Tumor suppressor BTG1 limits activation of BCL6 expression downstream of ETV6-RUNX1

Translocation t(12;21) (p13;q22), giving rise to the ETV6-RUNX1 fusion gene, is the most common genetic abnormality in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This translocation usually arises in utero, but its expression is insufficient to induce leukemia and requires other cooperating genetic lesions for BCP-ALL to develop. Deletions affecting the transcriptional coregulator BTG1 are frequently observed in ETV6-RUNX1-positive leukemia. Here we report that Btg1 deficiency enhances the self-renewal capacity of ETV6-RUNX1-positive mouse fetal liver-derived hematopoietic progenitors (FL-HPCs). Combined expression of the fusion protein and a loss of BTG1 drive upregulation of the proto-oncogene Bcl6 and downregulation of BCL6 target genes, such as p19Arf and Tp53. Similarly, ectopic expression of BCL6 promotes the self-renewal and clonogenic replating capacity of FL-HPCs, by suppressing the expression of p19Arf and Tp53. Together these results identify BCL6 as a potential driver of ETV6-RUNX1-mediated leukemogenesis, which could involve loss of BTG1-dependent suppression of ETV6-RUNX1 function

Scaling relationships based on partition coefficients and body sizes have similarities and interactions

The LC50 of compounds with a similar biological effect, at a given exposure period, is frequently plotted log-log against the octanol-water partition coefficient and a straight line is fitted for interpolation purposes. This is also frequently done for physiological properties, such as the weight-specific respiration rate, as function of the body weight of individuals. This paper focuses on the remarkable observation that theoretical explanations for these relationships also have strong similarities. Both can be understood as result of the covariation of the values of parameters of models of a particular type for the underlying processes, while this covariation follows logically from the model structure. The one-compartment model for the uptake and elimination of compounds by organisms is basic to the BioConcentration Factor (BCF), or the partition coefficient; the standard Dynamic Energy Budget model is basic to the (ultimate) body size. The BCF is the ratio of the uptake and the elimination rates; the maximum body length is the ratio of the assimilation (i.e. uptake of resources) and the maintenance (i.e. use of resources) rates. This paper discusses some shortcomings of descriptive approaches and conceptual aspects of theoretical explanations. The strength of the theory is in the combination of why metabolic transformation depends both on the BCF and the body size. We illustrate the application of the theory with several data sets from the literature

Targeted prevention in primary care aimed at lifestyle-related diseases:a study protocol for a non-randomised pilot study

Background: The consequences of lifestyle-related disease represent a major burden for the individual as well as for society at large. Individual preventive health checks to the general population have been suggested as a mean to reduce the burden of lifestyle-related diseases, though with mixed evidence on effectiveness. Several systematic reviews, on the other hand, suggest that health checks targeting people at high risk of chronic lifestyle-related diseases may be more effective. The evidence is however very limited. To effectively target people at high risk of lifestyle-related disease, there is a substantial need to advance and implement evidence-based health strategies and interventions that facilitate the identification and management of people at high risk. This paper reports on a non-randomized pilot study carried out to test the acceptability, feasibility and short-term effects of a healthcare intervention in primary care designed to systematically identify persons at risk of developing lifestyle-related disease or who engage in health-risk behavior, and provide targeted and coherent preventive services to these individuals. Methods: The intervention took place over a three-month period from September 2016 to December 2016. Taking a two-pronged approach, the design included both a joint and a targeted intervention. The former was directed at the entire population, while the latter specifically focused on patients at high risk of a lifestyle-related disease and/or who engage in health-risk behavior. The intervention was facilitated by a digital support system. The evaluation of the pilot will comprise both quantitative and qualitative research methods. All outcome measures are based on validated instruments and aim to provide results pertaining to intervention acceptability, feasibility, and short-term effects. Discussion: This pilot study will provide a solid empirical base from which to plan and implement a full-scale randomized study with the central aim of determining the efficacy of a preventive health intervention. Trial registration: Registered at Clinical Trial Gov (Unique Protocol ID: TOFpilot2016). Registered 29 April 2016. The study adheres to the SPIRIT guidelines

The Rotterdam Study: 2012 objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods

Brain connectivity changes occurring following cognitive behavioural therapy for psychosis predict long-term recovery

Little is known about the psychobiological mechanisms of cognitive behavioural therapy for psychosis (CBTp) and which specific processes are key in predicting favourable long-term outcomes. Following theoretical models of psychosis, this proof-of-concept study investigated whether the long-term recovery path of CBTp completers can be predicted by the neural changes in threatbased social affective processing that occur during CBTp. We followed up 22 participants who had undergone a social affective processing task during functional magnetic resonance imaging along with self-report and clinician-administered symptom measures, before and after receiving CBTp. Monthly ratings of psychotic and affective symptoms were obtained retrospectively across 8 years since receiving CBTp, plus self-reported recovery at final follow-up. We investigated whether these long-term outcomes were predicted by CBTp-led changes in functional connections with dorsal prefrontal cortical and amygdala during the processing of threatening and prosocial facial affect. Although long-term psychotic symptoms were predicted by changes in prefrontal connections during prosocial facial affective processing, long-term affective symptoms were predicted by threat-related amygdalo-inferior parietal lobule connectivity. Greater increases in dorsolateral prefrontal cortex connectivity with amygdala following CBTp also predicted higher subjective ratings of recovery at long-term follow-up. These findings show that reorganisation occurring at the neural level following psychological therapy can predict the subsequent recovery path of people with psychosis across 8 years. This novel methodology shows promise for further studies with larger sample size, which are needed to better examine the sensitivity of psychobiological processes, in comparison to existing clinical measures, in predicting long-term outcomes.Wellcome Trust; Biomedical Research Centre for Mental Health at the Institute of Psychiatry, Psychology & Neuroscience, King’s College London and South London and Maudsley NHS Foundation Trust, U

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns

Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10⁻⁶, 1.7 × 10⁻⁹, 3.5 × 10⁻¹² and 1.0 × 10⁻⁴, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes