Improving treatment of glioblastoma: new insights in targeting cancer stem cells effectively

Glioblastoma is the most common primary malignant brain tumour in the adult population. Despite multimodality treatment with surgery, radiotherapy and chemotherapy, outcomes are very poor, with less than 15% of patients alive after two years. Increasing evidence suggests that glioblastoma stem cells (GSCs) are likely to play an important role in the biology of this disease and are involved in treatment resistance and tumour recurrence following standard therapy. My thesis aims to address two main aspects of this research area: 1) optimization of methods to evaluate treatment responses of GSCs and their differentiated counterparts (non-GSCs), with a particular focus on a tissue culture model that resembles more closely the tumoral niche; 2) characterization of cell division and centrosome cycle of GSCs, investigating possible differences between these cells and non-GSCs, that would allow the identification of targets for new therapeutic strategies against glioblastomas. In the first part of my project, I optimized a clonogenic survival assay, to compare sensitivity of GSCs and non-GSCs to various treatments, and I developed the use of a 3-dimentional tissue culture system, that allows analysis of features and radiation responses of these two subpopulations in the presence of specific microenvironmental factors from the tumoral niche. In the second part, I show that GSCs display mitotic spindle abnormalities more frequently than non-GSCs and that they have distinctive features with regards to the centrosome cycle. I also demonstrate that GSCs are more sensitive than non-GSCs to subtle changes in Aurora kinase A activity, which result in a rapid increase in polyploidy and subsequently in senescence, with a consistent reduction in clonogenic survival. Based on these findings, I propose that kinases involved in the centrosome cycle need to be explored as a novel strategy to target GSCs effectively and improve outcomes of glioblastoma patients

Philosophy at Cambridge, Newsletter of the Faculty of Philosophy

Philosophy newsletter. Articles by: Jane Heal: From the Chair Jonathan Lear: Radical Hope. Ben Colburn: Philosophy at Cambridge through the Years Lewis Evans; Adrian Boutel: From Law to Philosophy. Jonathan Brown: Part I, Part II, Part Yonder. Barbara Kay: The Moral Sciences ClubPhilosophy at Cambridge. Newsletter of the Philosophy Facult

Translating novel findings of perceptual-motor codes into the neuro-rehabilitation of movement disorders

The bidirectional flow of perceptual and motor information has recently proven useful as rehabilitative tool for re-building motor memories. We analyzed how the visual-motor approach has been successfully applied in neurorehabilitation, leading to surprisingly rapid and effective improvements in action execution. We proposed that the contribution of multiple sensory channels during treatment enables individuals to predict and optimize motor behavior, having a greater effect than visual input alone. We explored how the state-of-the-art neuroscience techniques show direct evidence that employment of visual-motor approach leads to increased motor cortex excitability and synaptic and cortical map plasticity. This super-additive response to multimodal stimulation may maximize neural plasticity, potentiating the effect of conventional treatment, and will be a valuable approach when it comes to advances in innovative methodologies

Loss of agency in apraxia

The feeling of acting voluntarily is a fundamental component of human behavior and social life and is usually accompanied by a sense of agency. However, this ability can be impaired in a number of diseases and disorders. An important example is apraxia, a disturbance traditionally defined as a disorder of voluntary skillful movements that often results from frontal-parietal brain damage. The first part of this article focuses on direct evidence of some core symptoms of apraxia, emphasizing those with connections to agency and free will. The loss of agency in apraxia is reflected in the monitoring of internally driven action, in the perception of specifically self-intended movements and in the neural intention to act. The second part presents an outline of the evidences supporting the functional and anatomical link between apraxia and agency. The available structural and functional results converge to reveal that the frontal-parietal network contributes to the sense of agency and its impairment in disorders such as apraxia. The current knowledge on the generation of motor intentions and action monitoring could potentially be applied to develop therapeutic strategies for the clinical rehabilitation of voluntary action

The reliability, validity, and accuracy of self-reported absenteeism from work: a meta-analysis

Because of a variety of access limitations, self-reported absenteeism from work is often employed in research concerning health, organizational behavior, and economics, and it is ubiquitous in large scale population surveys in these domains. Several well established cognitive and social-motivational biases suggest that self-reports of absence will exhibit convergent validity with records-based measures but that people will tend to underreport the behavior. We used meta-analysis to summarize the reliability, validity, and accuracy of absence self-reports. The results suggested that self-reports of absenteeism offer adequate test–retest reliability and that they exhibit reasonably good rank order convergence with organizational records. However, people have a decided tendency to underreport their absenteeism, although such underreporting has decreased over time. Also, self-reports were more accurate when sickness absence rather than absence for any reason was probed. It is concluded that self-reported absenteeism might serve as a valid measure in some correlational research designs. However, when accurate knowledge of absolute absenteeism levels is essential, the tendency to underreport could result in flawed policy decisions

Plasticity and awareness of bodily distortion

Knowledge of the body is filtered by perceptual information, recalibrated through predominantly innate stored information, and neurally mediated by direct sensory motor information. Despite multiple sources, the immediate prediction, construction, and evaluation of one’s body are distorted. The origins of such distortions are unclear. In this review, we consider three possible sources of awareness that inform body distortion. First, the precision in the body metric may be based on the sight and positioning sense of a particular body segment. This view provides information on the dual nature of body representation, the reliability of a conscious body image, and implicit alterations in the metrics and positional correspondence of body parts. Second, body awareness may reflect an innate organizational experience of unity and continuity in the brain, with no strong isomorphism to body morphology. Third, body awareness may be based on efferent/afferent neural signals, suggesting that major body distortions may result from changes in neural sensorimotor experiences. All these views can be supported empirically, suggesting that body awareness is synthesized from multimodal integration and the temporal constancy of multiple body representations. For each of these views, we briefly discuss abnormalities and therapeutic strategies for correcting the bodily distortions in various clinical disorder

Commentary on: “The body social: an enactive approach to the self“. A tool for merging bodily and social self in immobile individuals

Commentary on: “The body social: an enactive approach to the self“. A tool for merging bodily and social self in immobile individual

Action Observation for Neurorehabilitation in Apraxia

Neurorehabilitation and brain stimulation studies of post-stroke patients suggest that action-observation effects can lead to rapid improvements in the recovery of motor functions and long-term motor cortical reorganization. Apraxia is a clinically important disorder characterized by marked impairment in representing and performing skillful movements [gestures], which limits many daily activities and impedes independent functioning. Recent clinical research has revealed errors of visuo-motor integration in patients with apraxia. This paper presents a rehabilitative perspective focusing on the possibility of action observation as a therapeutic treatment for patients with apraxia. This perspective also outlines impacts on neurorehabilitation and brain repair following the reinforcement of the perceptual-motor coupling. To date, interventions based primarily on action observation in apraxia have not been undertaken