Thesis (M.S.)--Indiana University, 2007. / Title from screen (viewed on Apr. 27, 2007) Department of Pharmacology & Toxicology, Indiana University-Purdue University Indianapolis (IUPUI) Includes vita. Includes bibliographical references (leaves 71-84)

Thesis (B.A. (Hons.)) - University of Queensland, 2006. / Includes bibliography.

Thesis (Ph. D.)--University of Hong Kong, 2006. / Also available online.

Thesis (Ph. D.)--Case Western Reserve University, 2007. / [School of Medicine] Department of Pharmacology. Includes bibliographical references. Available online via OhioLINK's ETD Center.

No description available.

This study examines the validity of using a combination of two psychometric measures, an emotional adjustment measure, and functional assessment measures to predict vocational outcome in a traumatically brain injured population. Patients included 33 males and 11 females, with an average age of 32.3 years, and a stable work history over the past three years prior to injury. All had sustained a traumatic brain injury in the 12 months prior to initial testing, with a mean of 3.8 months since injury. Levels of severity of injury included 24 patients with severe injury, 12 patients with moderate injury, and 8 patients with mild injury. Patients completed the Logical Memory subtest (LM) of the Wechsler Memory Scale-Revised, Paced Auditory Serial Addition Test (PASAT), Beck Depression Inventory (BDI), and Personal Capacities Questionnaire (PCQ). A clinician working closely with the patient also completed the Functional Assessment Inventory (FAI) and the Behavior Checklist (BC) at the time of initial testing. Follow-up testing on available patients (n=16) was completed approximately six months after initial testing. Comparison of the functional assessment measures demonstrated that patients exhibited a decreased awareness of functional limitations relative to clinician's ratings, but identified an increased number of personal strengths. The present study demonstrates the first comparison of FAI and PCQ ratings in a TBI population, as well as the first available field research using the PCQ. Results also indicated that the only significant predictor on earned income after six months was the overall functional limitations score on the PCQ. The only significant difference in patients' test performance at six months with scores at initial testing was seen on the PASAT, which suggested that patients had a significant improvement in their speed of information processing after six months. In addition, comparison of patients from Canadian and American rehabilitation agencies, respectively, revealed no significant differences between patients at either initial testing or at follow-up. / Graduate

