Thesis (M.S.)--Florida State University, 2006. / Advisor: James Whyte IV, Florida State University, School of Nursing. Title and description from dissertation home page (viewed June 13, 2006). Document formatted into pages; contains vii, 90 pages. Includes bibliographical references.

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 95-105).

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2’ -5’ –oligoadenylate synthetase 1 (OAS1) is an antiviral enzyme that in the presence of double-stranded RNA structures, such as viral genomes or single-stranded RNA transcripts with significant double-stranded character, converts ATP to a series of 2’ -5’ –oligoadenylates (2-5A). 2-5A promotes dimerization of latent ribonuclease (RNaseL) to form catalytically active RNaseL, a candidate hereditary prostate cancer (PCa) gene. RNaseL is anti-proliferative and promotes senescence and apoptosis in PCa cells. Genotyping analysis was completed on over 600 genomic DNA samples from African-American and Caucasian, normal and PCa subjects. Genotyping was performed to screen the following SNPs in the last exon of OAS1 (rs10774671, rs1131476, rs1051042 and rs2660) to determine splicing and linkage disequilibrium (LD) or LD decay in relation to PCa. The rs10774671 GG and AA genotypes generate isoform 1 (p46) and isoform 3 (p48), respectively and were distributed equally in the healthy population. However, in cases, the AA genotype (p46) was significantly associated with PCa risk (OR: 1.80, P-value: < 0.0001). The genotypic frequencies of rs1131476, rs1051042 and rs2660 demonstrated significant LD but showed no association to PCa risk. We also identified protective (AACA, OR =0.06612, P < 0.001) and risk (GACA, OR= 2.31, p Additionally, we utilized two genome-wide association studies analyzing OAS1 and variants found on chromosome 12 to determine their relationship with PCa susceptibility for meta-analysis: This was done to elucidate the role of OAS1 SNPs and chromosome 12 variants in a larger population cohort with PCa susceptibility for a greater understanding of gene to gene interactions. The genome wide association studies used were, the Geneva Multiethnic Genome-wide Scan of Prostate Cancer (MEC), containing 2,841 African-American samples (1,343 cases and 1,498 controls) and 1,660 Japanese/Latino samples (834 cases and 826 controls), as well as Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer-Primary Scan (Stage 1) - PLCO which contains 2,841 samples of European ancestry (1,172 cases and 1,157 controls). We used PLINK, a whole genome association analysis toolset, to extract data on SNPs in association with PCa.

Purpose of this study was to validate a novel CyberKnife stereotactic body radiotherapy (SBRT) treatment planning on an MRI-based 3D prostate model insert in an anthropomorphic pelvis phantom using Gafchromic EBT3 films to perform dosimetric measurements. The methodology of this study is based on a pelvis phantom and a physical printed 3D model of the prostate with dominant intra-prostatic-lesion and surrounding organs at risk segmented from a patient MR images. Cyberknife prostate treatment planning was performed to have at least 95% the planning target volumes (PTV: prostate expanded with margins of 5 mm in all directions except 3 mm posteriorly) covered by 3625 cGy (725x5) and a simultaneous dose escalation to 4750 cGy on the dominant intra-prostatic-lesion. Plan dosimetry verification was performed using Gafchromic EBT3 films on a Stereotactic Dose Verification Phantom. First, film calibration was done on Gafchromic EBT3 films exposed to various doses of 0-2500 cGy based on a LINAC (Trilogy) and CyberKnife monthly quality assurance (QA) for machine output calibration. Second, absolute dose measurements were taken by using films within the dose range 0-2250 cGy. Third, Gafchromic EBT3 films were placed in coronal and sagittal planes on the standard “blue phantom” or Stereotactic Dose Verification Phantom (SDVP) on which one fraction of the treatment plan is delivered for verification measurements. Then, on the prostate-pelvis phantom, a dosimetry inserts were used with films through the DIL region. After the calibration, the accuracy of absolute dose measurements with EBT3 was verified to be ≤ 1% in the dose range of interest (500-1500 cGy). On the SDVP phantom, comparison of films vs. plan for the coronal plane yielded ≥ 99.7% passing rates while for sagittal plane yielded ≥ 95.3% passing rates under the gamma criteria of ≤ 2% in dose and ≤ 2mm in distance to agreement (DTA). This study demonstrated that it is feasible to plan and deliver a SBRT treatment to prostate with a simultaneous dose escalation to the dominant intra-prostatic lesion.

