From behavioural economics to neuroeconomics to decision neuroscience: the ascent of biology in research on human decision making

Here, we briefly review the evolution of research on human decision-making over the past few decades. We discern a trend whereby biology moves from subserving economics (neuroeconomics), to providing the data that advance our knowledge of the nature of human decision-making (decision neuroscience). Examples illustrate that the integration of behavioural and biological models is fruitful especially for understanding heterogeneity of choice in humans

Dopamine and the development of executive dysfunction in autism spectrum disorders.

Persons with autism regularly exhibit executive dysfunction (ED), including problems with deliberate goal-directed behavior, planning, and flexible responding in changing environments. Indeed, this array of deficits is sufficiently prominent to have prompted a theory that executive dysfunction is at the heart of these disorders. A more detailed examination of these behaviors reveals, however, that some aspects of executive function remain developmentaly appropriate. In particular, while people with autism often have difficulty with tasks requiring cognitive flexibility, their fundamental cognitive control capabilities, such as those involved in inhibiting an inappropriate but relatively automatic response, show no significant impairment on many tasks. In this article, an existing computational model of the prefrontal cortex and its role in executive control is shown to explain this dichotomous pattern of behavior by positing abnormalities in the dopamine-based modulation of frontal systems in individuals with autism. This model offers excellent qualitative and quantitative fits to performance on standard tests of cognitive control and cognitive flexibility in this clinical population. By simulating the development of the prefrontal cortex, the computational model also offers a potential explanation for an observed lack of executive dysfunction early in life

Long-term outcome and treatment-related toxicity in patients with breast and testicular cancer

Heart muscle impairment on ultrasound is linked to the administered dose of anthracycline chemotherapy in women who have been treated for early breast cancer. That is the conclusion of the HARBOR study, a collaborative effort of the UMCG and AVL included in this thesis. The 569 participating women had been treated with radiotherapy and/or chemotherapy over five years ago. Of note, about half of the participants was overweight, a quarter had high blood pressure and/or high cholesterol, and 15% smoked – targets of interest to manage the risk of heart and blood vessel disease in these patients after cancer treatment.In addition, this thesis contains long-term follow-up of a nationwide trial that compared high-dose to normal-dose chemotherapy in 885 women with breast cancer that had spread to four or more armpit lymph nodes. This N4+ study was conducted between 1993 and 1999 in ten Dutch hospitals. In the follow-up study, high-dose chemotherapy did not appear to improve survival. However, specifically in women with ten or more affected lymph nodes, 15% more patients were still alive twenty years after treatment with high-dose compared to normal-dose chemotherapy. To address long term outcome in male cancer patients, this thesis also addresses adverse effects of the treatment of testicular cancer. The protein INSL3 was investigated in relation to the decreased testosterone production found in some patients. Furthermore, analysis of the genetic makeup of 375 patients provided clues why some patients with testicular cancer get heart or blood vessel disease after treatment, and others do not

Ethical implications of epigenetics in the era of personalized medicine

Given the increasing research activity on epigenetics to monitor human diseases and its connection with lifestyle and environmental expositions, the field of epigenetics has attracted a great deal of interest also at the ethical and societal level. In this review, we will identify and discuss current ethical, legal and social issues of epigenetics research in the context of personalized medicine. The review covers ethical aspects such as how epigenetic information should impact patient autonomy and the ability to generate an intentional and voluntary decision, the measures of data protection related to privacy and confidentiality derived from epigenome studies (e.g., risk of discrimination, patient re-identification and unexpected findings) or the debate in the distribution of responsibilities for health (i.e., personal versus public responsibilities). We pay special attention to the risk of social discrimination and stigmatization as a consequence of inferring information related to lifestyle and environmental exposures potentially contained in epigenetic data. Furthermore, as exposures to the environment and individual habits do not affect all populations equally, the violation of the principle of distributive justice in the access to the benefits of clinical epigenetics is discussed. In this regard, epigenetics represents a great opportunity for the integration of public policy measures aimed to create healthier living environments. Whether these public policies will coexist or, in contrast, compete with strategies reinforcing the personalized medicine interventions needs to be considered. The review ends with a reflection on the main challenges in epigenetic research, some of them in a technical dimension (e.g., assessing causality or establishing reference epigenomes) but also in the ethical and social sphere (e.g., risk to add an epigenetic determinism on top of the current genetic one). In sum, integration into life science investigation of social experiences such as exposure to risk, nutritional habits, prejudice and stigma, is imperative to understand epigenetic variation in disease. This pragmatic approach is required to locate clinical epigenetics out of the experimental laboratories and facilitate its implementation into societ

