardiography were assessed. COPD groups were identified by partitioning cluster analysis and validated prospectively against cause-specific hospitalisations and all-cause mortality during a 4 year follow-up. Results Three COPD groups were identified: group 1 (n ¼ 126, 67 years) was characterised by severe airflow limitation (postbronchodilator forced expiratory volume in 1 s (FEV 1 ) 38% predicted) and worse performance in most of the respiratory domains of the disease; group 2 (n ¼ 125, 69 years) showed milder airflow limitation (FEV 1 63% predicted); and group 3 (n ¼ 91, 67 years) combined a similarly milder airflow limitation (FEV 1 58% predicted) with a high proportion of obesity, cardiovascular disorders, iabetes and systemic inflammation. During follow-up, group 1 had more frequent hospitalisations due to COPD (HR 3.28, p < 0.001) and higher all-cause mortality (HR 2.36, p ¼ 0.018) than the other two groups, whereas group 3 had more admissions due to cardiovascular disease (HR 2.87, p ¼ 0.014). Conclusions In patients with COPD recruited at their first hospitalisation, three different COPD subtypes were identified and prospectively validated:"severe respiratory COPD","moderate respiratory COPD", and"systemic COPD'

Acting Rehearsal in Collaborative Multimodal Mixed Reality Environments

This paper presents the use of our multimodal mixed reality telecommunication system to support remote acting rehearsal. The rehearsals involved two actors, located in London and Barcelona, and a director in another location in London. This triadic audiovisual telecommunication was performed in a spatial and multimodal collaborative mixed reality environment based on the 'destination-visitor' paradigm, which we define and put into use. We detail our heterogeneous system architecture, which spans the three distributed and technologically asymmetric sites, and features a range of capture, display, and transmission technologies. The actors' and director's experience of rehearsing a scene via the system are then discussed, exploring successes and failures of this heterogeneous form of telecollaboration. Overall, the common spatial frame of reference presented by the system to all parties was highly conducive to theatrical acting and directing, allowing blocking, gross gesture, and unambiguous instruction to be issued. The relative inexpressivity of the actors' embodiments was identified as the central limitation of the telecommunication, meaning that moments relying on performing and reacting to consequential facial expression and subtle gesture were less successful.

Touching the void: exploring virtual objects through a vibrotactile glove

This paper describes a simple low-cost approach toadding an element of haptic interaction within a virtualenvironment. Using off-the-shelf hardware and software wedescribe a simple setup that can be used to explore physically virtual objects in space. This setup comprises of a prototype glove with a number of vibrating actuators to provide the haptic feedback, a Kinect camera for the tracking of the user's hand and a virtual reality development environment. As proof of concept and to test the efficiency of the system as well as its potential applications, we developed a simple application where we created 4 different shapes within a virtual environment in order to try toexplore them and guess their shape through touch alone.

Acting rehearsal in collaborative multimodal mixed reality environments

This paper presents the use of our multimodal mixed reality telecommunication system to support remote acting rehearsal. The rehearsals involved two actors, located in London and Barcelona, and a director in another location in London. This triadic audiovisual telecommunication was performed in a spatial and multimodal collaborative mixed reality environment based on the 'destination-visitor' paradigm, which we define and put into use. We detail our heterogeneous system architecture, which spans the three distributed and technologically asymmetric sites, and features a range of capture, display, and transmission technologies. The actors' and director's experience of rehearsing a scene via the system are then discussed, exploring successes and failures of this heterogeneous form of telecollaboration. Overall, the common spatial frame of reference presented by the system to all parties was highly conducive to theatrical acting and directing, allowing blocking, gross gesture, and unambiguous instruction to be issued. The relative inexpressivity of the actors' embodiments was identified as the central limitation of the telecommunication, meaning that moments relying on performing and reacting to consequential facial expression and subtle gesture were less successful.

Beaming into the rat world: enabling real-time intereaction between rat and human each at their own scale

Immersive virtual reality (IVR) typically generates the illusion in participants that they are in the displayed virtual scene where they can experience and interact in events as if they were really happening. Teleoperator (TO) systems place people at a remote physical destination embodied as a robotic device, and where typically participants have the sensation of being at the destination, with the ability to interact with entities there. In this paper, we show how to combine IVR and TO to allow a new class of application. The participant in the IVR is represented in the destination by a physical robot (TO) and simultaneously the remote place and entities within it are represented to the participant in the IVR. Hence, the IVR participant has a normal virtual reality experience, but where his or her actions and behaviour control the remote robot and can therefore have physical consequences. Here, we show how such a system can be deployed to allow a human and a rat to operate together, but the human interacting with the rat on a human scale, and the rat interacting with the human on the rat scale. The human is represented in a rat arena by a small robot that is slaved to the human"s movements, whereas the tracked rat is represented to the human in the virtual reality by a humanoid avatar. We describe the system and also a study that was designed to test whether humans can successfully play a game with the rat. The results show that the system functioned well and that the humans were able to interact with the rat to fulfil the tasks of the game. This system opens up the possibility of new applications in the life sciences involving participant observation of and interaction with animals but at human scale.