It has been shown that tumour cells are capable of switching to glycolytic metabolism for the production of ATP even in the presence of oxygen, this is known as aerobic glycolysis or the 'Warburg effect'. The glycolytic phenotype has been associated with tumour aggressiveness and poor outcome in several cancer types. This makes the area of cancer metabolism an attractive area for the potential identification of new therapeutic targets. One key component, required for cells to maintain the glycolytic phenotype, is the presence of monocarboxylate transporters that are capable of exporting lactate. These transporters are vital for the maintenance of the intracellular pH of cells under these conditions. This study was centred around the hypothesis that altering expression of MCTs would impact on the metabolism of tumour cells and, therefore, other key characteristics of cells relating to metastatic capabilities and survival following treatment. For the purpose of this work, prostate cancer cell lines were transfected with lentiviral particles targeting overexpression of MCT1 or MCT4, or knockdown of MCT4. Following transfection, cellular metabolic profiles were assessed under normoxic and hypoxic conditions and the metastatic phenotype of each cell line was investigated. Additionally, the effect of MCT expression on response to chemotherapy and radiation therapy was explored, and a siRNA metabolome screen was performed to identify combinations of targets that may produce synthetic lethality in prostate cancer cell lines. It was shown that changes in the expression of MCT1 or MCT4 did not cause significant changes in the metastatic phenotypes of the prostate cancer cell lines investigated. Some differences were observed in the metabolic pathways used by these prostate cancer cells following alterations in MCT expression. For example, overexpression of MCT1 in DU145 cells resulted in an increase in intracellular lactate. Additionally, MCT4 knockdown in PC3 cells was able to reduce OXPHOS under reduced oxygen. MCT1 overexpression was able to sensitise androgen-independent prostate cancer cells to treatment with chemotherapy and radiation therapy. Furthermore, combinations of siRNA treatments were identified that may be capable of producing synthetic lethality. In summary, findings in this study indicated that targeting MCT1 and MCT4 expression could offer therapeutic benefit in prostate cancer. However, it was also highlighted that the roles of these transporters are specific to cancer type, and even cell line.

In the US, the incidence and mortality rates of prostate cancer (PCa) are higher among African American men compared to European American men. Obesity is an important risk factor of PCa. Obesity is known to alter the gene expression profiles in prostate tumors. This study evaluates the impact of obesity and the expression of obesity-related genes on the progression of PCa in African American men. The primary outcome of interest is biochemical recurrence (BCR) of PCa. There were 48 African American prostate cancer patients in the study. The tissue samples included 42 normal tissues, 40 Prostate Intraepithelial Neoplasia (PIN) and 45 tumor tissues (127 tissue samples in total). We assembled 99 obesity-related genes and determined the levels of their expression in the three types of tissue samples using Nanostring Technologies. An ANOVA test was used to compare the means for gene expression among normal, PIN and tumor tissue samples. Unconditional logistic regression models were used to calculate odds ratios (ORs) and their respective 95% confidence intervals (95% CIs) to determine the association between obesity and BCR as well as gene expression and BCR. Results were regarded as statistically significant if p-values were less than 0.05. A Kaplan Meier Curve was constructed to depict the survival time and time to event (BCR) among obese and non-obese African American prostate cancer patients. Patients were followed up from the date of first surgery to the date of biochemical recurrence or date of last follow-up. Statistical analysis was done with SAS 9.4 software. Forty-three obesity-related genes were statistically significantly associated with biochemical recurrence. There was no association between obesity and biochemical recurrence (BCR) in obese African American men compared to non-obese African American men (OR= 2.03, 95% CI = 0.22 - 18.77, p-value= 0.53). Twenty genes showed an upward trend in gene expression among normal, PIN and tumor tissue samples including ADIPOR1, AKRIC4, ALOX12, ALOX15, CRYBB2, EIF5A, ERG, GNPDA2, HNF1B, HSD3B1, KLK4, LEP, MC4R, MTCH2, PCSK1, PIK3CB, SLC2A2, STAT1, SULT1A1, YY1. The probability of survival (not having BCR) is lower in obese African American men compared to non-obese African American men as indicted in the Kaplan Meier curve. In other words, the probability of developing BCR is higher in obese African American men compared to non-obese African American men. We did not find a significant association between obesity and biochemical recurrence. However, we elucidated some obesity-related genes that could explain PCa carcinogenesis. Further studies are needed to determine functional significance of these selected obesity-related genes and the role they play in encouraging PCa progression in African American men.

