Across species, increases in white matter volume outpace increases in gray-matter volume, but increases in gray- matter volume outpace increases in the size of the corpus callosum. This dissertation explores the hypothesis that this hyposcaling of the callosum stems from the impact of the conduction delays and cellular costs of the long- distance connections on normal developmental mechanisms. Neuroanatomy research to date has only indirectly examined this relation, using measures such as brain volume. The research in this dissertation uses diffusion tensor imaging to more directly measure the relation between the length of the interhemispheric connections and the degree of connectivity -- the ratio of between-area connections to total projection neurons in the areas connected. Using tractography to detail the patterns of interhemispheric connectivity and to determine the length of the connections, and formulae based on histological results to estimate degree of connectivity, we show that, across normal young adult males, connection length is significantly negatively correlated with degree of connectivity in the anterior, posterior, and body of the callosum. Using the same methodology, in typically developing boys a significant relation between connection length and degree of connectivity was found only in the posterior of the callosum. The combined results indicate that the relation between connection length and degree of connectivity develops during childhood and adolescence. Children with autism are known to have enlarged brains during the first years of life. This is predicted to lead to decreased long-distance connectivity. To explore this prediction, neural networks which modeled inter- hemispheric interaction were grown at the rate of either typically developing children or children with autism. By 2 years of simulated age, the networks that modeled autistic growth showed a reduced reliance on long-distance connections, performance reductions, and reductions in structural connectivity. Using the same methodology as with the adults and children, the relation between connection length and degree of connectivity in adults with autism was examined. Connection length and degree of connectivity showed the typical negative relation, but with a reduced degree of connectivity in anterior regions -- the locus of development during the period of maximal brain overgrowth, and where axon diameters are smallest

Tumor heterogeneity confounds cancer diagnosis and the outcome of therapy, necessitating analysis of tumor cell subsets within the tumor mass. Elevated expression of hyaluronan (HA) and HA receptors, receptor for HA-mediated motility (RHAMM)/HA-mediated motility receptor and cluster designation 44 (CD44), in breast tumors correlates with poor outcome. We hypothesized that a probe for detecting HA-HA receptor interactions may reveal breast cancer (BCa) cell heterogeneity relevant to tumor progression. A fluorescent HA (F-HA) probe containing a mixture of polymer sizes typical of tumor microenvironments (10-480 kDa), multiplexed profiling, and flow cytometry were used to monitor HA binding to BCa cell lines of different molecular subtypes. Formulae were developed to quantify binding heterogeneity and to measure invasion in vivo. Two subsets exhibiting differential binding (HA(-/low) vs. HA(high)) were isolated and characterized for morphology, growth, and invasion in culture and as xenografts in vivo. F-HA-binding amounts and degree of heterogeneity varied with BCa subtype, were highest in the malignant basal-like cell lines, and decreased upon reversion to a nonmalignant phenotype. Binding amounts correlated with CD44 and RHAMM displayed but binding heterogeneity appeared to arise from a differential ability of HA receptor-positive subpopulations to interact with F-HA. HA(high) subpopulations exhibited significantly higher local invasion and lung micrometastases but, unexpectedly, lower proliferation than either unsorted parental cells or the HA(-/low) subpopulation. Querying F-HA binding to aggressive tumor cells reveals a previously undetected form of heterogeneity that predicts invasive/metastatic behavior and that may aid both early identification of cancer patients susceptible to metastasis, and detection/therapy of invasive BCa subpopulations.

Purpose

Globally, prostate cancer treatment and outcomes for men vary according to where they live, their race and the care they receive. The TrueNTH Global Registry project was established as an international registry monitoring care provided to men with localised prostate cancer (CaP).

Participants

Sites with existing CaP databases in Movember fundraising countries were invited to participate in the international registry. In total, 25 Local Data Centres (LDCs) representing 113 participating sites across 13 countries have nominated to contribute to the project. It will collect a dataset based on the International Consortium for Health Outcome Measures (ICHOM) standardised dataset for localised CaP.

Findings to date

A governance strategy has been developed to oversee registry operation, including transmission of reversibly anonymised data. LDCs are represented on the Project Steering Committee, reporting to an Executive Committee. A Project Coordination Centre and Data Coordination Centre (DCC) have been established. A project was undertaken to compare existing datasets, understand capacity at project commencement (baseline) to collect the ICHOM dataset and assist in determining the final data dictionary. 21/25 LDCs provided data dictionaries for review. Some ICHOM data fields were well collected (diagnosis, treatment start dates) and others poorly collected (complications, comorbidities). 17/94 (18%) ICHOM data fields were relegated to non-mandatory fields due to poor capture by most existing registries. Participating sites will transmit data through a web interface biannually to the DCC.

Future plans

Recruitment to the TrueNTH Global Registry-PCOR project will commence in late 2017 with sites progressively contributing reversibly anonymised data following ethical review in local regions. Researchers will have capacity to source deidentified data after the establishment phase. Quality indicators are to be established through a modified Delphi approach in later 2017, and it is anticipated that reports on performance against quality indicators will be provided to LDCs.