Beaming into the rat world: enabling real-time intereaction between rat and human each at their own scale

Immersive virtual reality (IVR) typically generates the illusion in participants that they are in the displayed virtual scene where they can experience and interact in events as if they were really happening. Teleoperator (TO) systems place people at a remote physical destination embodied as a robotic device, and where typically participants have the sensation of being at the destination, with the ability to interact with entities there. In this paper, we show how to combine IVR and TO to allow a new class of application. The participant in the IVR is represented in the destination by a physical robot (TO) and simultaneously the remote place and entities within it are represented to the participant in the IVR. Hence, the IVR participant has a normal virtual reality experience, but where his or her actions and behaviour control the remote robot and can therefore have physical consequences. Here, we show how such a system can be deployed to allow a human and a rat to operate together, but the human interacting with the rat on a human scale, and the rat interacting with the human on the rat scale. The human is represented in a rat arena by a small robot that is slaved to the human"s movements, whereas the tracked rat is represented to the human in the virtual reality by a humanoid avatar. We describe the system and also a study that was designed to test whether humans can successfully play a game with the rat. The results show that the system functioned well and that the humans were able to interact with the rat to fulfil the tasks of the game. This system opens up the possibility of new applications in the life sciences involving participant observation of and interaction with animals but at human scale.

Pathophysiology of muscle dysfunction in COPD

Muscle dysfunction often occurs in patients with chronic obstructive pulmonary disease (COPD) and may involve both respiratory and locomotor (peripheral) muscles. The loss of strength and/or endurance in the former can lead to ventilatory insufficiency, whereas in the latter it limits exercise capacity and activities of daily life. Muscle dysfunction is the consequence of complex interactions between local and systemic factors, frequently coexisting in COPD patients. Pulmonary hyperinflation along with the increase in work of breathing that occur in COPD appear as the main contributing factors to respiratory muscle dysfunction. By contrast, deconditioning seems to play a key role in peripheral muscle dysfunction. However, additional systemic factors, including tobacco smoking, systemic inflammation, exercise, exacerbations, nutritional and gas exchange abnormalities, anabolic insufficiency, comorbidities and drugs, can also influence the function of both respiratory and peripheral muscles, by inducing modifications in their local microenvironment. Under all these circumstances, protein metabolism imbalance, oxidative stress, inflammatory events, as well as muscle injury may occur, determining the final structure and modulating the function of different muscle groups. Respiratory muscles show signs of injury as well as an increase in several elements involved in aerobic metabolism (proportion of type I fibers, capillary density, and aerobic enzyme activity) whereas limb muscles exhibit a loss of the same elements, injury, and a reduction in fiber size. In the present review we examine the current state of the art of the pathophysiology of muscle dysfunction in COPD.

Identification of Methylated Genes Associated with Aggressive Clinicopathological Features in Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is genetically characterized by the t(11;14)(q13;q32) translocation and a high number of secondary chromosomal alterations. The contribution of DNA methylation to MCL lymphomagenesis is not well known. We sought to identify epigenetically silenced genes in these tumours that might have clinical relevance. Methodology/Principal Findings: To identify potential methylated genes in MCL we initially investigated seven MCL cell lines treated with epigenetic drugs and gene expression microarray profiling. The methylation status of selected candidate genes was validated by a quantitative assay and subsequently analyzed in a series of primary MCL (n=38). After pharmacological reversion we identified 252 potentially methylated genes. The methylation analysis of a subset of these genes (n=25) in the MCL cell lines and normal B lymphocytes confirmed that 80% of them were methylated in the cell lines but not in normal lymphocytes. The subsequent analysis in primary MCL identified five genes (SOX9,HOXA9,AHR,NR2F2 ,and ROBO1) frequently methylated in these tumours. The gene methylation events tended to occur in the same primary neoplasms and correlated with higher proliferation, increased number of chromosomal abnormalities, and shorter survival of the patients. Conclusions: We have identified a set of genes whose methylation degree and gene expression levels correlate with aggressive clinicopathological features of MCL. Our findings also suggest that a subset of MCL might show a CpG island methylator phenotype (CIMP) that may influence the behaviour of the tumours.

