This small exploratory study was designed to test the hypothesis that thin melanoma lesions contain nuclei of two similar phenotypes, in different proportions. In lesions likely to progress to metastatic disease, one of these phenotypes predominates. Histopathological sections from 18 cases of thin melanomas which did not progress to metastasis, and from 10 cases which did progress were imaged and digitized at high resolution, with a total of 2084 and 1148 nuclei, respectively, recorded. Five karyometric features were used to discriminate between nuclei from indolent and from potentially metastatic lesions. For each case, the percentage of nuclei classified by the discriminant function as having come from a potentially metastatic lesion was determined and termed as case classification criterion. Standard histopathological criteria, such as ulceration and high mitotic index, indicated in this material the need for intensive therapy for only one of the 10 participants, as compared with 7/10 identified correctly by the karyometric measure. Using a case classification criterion threshold of 40%, the overall accuracy was 86% in the test set. The proportion of nuclei of an aggressive phenotype may lend itself as an effective prognostic clue for thin melanoma lesions. The algorithm developed in this training set appears to identify those patients at high risk for metastatic disease, and demonstrates a basis for a further study to assess the utility of prognostic clues for thin melanomas.

No description available.

Brain and behavioural disorders represent a leading cause of morbidity and suffering worldwide. The 'fierce' mouse has a spontaneous deletion of Nr2e1 that results in a complex phenotype that includes cortical hypoplasia and socially abnormal behaviours. Notably, functional protein and regulatory equivalency of mouse and human NR2E1 has been established. Furthermore, human studies implicate the genomic region containing NR2E1 in mental illness, although a role for NR2E1 in humans is currently unknown. Here, I integrate mouse models and human molecular genetics to understand the involvement of NR2E1 in human brain-behaviour development. First, we test the hypothesis that the spontaneous 'fierce' deletion involves onlyNr2el. It was demonstrated that the 'fierce' mutation results in the loss of all Nr2e1 exons without affecting neighbouring genes. Next, the hypothesis that some humans with cortical malformations will harbour NR2E1 mutations was tested by sequencing the coding, untranslated, splice-site, proximal promoter, and evolutionarily conserved regions of this gene in 60 subjects with microcephaly. Four candidate regulatory mutations were identified. To help interpret these findings, the genomic architecture and molecular evolution of NR2E1 were characterized in 94ethnically-diverse humans and 13 non-human primates, which indicated strong functional constraint. Finally, the hypothesis that some humans with behavioural and psychiatric disorders will harbour mutations in NR2E1 was tested by sequencing the regions outlined above in 126humans with impulsive-aggressive disorders, bipolar disorder, or schizophrenia. Eleven candidate regulatory mutations were identified. Taken together, the findings presented in this thesis are consistent with the proposal that non-coding regulatory mutations may be important to the pathogenesis of brain-behavioural disorders in some humans.

Aggressive fibromatosis is a benign fibroproliferative tumour that can occur as a sporadic lesion or a manifestation in patients with familial syndromes, such as familial adenomatous polyposis. Tumours are characterized by the stabilization of β-catenin and the activation of β-catenin-mediated transcription. Current treatment results are far from ideal, and recurrence rates are high. As a result, there remains a need for more effective therapeutic strategies. In this work, we demonstrate the effect of hedgehog signalling inhibition on aggressive fibromatosis tumour development and β-catenin modulation. We found that hedgehog inhibition decreased cell viability and proliferation as well as total β-catenin levels in human aggressive fibromatosis tumour cells in vitro. Furthermore, following hedgehog inhibition in Apc+/Apc1638N aggressive fibromatosis mouse model, the number and volume of the tumours formed was reduced. Together, this work suggests that hedgehog signalling inhibitor agents are potential candidates to effectively manage aggressive fibromatosis.

Aggressive fibromatosis is a benign fibroproliferative tumour that can occur as a sporadic lesion or a manifestation in patients with familial syndromes, such as familial adenomatous polyposis. Tumours are characterized by the stabilization of β-catenin and the activation of β-catenin-mediated transcription. Current treatment results are far from ideal, and recurrence rates are high. As a result, there remains a need for more effective therapeutic strategies. In this work, we demonstrate the effect of hedgehog signalling inhibition on aggressive fibromatosis tumour development and β-catenin modulation. We found that hedgehog inhibition decreased cell viability and proliferation as well as total β-catenin levels in human aggressive fibromatosis tumour cells in vitro. Furthermore, following hedgehog inhibition in Apc+/Apc1638N aggressive fibromatosis mouse model, the number and volume of the tumours formed was reduced. Together, this work suggests that hedgehog signalling inhibitor agents are potential candidates to effectively manage aggressive fibromatosis.

Thesis (Ph.D.)--Bowling Green State University, 2009. / Document formatted into pages; contains vi, 78 p. : ill. Includes bibliographical references.

Source: Masters Abstracts International, Volume: 47-02, page: 0949. Adviser: Tommy Douglas. Includes bibliographical references.

Thesis (Ph.D.)--York University, 1999. Graduate Programme in Psychology. / Typescript. Includes bibliographical references (leaves 99-120). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:NQ39272

Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: aggression; swimming performance; assessment. Includes bibliographical references (p. 36-39).

Thesis (Ph. D.)--University of Texas at Austin, 2002. / Supervisor: Walter Wilczynski. Vita. Includes bibliographical references. Also available from UMI.