Orientador: Daisy Maria Fávero Salvadori / Banca: Noeme Souza Rocha / Banca: Maria Inês de Campos Pardini / Banca: Catarina Satie Takahashi / Banca: Eneida de Moraes Marcílio Cerqueira / Resumo: Os linfomas representam um grupo heterogêneo de tumores que acometem o tecido linfóide nodal e extranodal. O tratamento, baseado na utilização da poliquimioterapia associada ou não à radioterapia, tem proporcionado altas taxas de cura. Entretanto, é sabido que tais terapias podem induzir mutações genéticas que, mais tarde, podem ser responsáveis pelo desenvolvimento de neoplasias secundárias. Assim sendo, o presente estudo objetivou avaliar os efeitos tardios das terapias antineoplásicas para linfomas. Para isso, foram investigados os danos no DNA e a capacidade de reparo da molécula pelo teste do cometa, e a relação entre polimorfismos e expressão de dois genes de reparo do DNA - XRCC1 (codons 280 e 399) e hOGG1 (codon 326) - com os níveis de lesões genotóxicas. A casuística do estudo incluiu 3 grupos de indivíduos: 14 pacientes recém-diagnosticados com linfoma e antes de qualquer tratamento antineoplásístico (grupo pré-terapia); 29 pacientes com história de linfoma e que haviam finalizado o tratamento há no mínimo 2 anos (histopatologicamente negativos para neoplasia; grupo pós-terapia); 29 indivíduos saudáveis pareados por sexo, idade e hábito tabagista (grupo controle). Os resultados mostraram que os pacientes com diagnótico ou história de linfoma (pré e pós-terapia, respectivamente), apresentavam níveis aumentados de danos no DNA quando comparados aos indivíduos saudáveis. Esses dados evidenciam a relação entre a presença da doença e lesões no DNA, e que mesmo com diagnóstico negativo, os indivíduos com história de linfoma apresentam níveis aumentados de genotoxicidade até, em média, sete anos após o término da terapia. A menor capacidade de reparo do DNA observada nos pacientes do grupo pós-terapia, e o menor nível de expressão dos genes XRCC1 e hOGG1 nos pacientes pré e pós-terapia, poderiam ser explicações para tais achados... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Lymphomas are a heterogenous group of malignancies that arise in nodal sites with or without extranodal involvement. The treatment, based on polychemotherapy associated or not with radiotherapy, has provided high cure rates. However, it is known that such therapies can induce genetic mutations that could be related to development of second malignancies. Therefore, the present study aimed to evaluate the late effects of antienoplastic therapies for lymphomas. DNA damage and repair capability as depicted by the comet assay, and the relationship between DNA repair genes polymorphisms (XRCC1 codons 280 and 399, hOGG1 codon 326) or gene expressions and the levels of DNA lesions were investigated. Three groups were included in this study: pre-therapy, with 14 patients newly diagnosed with lymphoma and before any antienoplastic; post-therapy, with 29 patients with history of lymphoma and who had finished treatment at least three years before blood collection (histopathologically negative for neoplasia); control, with 29 healthy subjects matched for age, sex and smoking habit. The results showed that patients from pre- and post-therapy groups presented higher amount of DNA damage than the healthy subjects. These data first indicated that individuals with lymphoma have high frequency of primary DNA lesion in lymphocytes, then, that even with negative histopathological diagnostic, patients with history of lymphoma presented increased DNA damage until the average of 7 years after the end of therapy. The reduced DNA repair capability and the low XRCC1 and hOGG1 expression observed in the post-therapy group could explain such findings. Furthermore, higher DNA repair capability was observed in those subjects with XRCC399arg/arg, XRCC1280arg/his and hOGG1326ser/ser genotypes. In conclusion, our data demonstrated that lymphomas were associated with high level of damage and low DNA repai... (Complete abstract click electronic access below) / Doutor

Cells respond to the induction of DNA damage with activation of the DNA damage response (DDR), a complex signalling network which orchestrates cell cycle arrest and DNA repair in order to maintain genomic stability and cell viability. Activation of these signalling pathways enables cancer cells to survive DNA damaging chemo- or radiotherapy and contributes to the development of therapy resistance. Therefore, components of the DDR have become attractive targets for chemo- or radiosensitisation. Furthermore, cancer cells frequently exhibit defects in certain DDR components and may, as a consequence, become highly dependent on remaining DDR pathways to survive DNA damage. Two apical mediators of the DDR are the serine/threonine protein kinases ATM and ATR. ATM is frequently mutated in non-small cell lung cancer (NSCLC), and defects in ATM may render the tumour cells dependent on ATR signalling for survival. In this study, we characterised the functional consequences of ATM mutations in NSCLC cell lines and established an immunohistochemistry-based assay to identify patients with loss of ATM expression. As a single agent, pharmacological ATR inhibition (ATRi) was selectively cytotoxic for cells deficient in both ATM and p53. Furthermore, ATRi in combination with either ATM or PARP inhibition selectively killed tumour cells with mutant p53. We show that following ATR inhibition, ATM and p53 perform critical cell cycle checkpoint functions, independently of each other. Our results suggest that while retained function in any of these pathways is sufficient to maintain cell viability, functional loss of ATM, ATR and p53 results in premature mitotic entry, chromosome fragmentation and mitotic catastrophe. We conclude that in NSCLC the functional status of both ATM and p53 determines the cellular response to ATR inhibition, and propose that a combination of ATR inhibition with ATM or PARP inhibition may have broad utility for the treatment of p53-mutated NSCLC.