Orientador: Renée Laufer Amorim / Coorientador: Rosemeri de Oliveira Vasconcelos / Banca: Carlos Eduardo Fonseca Alves / Banca: Andrigo Barboza De Nardi / Banca: Felipe Augusto Ruiz Sueiro / Banca: Antonio Carlos Alessi / Resumo: O câncer é uma doença complexa que precisa de um microambiente favorável para seu crescimento e progressão. Esse microambiente tumoral esta constituido por células neoplásicas, vasos sanguíneos, células imunes, fibroblastos e a matriz extracellular (MEC). Geralmente, as células neoplásicas apresentam modificações nas suas vias de sinalização. No homem, a via mTOR/4E-BP1/eIF4E foi descrita como alterada em diferentes tumores, incluindo o câncer de próstata (CP).Além do homem, o cão é espécie doméstica que desenvolve com mais frequência o CP, sendo considerada um potencial modelo para estudos na área de Oncologia Comparada. Devido à limitada informação sobre a via mTOR/4E-BP1/eIF4E e os componentes da MEC nos CP caninos, o objetivo deste estudo foi avaliar a expressão gênica e protéica de mTOR, 4E-BP-1 e eIF4E neste tipo de tumor. Outrossim, avaliar a expressão dos colágenos (C-I e C-III) pela técnica Picrosirius (PSR) e imuno-histoquímica no tecido prostático normal e neoplásico. Foram utilizadas 35 amostras de tecido prostático caninos. Identificou-se alta expressão protéica de p-mTOR e eIF4E nos CP caninos com alto GS (≥ 8), assim como, correlação positiva entre essas proteínas. Nos colágenos não foi observada diferença de expressão quando comparadas amostras de próstata normal e CP canino. De forma similar com o CP humano, estes resultados sugerem que p-mTOR e eIF4E podem ser bons marcadores para o processo carcinogênico prostático canino e estão correlacionados com alto GS... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Cancer is a complex disease that needs a favorable microenvironment for its growth and progression. This tumor microenvironment consists of neoplastic cells, blood vessels, immune cells, fibroblasts and extracellular matrix (ECM). Generally, neoplastic cells show modification in their signaling pathways. In men, the mTOR/4EBP1/eIF4E pathway has been described as altered in different tumors, including prostate cancer (PC). Apart from men, the dog is the only species that develops with high frequency the PC, being considered a potential model for comparative oncology initiatives. Due to limited information on this pathway and ECM components in canine tumors, this study aimed to investigate mTOR, 4E-BP1 and eIF4E gene and protein expression in canine PC. Additionally, to evaluate the expression of collagens (C-I and C-III) by Picrosirius Red and Immunohistochemistry in normal samples and canine PC. Were used a total of 35 formalin-fixed paraffin-embedded (FFPE) samples from canine prostatic tissue. We identified higher p-mTOR and eIF4E protein levels in the canine PC with higher GS (≥ 8), as well as, significant positive correlation between these proteins. No difference statistical was observed in the collagen expression between normal samples and canine PC. Similar to human PC; our data suggested that p-mTOR and eIF4E good markers for canine prostatic carcinogenic process and are correlated with higher GS. Also, the distribution and collagen levels are similar in normal and neo... (Complete abstract click electronic access below) / Doutor

Objetivo: Analisar a casuística de prostatovesiculectomias radicais com linfadenectomia ilíaca avaliando a validade das Tabelas de Partin versão 2001. Estudar variáveis que possam interferir no confinamento ou não da neoplasia como retardo cirúrgico, peso prostático, resultados referentes à biópsia e ano da cirurgia. Material e Métodos: Avaliação retrospectiva de 568 prontuários de pacientes submetidos à cirurgia para câncer de próstata clinicamente localizado entre 1995 até agosto de 2005 no Hospital de Clínicas de Porto Alegre. Foram excluidos quem tivesse feito hormonioterapia neoadjuvante ou com diagnóstico feito por ressecção endoscópica da próstata e aqueles com insuficiência dos dados no prontuário. Estágio clínico pelo toque retal , valores de PSA e dados da biópsia que diagnosticou a neoplasia, assim como dos dados da peça da prostatectomia radical foram coletados. Os valores preditivos das Tabelas de Partin, versão 2001 foram comparados com os do espécime