Comparison of monoclonal antibodies 17-1A and 323/A3: the influence of the affinity on tumour uptake and efficacy of radioimmunotherapy in human ovarian cancer xenografts.

The low-affinity monoclonal antibody (MAb) chimeric 17-1A(c-17-1A) and the high-affinity MAb mouse 323/A3 (m-323/A3) were used to study the effect of the MAb affinity on the tumour uptake and efficacy of radioimmunotherapy in nude mice bearing subcutaneously the human ovarian cancer xenografts FMa, OVCAR-3 and Ov.Pe. Both MAbs are directed against the same pancarcinoma glycoprotein. In vitro, the number of binding sites on tumour cells at 4 degrees C was similar for both MAbs, but m-323/A3 had an approximately 5-fold higher affinity (1.3-3.0x10(9) M-1) than c-17-1A (3.0-5.4x10(8) M-1). This difference in affinity was more extreme at 37 degrees C, when no binding of c-17-1A could be observed. MAb m-323/A3 completely blocked binding of c-17-1A to tumour cells, whereas the reverse was not observed. Immunohistochemistry showed a similar but more intense staining pattern of m-323/A3 in human ovarian cancer xenografts than of c-17-1A. In vivo, the blood clearance in non-tumour-bearing nude mice was similar for both MAbs with terminal half-lives of 71.4 h for m-323/A3 and 62.7 h for c-17-1A. MAb m-323/A3 targeted better to tumour tissue, but was more heterogeneously distributed than c-17-1A. The cumulative absorbed radiation dose delivered by m-323/A3 to tumour tissue was 2.5- to 4.7-fold higher than that delivered by c-17-1A. When mice were treated with equivalent radiation doses of 131(I)m-323/A3 and 131(I)c-17-1A, based on a correction for the immunoreactivity of the radiolabelled MAbs, m-323/A3 induced a better growth inhibition in two of the three xenografts. When the radiation doses were adjusted to obtain a similar amount of radiation in the tumour c-17-1A was more effective in tumour growth inhibition in all three xenografts

Challenges and Solutions to the Measurement of Neurocognitive Mechanisms in Developmental Settings

Identifying early neurocognitive mechanisms that confer risk for mental health problems is one important avenue as we seek to develop successful early interventions. Currently, however, we have limited understanding of the neurocognitive mechanisms involved in shaping mental health trajectories from childhood through young adulthood, and this constrains our ability to develop effective clinical interventions. In particular, there is an urgent need to develop more sensitive, reliable, and scalable measures of individual differences for use in developmental settings. In this review, we outline methodological shortcomings that explain why widely used task-based measures of neurocognition currently tell us little about mental health risk. We discuss specific challenges that arise when studying neurocognitive mechanisms in developmental settings, and we share suggestions for overcoming them. We also propose a novel experimental approach—which we refer to as “cognitive microscopy”—that involves adaptive design optimization, temporally sensitive task administration, and multilevel modeling. This approach addresses some of the methodological shortcomings outlined above and provides measures of stability, variability, and developmental change in neurocognitive mechanisms within a multivariate framework

Common Cause Versus Dynamic Mutualism: An Empirical Comparison of Two Theories of Psychopathology in Two Large Longitudinal Cohorts

Mental disorders are among the leading causes of global disease burden. To respond effectively, a strong understanding of the structure of psychopathology is critical. We empirically compared two competing frameworks, dynamic-mutualism theory and common-cause theory, that vie to explain the development of psychopathology. We formalized these theories in statistical models and applied them to explain change in the general factor of psychopathology (p factor) from early to late adolescence ( N = 1,482) and major depression in middle adulthood and old age ( N = 6,443). Change in the p factor was better explained by mutualism according to model-fit indices. However, a core prediction of mutualism was not supported (i.e., predominantly positive causal interactions among distinct domains). The evidence for change in depression was more ambiguous. Our results support a multicausal approach to understanding psychopathology and showcase the value of translating theories into testable statistical models for understanding developmental processes in clinical sciences

Cognitive Dimensions of Learning in Children With Problems in Attention, Learning, and Memory.

A data-driven, transdiagnostic approach was used to identify the cognitive dimensions linked with learning in a mixed group of 805 children aged 5 to 18 years recognised as having problems in attention, learning and memory by a health or education practitioner. Assessments included phonological processing, information processing speed, short-term and working memory, and executive functions, and attainments in word reading, spelling, and maths. Data reduction methods identified three dimensions of phonological processing, processing speed and executive function for the sample as a whole. This model was comparable for children with and without ADHD. The severity of learning difficulties in literacy was linked with phonological processing skills, and in maths with executive control. Associations between cognition and learning were similar across younger and older children and individuals with and without ADHD, although stronger links between learning-related problems and both executive skills and processing speed were observed in children with ADHD. The results establish clear domain-specific cognitive pathways to learning that distinguish individuals in the heterogeneous population of children struggling to learn

Common cause versus dynamic mutualism:An empirical comparison of two theories of psychopathology in two large longitudinal cohorts

Stress and Psychopatholog

Noradrenergic-dependent functions are associated with age-related locus coeruleus signal intensity differences.

The locus coeruleus (LC), the origin of noradrenergic modulation of cognitive and behavioral function, may play an important role healthy ageing and in neurodegenerative conditions. We investigated the functional significance of age-related differences in mean normalized LC signal intensity values (LC-CR) in magnetization-transfer (MT) images from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) cohort - an open-access, population-based dataset. Using structural equation modelling, we tested the pre-registered hypothesis that putatively noradrenergic (NA)-dependent functions would be more strongly associated with LC-CR in older versus younger adults. A unidimensional model (within which LC-CR related to a single factor representing all cognitive and behavioral measures) was a better fit with the data than the a priori two-factor model (within which LC-CR related to separate NA-dependent and NA-independent factors). Our findings support the concept that age-related reduction of LC structural integrity is associated with impaired cognitive and behavioral function

Annual Research Review: The transdiagnostic revolution in neurodevelopmental disorders.

Practitioners frequently use diagnostic criteria to identify children with neurodevelopmental disorders and to guide intervention decisions. These criteria also provide the organising framework for much of the research focussing on these disorders. Study design, recruitment, analysis and theory are largely built on the assumption that diagnostic criteria reflect an underlying reality. However, there is growing concern that this assumption may not be a valid and that an alternative transdiagnostic approach may better serve our understanding of this large heterogeneous population of young people. This review draws on important developments over the past decade that have set the stage for much-needed breakthroughs in understanding neurodevelopmental disorders. We evaluate contemporary approaches to study design and recruitment, review the use of data-driven methods to characterise cognition, behaviour and neurobiology, and consider what alternative transdiagnostic models could mean for children and families. This review concludes that an overreliance on ill-fitting diagnostic criteria is impeding progress towards identifying the barriers that children encounter, understanding underpinning mechanisms and finding the best route to supporting them

Связи изменений среднемесячных ОСО над Антарктикой и площади теплого тропического бассейна Тихого океана при современном потеплении климата

Объектом данного исследования выбраны изменения распределения среднемесячных значений ОСО над Антарктикой, а также площади ТТБ в западном полушарии. Предметом исследования есть изменения статистических связей между указанными процессами, происходившими за период современного потепления климата. Целью работы есть выявление их связей, которые на протяжении периода современного потепления климата усиливались устойчиво и ныне являются значимыми