Beaming into the rat world: enabling real-time intereaction between rat and human each at their own scale

Immersive virtual reality (IVR) typically generates the illusion in participants that they are in the displayed virtual scene where they can experience and interact in events as if they were really happening. Teleoperator (TO) systems place people at a remote physical destination embodied as a robotic device, and where typically participants have the sensation of being at the destination, with the ability to interact with entities there. In this paper, we show how to combine IVR and TO to allow a new class of application. The participant in the IVR is represented in the destination by a physical robot (TO) and simultaneously the remote place and entities within it are represented to the participant in the IVR. Hence, the IVR participant has a normal virtual reality experience, but where his or her actions and behaviour control the remote robot and can therefore have physical consequences. Here, we show how such a system can be deployed to allow a human and a rat to operate together, but the human interacting with the rat on a human scale, and the rat interacting with the human on the rat scale. The human is represented in a rat arena by a small robot that is slaved to the human"s movements, whereas the tracked rat is represented to the human in the virtual reality by a humanoid avatar. We describe the system and also a study that was designed to test whether humans can successfully play a game with the rat. The results show that the system functioned well and that the humans were able to interact with the rat to fulfil the tasks of the game. This system opens up the possibility of new applications in the life sciences involving participant observation of and interaction with animals but at human scale.

Beaming into the rat world: enabling real-time intereaction between rat and human each at their own scale

Immersive virtual reality (IVR) typically generates the illusion in participants that they are in the displayed virtual scene where they can experience and interact in events as if they were really happening. Teleoperator (TO) systems place people at a remote physical destination embodied as a robotic device, and where typically participants have the sensation of being at the destination, with the ability to interact with entities there. In this paper, we show how to combine IVR and TO to allow a new class of application. The participant in the IVR is represented in the destination by a physical robot (TO) and simultaneously the remote place and entities within it are represented to the participant in the IVR. Hence, the IVR participant has a normal virtual reality experience, but where his or her actions and behaviour control the remote robot and can therefore have physical consequences. Here, we show how such a system can be deployed to allow a human and a rat to operate together, but the human interacting with the rat on a human scale, and the rat interacting with the human on the rat scale. The human is represented in a rat arena by a small robot that is slaved to the human"s movements, whereas the tracked rat is represented to the human in the virtual reality by a humanoid avatar. We describe the system and also a study that was designed to test whether humans can successfully play a game with the rat. The results show that the system functioned well and that the humans were able to interact with the rat to fulfil the tasks of the game. This system opens up the possibility of new applications in the life sciences involving participant observation of and interaction with animals but at human scale.

Multisensory stimulation can induce an illusion of larger belly size in immersive virtual reality

Body change illusions have been of great interest in recent years for the understanding of how the brain represents the body. Appropriate multisensory stimulation can induce an illusion of ownership over a rubber or virtual arm, simple types of out-of-the-body experiences, and even ownership with respect to an alternate whole body. Here we use immersive virtual reality to investigate whether the illusion of a dramatic increase in belly size can be induced in males through (a) first person perspective position (b) synchronous visual-motor correlation between real and virtual arm movements, and (c) self-induced synchronous visual-tactile stimulation in the stomach area.

Standardized evaluation methodology and reference database for evaluating IVUS image segmentation

This paper describes an evaluation framework that allows a standardized and quantitative comparison of IVUS lumen and media segmentation algorithms. This framework has been introduced at the MICCAI 2011 Computing and Visualization for (Intra)Vascular Imaging (CVII) workshop, comparing the results of eight teams that participated. We describe the available data-base comprising of multi-center, multi-vendor and multi-frequency IVUS datasets, their acquisition, the creation of the reference standard and the evaluation measures. The approaches address segmentation of the lumen, the media, or both borders; semi- or fully-automatic operation; and 2-D vs. 3-D methodology. Three performance measures for quantitative analysis have been proposed. The results of the evaluation indicate that segmentation of the vessel lumen and media is possible with an accuracy that is comparable to manual annotation when semi-automatic methods are used, as well as encouraging results can be obtained also in case of fully-automatic segmentation. The analysis performed in this paper also highlights the challenges in IVUS segmentation that remains to be solved.

Systems Medicine and Integrated Care to Combat Chronic Noncommunicable Diseases.

We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.