cirúrgico e analisados através de Curvas R.OC. Foram também avaliados tempo de espera para cirurgia, peso da próstata, ano da cirurgia, uni ou bilateralidade tumoral na biópsia e qual a biópsia que diagnosticou (primeira ou ulterior) e analisados como fatores preditivos para confinamento ou não da neoplasia. Resultados: A idade média do pacientes foi 63 (42-77). A percentagem de estágio T1c foi de 63 %. Pacientes com escore de Gleason 2-4 na biópsia constituiram 20,2 %, notadamente antes de 2000. O percentual de pacientes com níveis de PSA menores de 4,0 ng/ml foi de 8,3 % e acima de 10,0 ng/ml foi de 35 %. Os percentuais de doença confinada ao órgão, extensão extra-prostática, invasão de vesículas seminais e metástases linfonodais foram 48,2 %, 35,3%, 13,9% e 2,6% , respectivamente. A área sob a curva calculada para doença confinada ao órgão foi de 0,65 , enquanto as áreas sob as curvas para extensão extra-prostática, invasão de vesículas seminais e metástases linfonodais foi respectivamente 0,54; 063 e 0,77. Pacientes que tiveram o diagnóstico já na primeira biópsia, ou com biópsias bilateralmente comprometidas e aqueles operados antes de 2000 tinham tendência ao não confinamento. Biópsias realizadas a partir de 2000 que já foram positivas na primeira tentativa tiveram maior tendência ao confinamento do que até 1999. Conclusão: As Tabelas de Partin tiveram valor preditivo marginal para as características patológicas finais como doença confinada ao órgão e invasão de vesículas seminais e valor preditivo importante para metástases linfonodais. Não mostraram valor preditivo para extensão extra-prostática. Bilateralidade tumoral na biópsia, diagnóstico na primeira biópsia (especialmente até 1999) e cirurgia antes de 2000 configuraram situações com tendência a tumores não confinados. / Objective: The predictive value of current Partin tables (2001) has been not validated in most of the countries as well Brazil. Therefore, we evaluated the validity of 2001 Partin tables for the ability to predict the pathological stage in specimens of radical prostatectomy. Also, we analysed how biopsies can predict results for organ confinement or not and as well what the year of the surgery can make in organ confinement issue . Materials and methods: The clinical and pathological findings of 568 patients who have had radical prostatectomy and iliac lymphadenectomy from 1995 to 2005 at Hospital de Clínicas de Porto Alegre were assessed. Those with missing information, patients who had neoadjuvant endocrine treatment and those who had the diagnosis by transurethral ressection of prostate were excluded. Serum PSA, clinical stage, biopsy characteristics and the pathological features of the specimens were collected. The predictive value of Partin tables and pathological findings of prostatectomy specimens were compared and analyzed according to Receiver Operating Characteristics curves. The delay of the surgery, prostate weight, year of the surgery, bilaterality of the biopsies and if the diagnostic biopsy was the first or not were important for the organ confined disease were also tested. Results: Median age of the patients was 63(42-77). The percentage of patients with clinical stage T1c was 63%. Gleason score 2-4 in biopsy constituted 20,2 %, at mainly before 2000. The ratio of patients with serum PSA above 4,0 ng/ml was 8,3% and higher than 10,0 ng/ml was 35%.Organ confined disease, extra-prostatic extension, seminal vesicle involvement and lymph node metastasis were 48,2%; 35,3%; 13,9 % and 2,6% respectively. Area under curve (AUC) values for organ confined disease, extra-prostatic extension, seminal vesicle invasion and lymph node involvement were 0,65 ; 0,54; 0,63 and 0,77. Tumor bilaterallity at biopsy and positive biopsy at the first procedure (at least until 1999) as well radical prostatectomy before 2000 were predictors for non organ confined prostate cancer. Conclusion: Partin tables have a marginally predictive value for the pathological features like organ confined disease and seminal vesicle involvement and a good predictive value for lymph node metastasis prediction. They don’t have predictive value for extra-prostatic extension. Positive first biopsy, bilateral tumor at biopsy and radical prostatectomy before 2000 were predictive for non organ confined disease.