abstract: In-situ fatigue damage diagnosis and prognosis is a challenging problem for both metallic and composite materials and structures. There are various uncertainties arising from material properties, component geometries, measurement noise, feature extraction techniques, and modeling errors. It is essential to manage and incorporate these uncertainties in order to achieve accurate damage detection and remaining useful life (RUL) prediction. The aim of this study is to develop an integrated fatigue damage diagnosis and prognosis framework for both metallic and composite materials. First, Lamb waves are used as the in-situ damage detection technique to interrogate the damaged structures. Both experimental and numerical analysis for the Lamb wave propagation within aluminum are conducted. The RUL of lap joints under variable and constant fatigue loading is predicted using the Bayesian updating by incorporating damage detection information and various sources of uncertainties. Following this, the effect of matrix cracking and delamination in composite laminates on the Lamb wave propagation is investigated and a generalized probabilistic delamination size and location detection framework using Bayesian imaging method (BIM) is proposed and validated using the composite fatigue testing data. The RUL of the open-hole specimen is predicted using the overall stiffness degradation under fatigue loading. Next, the adjoint method-based damage detection framework is proposed considering the physics of heat conduction or elastic wave propagation. Different from the classical wave propagation-based method, the received signal under pristine condition is not necessary for estimating the damage information. This method can be successfully used for arbitrary damage location and shape profiling for any materials with higher accuracy and resolution. Finally, some conclusions and future work are generated based on the current investigation. / Dissertation/Thesis / Doctoral Dissertation Mechanical Engineering 2016

Neuropsychologists are asked to provide information regarding a person's ability to work following a traumatic brain injury (TBI). The tests used by Neuropsychologists were not constructed to identify specific abilities required for successful job performance. The lack of criterion-related validity information makes it difficult to relate data obtained from neurospychological tests to specific occupations (Clemmons, 1985; Heaton & Chelune, 1978; Prigatano et al. 1986). This presents serious limitations for vocational assessment and rehabilitation of persons with traumatic brain injuries. The General Aptitude Test Battery (GATB) is the vocational aptitude battery most widely used in vocational assessment. The GATB's relationship to work demands makes it the most practical assessment tool available for job screening and matching. Interpretive data for the GATB with persons with brain damage are scant (Clemmons, 1985; Cole, 1984). The person's ability to work following a traumatic brain injury results from the interaction between their abilities/disabilities and demands of occupations. Research in neuropsychology related to the vocational abilities of brain-injured individuals has centered on measuring the person's incapacity. This research investigates the GATB as an aptitude test battery for use with individuals with brain injuries and its usefulness for job matching with this population. The relationship between the person's measured aptitudes (GATB) and aptitude demands of occupations (PAQ) is examined. This is referred to as the person-job fit measure. The GATB was administered to sixty (60) individuals with TBI. The Position Analysis Questionnaire (PAQ) was used to analyze participants' occupations. It provides an estimate of the GATB aptitude scores of incumbents successfully performing the position analyzed, that is, the aptitude demands of the job. Two categories of occupations were analysed: "Can do": Occupations participants have the ability to perform, including positions currently held and jobs they have held since being injured and are no longer performing for reasons unrelated to the brain injury; and "Cannot do": occupations participants are unable to return to, or were unable to maintain for reasons related to the brain injury. Occupations were considered only if the person's ability or inability to do the job could be verified with the employer, co-worker(s), or the professionals who assessed her (his) vocational potential. The structure of the GATB was investigated first with a large sample of regular job applicants and the confirmed structure was verified with the study sample. The GATB performance of this group of persons with TBI was examined. Lastly, the ability of the measure of person-job fit to correctly classify participants by job category was analyzed. The results confirmed that the eight GATB aptitudes can be regrouped into three composites. Although this is useful for some applications, for the clinical intervention in a vocational rehabilitation process, the use of all eight GATB aptitudes is recommended. The GATB scores of participants in this study tended to be lower than the General Working Population on many of the GATB aptitudes. This reinforces the need for vocational rehabilitation intervention to help brain-injured persons enter or reenter the work force. Results indicated that the measure of person-job fit using the GATB in conjunction with the PAQ provided a good indicator of that person's ability or inability to do a specific job. The person-job fit measures obtained from the GATB cognitive and perceptual aptitude composites are the best predictors of ability to work with this sample. The usefulness of the GATB motor aptitude and composite is questionable. / Graduate