RNAi Therapeutic Potentials and Prospects in CNS Disease

Over the past 20 years, RNA interference (RNAi) technology has provided a new regulatory paradigm in biology. This technique can efficiently suppress target genes of interest in mammalian cells. Small non-coding RNAs play important roles in gene regulation, including both in post-transcriptional and in translational regulation. For in vivo experiments, continuous development has resulted in successful new ways of designing, identifying, and delivering small interfering RNAs (siRNAs). Proof-of-principle studies in vivo have clearly demonstrated that both viral and non-viral delivery methods can provide selective and potent target gene suppression without any clear toxic effects. There are also the persistent problems with off-target effects (OTEs), competition with cellular RNAi components, and effective delivery in vivo. Although recent researches and trials from a large number of animal model studies have confirmed that most OTEs are not dangerous, other important issues need to be addressed before RNAi-based drugs are ready for clinical use. Currently, RNAi may be harnessed as a new therapeutic modality for brain diseases. Finally, there are already several RNAi-based human clinical trials in progress. It is hoped that this technology will have also effective applications in human central nervous system (CNS)-related disease

The gene SMART study: method, study design, and preliminary findings

The gene SMART (genes and the Skeletal Muscle Adaptive Response to Training) Study aims to identify genetic variants that predict the response to both a single session of High-Intensity Interval Exercise (HIIE) and to four weeks of High-Intensity Interval Training (HIIT). While the training and testing centre is located at Victoria University, Melbourne, three other centres have been launched at Bond University, Queensland University of Technology, Australia, and the University of Brighton, UK. Currently 39 participants have already completed the study and the overall aim is to recruit 200 moderately-trained, healthy Caucasians participants (all males 18–45 y, BMI \u3c 30). Participants will undergo exercise testing and exercise training by an identical exercise program. Dietary habits will be assessed by questionnaire and dietitian consultation. Activity history is assessed by questionnaire and current activity level is assessed by an activity monitor. Skeletal muscle biopsies and blood samples will be collected before, immediately after and 3 h post HIIE, with the fourth resting biopsy and blood sample taken after four weeks of supervised HIIT (3 training sessions per week). Each session consists of eight to fourteen 2-min intervals performed at the pre-training lactate threshold (LT) power plus 40 to 70% of the difference between pre-training lactate threshold (LT) and peak aerobic power (Wpeak). A number of muscle and blood analyses will be performed, including (but not limited to) genotyping, mitochondrial respiration, transcriptomics, protein expression analyses, and enzyme activity. The participants serve as their own controls. Even though the gene SMART study is tightly controlled, our preliminary findings still indicate considerable individual variability in both performance (in-vivo) and muscle (in-situ) adaptations to similar training. More participants are required to allow us to better investigate potential underlying genetic and molecular mechanisms responsible for this individual variability

Digitalization and Public Services: critical notes concerning emerging ways of administrating

The aim of the present work is to propose a legal perspective of analysis for issues of relationships that are relevant in field of digitalization and delivery of public services, in relation to services quality, protection of citizens and businesses, and risks of destructuring a system, which in Italian law, has been marked by an enduring regulatory instability