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2014-05-20T18:01:40Z No. of bitstreams: 1 Polyanna Carôzo de Oliveira. Ancrestalidade... 2014.pdf: 1254857 bytes, checksum: e5708eec3bc58766116c313a7e16ea18 (MD5) / Made available in DSpace on 2014-05-20T18:01:40Z (GMT). No. of bitstreams: 1 Polyanna Carôzo de Oliveira. Ancrestalidade... 2014.pdf: 1254857 bytes, checksum: e5708eec3bc58766116c313a7e16ea18 (MD5) Previous issue date: 2014 / Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / O Cancêr de Próstata (CaP) é um dos tipos de neoplasias mais frequentes nos homens em todo o mundo e também na população masculina brasileira. A incidência, mortalidade e agressividade do CaP são maiores em homens negros. De acordo com o IBGE a Bahia é o estado que apresenta a maior porcentagem de população afrodescendente e os indivíduos que moram em Salvador apresentam maior ancestralidade africana que os nascidos no interior do estado. O presente estudo verificou a associação entre maior ancestralidade genética africana e genes de suscetibilidade ao CaP em pacientes do estado da Bahia oriundos do setor particular e público de serviço à saúde. Participaram do estudo 189 homens com CaP, sendo 82 atendidos no serviço privado e 107 no serviço público e 112 homens saudáveis atendidos no serviço público. Foram utilizados 9 marcadores informativos de ancestralidade (AIM) para estimar a ancestralidade genética e quatro genes de suscetibilidade: CYP3A4, CYP17, GSTM1 e GSTT1.No grupo caso houve maior contribuição europeia (47%) e no grupo controle maior contribuição africana (43%). Entre os genes de suscetibilidade, observou-se que o genótipo GG, bem como a associação dos genótipos GG+AG na variante CYP3A4-392 A>G estiveram relacionados ao aumento do risco de CaP tanto de modo global, bem como em indivíduos com maior ancestralidade africana, além de estarem associado positivamente com o aumento da agressividade do tumor para esta população. A variante CYP17-34 T>C não apresentou relação com aumento do risco para o CaP entre casos e controles, mas ao estratificar a população observou-se maior risco associado ao genótipo heterozigoto (TC) em indivíduos com maior contribuição africana, mas não houve relação entre a variante e o aumento da agressividade do tumor. Por fim, o genótipo GSTM1-0 esteve associado ao aumento do risco para o CaP de modo geral, mas não esteve relacionado com o aumento da agressividade do tumor. Estes resultados podem auxiliar estudos de associação entre CaP e maior suscetibilidade de populações afrodescendentes e assim, ajudar na melhoria das estratégias em torno de programas de saúde que visem ampliar a triagem e o diagnóstico precoce para esta populações mais vulneráveis. / Prostate cancer (PCa) is one of the most common types of cancer in men worldwide and also in Brazilian male population. The incidence, mortality and PCa aggressiveness are higher in black men. According to the IBGE, Bahia is the state with the highest percentage of people of African descent and people who live in Salvador has the largest African ancestry born in the state. The present study sought to determine the association between African ancestry and greater susceptibility genes in PCa patients of Bahia state from public and private sector health service. The study included 189 men with PCa, 82 served in the private and 107 public service and 112 healthy men served in the public service. We used ancestry informative markers 9 (AIM) to estimate genetic ancestry and 4 susceptibility genes, among them: CYP3A4, CYP17, GSTM1 e GSTT1. The case group was greater European contribution (47%) in the control group and largest African contribution (43%). Between susceptibility genes, it was found that the GG genotype, and the association of the genotypes GG + GA in CYP3A4-392A>G varinatwere associated with an increased risk of PCa so both overall as well as for individuals with higher African ancestry, and are positively associated with increased tumor agressivadade for this population. The variant CYP17-34T>C gene was not associated with increased risk for PCa between cases and controls, but to stratify the population was more strongly associated with the risk genotype (TC) in subjects with higher African contribution, but there was no relationship between the variant and increased tumor aggressiveness. Finally, GSTM1-0 genotype was associated with increased risk for CaP generally, but not correlate with increasing tumor aggressiveness. These results may help studies of association between PCa and greater susceptibility of African descent populations and thus help improve strategies around health programs aimed at increasing screening and early diagnosis for this most vulnerable populations.