Developmental white matter microstructure in autism phenotype and corresponding endophenotype during adolescence.

During adolescence, white matter microstructure undergoes an important stage of development. It is hypothesized that the alterations of brain connectivity that have a key role in autism spectrum conditions (ASCs) may interact with the development of white matter microstructure. This interaction may be present beyond the phenotype of autism in siblings of individuals with ASC, who are 10 to 20 times more likely to develop certain forms of ASC. We use diffusion tensor imaging to examine how white matter microstructure measurements correlate with age in typically developing individuals, and how this correlation differs in n=43 adolescents with ASC and their n=38 siblings. Correlations observed in n=40 typically developing individuals match developmental changes noted in previous longitudinal studies. In comparison, individuals with ASC display weaker negative correlation between age and mean diffusivity in a broad area centred in the right superior longitudinal fasciculus. These differences may be caused either by increased heterogeneity in ASC or by temporal alterations in the group's developmental pattern. Siblings of individuals with ASC also show diminished negative correlation between age and one component of mean diffusivity-second diffusion eigenvalue-in the right superior longitudinal fasciculus. As the observed differences match for location and correlation directionality in our comparison of typically developing individuals to those with ASC and their siblings, we propose that these alterations constitute a part of the endophenotype of autism.This research was funded by an MRC Clinician Scientist Fellowship to MDS from the UK Medical Research Council (G0701919). LRC was supported by the Gates Cambridge Scholarship Trust. SB-C was supported by the Wellcome Trust, the MRC and the Autism Research Trust, during the period of this work.This is the final published version. It first appeared at http://www.nature.com/tp/journal/v5/n3/full/tp201523a.html

Whole-brain functional hypoconnectivity as an endophenotype of autism in adolescents.

Endophenotypes are heritable and quantifiable markers that may assist in the identification of the complex genetic underpinnings of psychiatric conditions. Here we examined global hypoconnectivity as an endophenotype of autism spectrum conditions (ASCs). We studied well-matched groups of adolescent males with autism, genetically-related siblings of individuals with autism, and typically-developing control participants. We parcellated the brain into 258 regions and used complex-network analysis to detect a robust hypoconnectivity endophenotype in our participant group. We observed that whole-brain functional connectivity was highest in controls, intermediate in siblings, and lowest in ASC, in task and rest conditions. We identified additional, local endophenotype effects in specific networks including the visual processing and default mode networks. Our analyses are the first to show that whole-brain functional hypoconnectivity is an endophenotype of autism in adolescence, and may thus underlie the heritable similarities seen in adolescents with ASC and their relatives.The authors wish to thank the participants and their families for their participation and the autism support organisations who assisted with recruitment. We thank colleagues at the Brain Mapping Unit for methodological discussions and thank Meng-Chuan Lai, Amber Ruigrok and Richard Bethlehem for the same. Data collection was funded by a Clinical Scientist Fellowship from the UK Medical Research Council (MRC) (G0701919) to MDS. LRC was supported by the Gates Cambridge Scholarship Trust. The study was conducted in associated with the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for Cambridgeshire, and Peterborough National Health Service (NHS) Foundation Trust. The present analysis was funded by a NARSAD Young Investigator award (to MR) and by the Isaac Newton Trust (to MR); RJFY is additionally supported by a Rubicon Fellowship from the Netherlands Organisation for Scientific Research. The Brain Mapping Unit (MR, RLM, RJFY, JS and ETB) is part of the Behavioural & Clinical Neuroscience Institute, which is funded by the MRC and the Wellcome Trust. High performance computing facilities were supported by the NIHR Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.nicl.2015.07.01

Targeted anti-vascular therapies for ovarian cancer: current evidence

Ovarian cancer presents at advanced stage in around 75% of women, and despite improvements in treatments such as chemotherapy, the 5-year survival from the disease in women diagnosed between 1996 and 1999 in England and Wales was only 36%. Over 80% of patients with advanced ovarian cancer will relapse and despite a good chance of remission from further chemotherapy, they will usually die from their disease. Sequential treatment strategies are employed to maximise quality and length of life but patients eventually become resistant to cytotoxic agents. The expansion in understanding of the molecular biology that characterises cancer cells has led to the rapid development of new agents to target important pathways but the heterogeneity of ovarian cancer biology means that there is no predominant defect. This review attempts to discuss progress to date in tackling a more general target applicable to ovary cancer-angiogenesis

Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual