Background: Vitamin D may be important in the causal pathway to breast cancer (BC) by influencing mammographic breast density (MD). However, previous study results in postmenopausal women are inconsistent. Study objectives were to prospectively examine the relationship between biomarkers of vitamin D (25-OH-D) and percent MD in postmenopausal women at northern latitudes. Potential effect modification by exemestane therapy, calcium or genetic polymorphisms in the vitamin D pathway was also examined. Methods: This study evaluated a sub-cohort of postmenopausal women at elevated BC risk who participated in the NCIC Clinical Trials Group placebo-controlled MAP.3 trial with exemestane. Levels of 25-OH-D were measured using LC-MS/MS from serum samples collected at baseline and year 1, averaged and adjusted for month of collection. Baseline and follow-up (≥ 3 year) percent MD was centrally assessed from film and digital mammograms with Cumulus software. Multivariable linear regression was used to estimate the effect of 25-OH-D on log transformed percent MD at follow-up and on the change in percent MD from baseline. Percent MD was also dichotomized and multivariable logistic regression was used to evaluate 25-OH-D levels between 1) women with lower (<25%) compared with higher (≥25%) percent MD and 2) women with a decrease compared with no change or an increase in percent MD over time. Results: Percent MD was measured for 568 participants with a follow-up mammogram and for 388 participants with a baseline mammogram in the same format as the follow-up. The geometric mean percent MD of the follow-up mammograms was 4.3% and few women (13.4%) had percent MD ≥ 25%. The unadjusted mean 25-OH-D concentration was 36.5 ng/mL (SD=10.6) based on pooled baseline and year one samples. After controlling for age, month of sampling and potential confounders, 25-OH-D was not predictive of log transformed percent MD at follow-up (p=0.36) or with annual mean changes from baseline (p=0.33). Similarly, results from the logistic regression analyses were not statistically significant and no interactions with exemestane, calcium or genetic polymorphisms were detected. Conclusion: No association was observed between vitamin D levels and percent MD at ≥3 year follow-up or change in percent MD from baseline. / Thesis (Ph.D, Community Health & Epidemiology) -- Queen's University, 2014-03-31 11:20:23.963

Breast cancer is the most frequently diagnosed cancer among women around the world. The hormone 17-estradiol (E2) is strongly implicated as a causative agent in this cancer. Since estrogen acts as a complete carcinogen, agents that interfere with the carcinogenic actions of E2 are required. Most agents effective against experimental mammary carcinogenesis have been employed as pure compounds disregarding the synergy that exists between several phytonutrients in a whole food. In these studies we have taken a unified approach, by employing a pure phytonutrient ellagic acid and whole foods that contain the phytonutrient at various levels berries, in the prevention of E2- induced mammary cancer in ACI rats. We have also used a tiered approach by screening several phytochemicals in vitro and implementing these results in both short- and long-term studies. Initially, several phytochemicals were tested as pure compounds against oxidative DNA damage induced by 4-hydroxy estradiol and CuCl2. Ellagic acid, was the most effective agent (andgt;98% reduction). In a short-term in vivo study, both dietary blueberry and strawberry (5% w/w), were ineffective in reducing the baseline oxidative DNA damage in the livers of CD-1 mice. However, red raspberry (5% w/w) was highly effective (50% reduction) and ellagic acid (400 ppm) was moderately effective (25% reduction). Further both diets up-regulated hepatic DNA repair genes in a similar fashion. In a long-term estradiol-induced mammary carcinogenicity study in ACI rats, dietary berries (2.5% w/w) and ellagic acid (400 ppm) reduced both tumor volume and tumors per animal to different extents (50-75%). One mechanism by which these dietary interventions inhibit mammary tumorigenesis may be via modulation of E2 metabolism, especially at the early stages of carcinogenesis. At 6 weeks after E2 treatment both berries and ellagic acid or berries alone significantly offset E2- induced changes in CYP1B1 and CYP1A1 expressions respectively. In addition, no toxicity or adverse effects are observed when rodents were fed either berries (1 - 5%) or ellagic acid (400 ppm). These data taken collectively support the possibility of using natural foods such as berries as an adjuvant to current pharmacological therapies in the prevention and treatment of breast cancer.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2007. / Title from PDF title page (viewed on Sept. 16, 2009). Includes bibliographical references (p. 87-96).

Thesis (Ph.D.)--Medical University of Ohio, 2006. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medical Sciences." Major advisor: Michael A. Pereira. Includes abstract. Document formatted into pages: v, 152 p. Title from title page of PDF document. Title at ETD Web site: Involvement of DNA methylation and CpG endonuclease activity in environmental carcinogenesis and cancer chemoprevention. Bibliography: pages 65-66, 90-92, 123-125, 137-150.

Orientador: Luís Fernando Barbisan / Resumo: A capsaicina (8-metil-N-vanilil-trans-6-nonamida) é uma substância alcaloide de natureza lipofílica, responsável pela pungência de pimentas e pimentões. Apresenta propriedades anti-inflamatória, antimicrobiana e antioxidante bem descritas na literatura científica. Assim, este projeto teve como objetivo investigar se a capsaicina apresenta efeito quimioprotetor quando administrada na etapa de promoção/progressão da carcinogênese de cólon induzida pela 1,2-dimetilhidrazina (DMH). Ratos Wistar machos foram alocados em seis grupos experimentais com 10 a 15 animais cada. Os animais dos grupos 1-3 receberam quatro injeções subcutâneas (s.c) do carcinógeno DMH (40mg/kg, duas doses/semana) e os animais do grupo 4-6 receberam quatro injeções s.c de solução de EDTA .Os grupos 2 e 4 receberam por gavagem 5mg/kg p.c e os grupos 3 e 5 receberam 50mg/kg p.c de capsaicina diluída em óleo de milho até o final da 24ª semana do experimento. Após a eutanásia dos animais, os cólons distal, medial e proximal foram corados com azul de metileno a 2% para detecção de focos de criptas aberrantes (FCA). Após a análise de FCAs, os cólons foram processados para análise histológica e classificação de tumores. As amostras congeladas foram utilizadas para análise de expressão de gênica pela técnica Taqman® Low Density Array (TLDA). Os níveis séricos de ALT (p=0,346) e creatinina (p=0,854) foram semelhantes entre os grupos, mostrando que as doses de capsaicina utilizadas não apresentaram ação citotóxica par... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Capsaicin (8-Methyl-N-vanillyl-(trans)-6-nonenamide) is a lipophilic alkaloid, responsible for the pungency in pepper. Its antiinflamatory, antimicrobial and antioxidant properties are well described in the scientific literature. Thus, the objective of this study was to investigate whether capsaicin exerts a chemoprotective effect when administered during 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis promotion/progression in rates. Male Wistar rats were allocated into six groups of 10-15 animals each. Groups 1-3 received 4 subcutaneous injections of DMH (40 mg/kg bw, 2 doses/week), while groups 4-6 received EDTA solution (DMH vehicle, 2 doses/week), followed by intragastric 5mg/kg bw capsaicin diluted in corn oil (G2, G4) or 50mg/kg bw (G3, G5) for 24 weeks (3 doses/week). After sacrifice, blood samples were drawn by heart puncture for the assessment of serum alanine aminotransferase (ALT) and creatinine levels, and the colon was removed. A segment of distal colon and colon tumor samples were frozen in liquid nitrogen at -80ºC. Distal, medial and proximal colon samples were stained with 2% methylene blue for the detection of aberrant crypt foci (ACF).After ACF analysis, colon tumors were processed for histological analysis and tumor classification. The frozen samples were used for the analysis of gene expression by Taqman® Low Density Array (TLDA). Serum ALT (p=0.346) and creatinine (p=0.854) levels were similar among groups, indicating that the capsaicin doses use... (Complete abstract click electronic access below) / Doutor

Orientador: Luis Fernando Barbisan / Resumo: A capsaicina (8-Metil-N-vanilil-(trans)-6-nonamida) é um composto alcaloide lipofílico e o principal componente responsável pela pungência em pimentas vermelhas, consumidas mundialmente. Estudos sobre o potencial mutagênico e genotóxico da capsaicina apontam resultados inconsistentes e conflitantes. Neste estudo, avaliamos o potencial genotóxico e os mecanismos moleculares envolvidos nos efeitos anti-proliferativos e pró-apoptóticos da capsaicina na carcinogênese de cólon induzida pela 1,2-dimetilhidrazina (DMH) em ratos. Ratos Wistar machos foram randomicamente alocados em seis grupos (n=16). Durante as quatro primeiras semanas do experimento, os grupos 1 e 6 receberam doses intragástricas de óleo de milho (veículo da capsaicina), enquanto a capsaicina foi administrada nas doses de 5mg/kg aos grupos 2 e 4 e 50 mg/kg aos grupos 3 e 5, três vezes por semana. Durante a terceira e quarta semana, todos os animais receberam quatro injeções subcutâneas de DMH (grupos 1-3, 40mg/kg) ou EDTA (grupos 4-6, veículo do DMH), duas vezes por semana. Os animais foram sacrificados 24 horas (n=6) e 22 semanas (n=10) após o tratamento com DMH. Vinte e quatro horas após o tratamento com a DMH, a administração de capsaicina diminuiu significativamente a genotoxicidade induzida pela DMH em leucócitos do sangue periférico, bem como a genotoxicidade da água fecal em células CaCO-2. A capsaicina também reduziu o índice de proliferação de Ki-67 e aumentou a expressão de caspase-3 ativada no cólon dos ... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Made available in DSpace on 2014-06-11T19:27:55Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-07-29Bitstream added on 2014-06-13T18:56:50Z : No. of bitstreams: 1 silva_frm_me_botfm.pdf: 2481576 bytes, checksum: 0cc379f4b864c599808f845e21be54a1 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O presente estudo foi delineado para investigar a possível ação quimioprotetora do quelato de zinco (ZnGly), na etapa de iniciação da carcinogênese do cólon, induzida pela 1,2- dimetilhidrazina (DMH) em ratos Wistar machos. Os animais foram distribuídos em quatro grupos experimentais e receberam três doses de 40mg/Kg, via subcutânea (sc) de DMH ou EDTA (veiculo da DMH) e 15mg/Kg de quelato de zinco (ZnGly) por gavagem durante quatro semanas. Após a narcose foram coletadas amostras de sangue e, em seguida fragmentos do cólon para dosagens de zinco. O cólon foi removido inteiro, fixado em formalina tamponada a 10%, corado com azul de metileno para análise de incidência de focos de criptas aberrantes (FCAs) e processado histologicamente para análise dos índices de proliferação celular e apoptose. A exposição à DMH aumentou significativamente os índices de proliferação celular e apoptose na mucosa do cólon. A administração do quelato de zinco (ZnGly) não alterou o número e multiplicidade de FCAs e não modificou as taxas de proliferação celular e de apoptose da mucosa do cólon, tanto no grupo tratado com DMH como no respectivo grupo controle. Os resultados deste estudo indicam o zinco não mostrou ação protetora na etapa de iniciação da carcinogênese do cólon induzida pela DMH em ratos Wistar machos / The present study was designed to investigate the possible chemopreventive action of zinc gluconate (ZnGly) on the initiation step of colon carcinogenesis induced by 1,2- dimethylhydrazine (DMH) in male Wistar rats. The animals were divided into four groups and received three doses of DMH (40 mg/Kg, s.c) or EDTA (DMH vehicle) and 15 mg/Kg of zinc glycine (ZnGly) administered by gavage for four weeks. After the narcosis, blood and colon fragments samples were collected for zinc dosage. The entire colon was removed, fixed in buffered formalin 10%, stained with methylene blue for the analysis of ACF formation. The rates of cell proliferation and apoptosis were also analyzed in epithelial crypt cells. The exposure to DMH significantly increased the rates of cell proliferation and apoptosis in epithelial cript cells. Treatment with zinc glycine (ZnGly) did not alter the number and multiplicity of ACFs, as well as apoptosis and cell proliferation indices in both DMH-treated and control group. The present findings indicate that zinc did not present chemopreventive effects on the initiation step of DMH-induced colon carcinogenesis in male Wistar rats

Made available in DSpace on 2014-06-11T19:29:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-03-05Bitstream added on 2014-06-13T19:38:11Z : No. of bitstreams: 1 dametto_ac_me_araiq.pdf: 739116 bytes, checksum: f5283ac0f16f0bbf99286af2ff4f59ae (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Eugenia jambolana é uma planta da famíla Myrtaceae, oriunda da Índia Oriental. No Brasil é conhecida como jambolão e suas folhas contêm uma mistura de polifenóis, especialmente flavonóides glicosilados, taninos elágicos e ácidos fenólicos. Os frutos contêm vitamina C, ácido gálico, taninos e antocianinas. As antocianinas constituem o maior grupo de flavonóides responsáveis pelas cores rosa, vermelho, violeta e azul encontradas em muitas flores, frutos e folhas. As antocianinas apresentam forte atividade antioxidante, e efeitos inibitórios no desenvolvimento de algumas linhagens de células cancerígenas. As condições de extração e de análise cromatográfica dos frutos foram otimizadas e oito antocianinas: delfinidina-diglicosídeo, cianidina-diglicosídeo, petunidina-diglicosídeo, malvidina-diglicosídeo, delfinidina-glicosídeo, cianidina-glicosídeo, petunidina-glicosídeo e malvidina-glicosídeo, presentes no extrato bruto dos frutos foram identificadas por CLAE-DAD e CLAE-EM/EM. As frações foram submetidas a diferentes técnicas de fracionamento, incluindo cromatografia em contracorrente de alta velocidade, cromatografia de permeação em gel, cromatografia em coluna usando sílica em fase reversa e cromatografia líquida de alta eficiência no modo preparativo. Estes fracionamentos, resultaram no isolamento e identificação de três antocianinas: delfinidina-3-O-gentiobiosídeo, petunidina-3-O-gentiobiosídeo e malvidina-3-O-gentiobiosídeo, através de análises de EM e RMN. Os extratos brutos dos frutos e das folhas e as frações obtidas das partições líquido-líquido foram testadas quanto às suas bioatividades e mostraram elevada ação sequestradora de radicais livres e quimiopreventiva, detectadas pelos ensaios com DPPH e pela indução da enzima quinona-redutase. Adicionalmente, as frações de E. jambolana testadas apresentaram atividade... / Eugenia jambolana is a plant from Myrtaceae, originally from eastern India. In Brazil it is known as “jambolão” and its leaves contain a mixture of polyphenols, especially flavonoid glycosides, ellagitannins and phenolic acids. The fruits contain vitamin C, gallic acid, tannins and anthocyanins. Anthocyanins are the largest group of flavonoids responsible for pink, red, violet and blue colors found in many flowers, fruits and leaves. The aglicone of anthocyanins is structurally based on the flavilium ion at pH <3. Anthocyanins exhibit strong antioxidant activity besides inhibitory effects on the development of some cancer cell lines. The conditions of extraction and chromatographic analysis of fruits were optimized and identification of eight anthocyanis: delfinidin-diglucoside, cyanidin-diglucoside, petunidin-diglucoside, malvidin-diglucoside, delfinidin-glucoside, cyanidin-glucoside, petunidin-glucoside and malvidin-glucoside, from the crude extract was carried out using HPLC-DAD and HPLC-MS/MS. Crude extracts and semipurified samples were subjected to various fractionation techniques, including HSCCC, GPC and reversed phase CC and preparative HPLC, which resulted in the isolation of three anthocyanins: delfinidin-3-O-gentiobioside, petunidin-3-O-gentiobioside and malvidin-3-O-gentiobioside through MS and NMR spectrometric analysis. Crude extracts of fruits and leaves, and the fractions resulting from liquid-liquid partition were evaluated for their bioactivity and displayed potent free radical scavenging and chemopreventive activities, using the DPPH and quinone-reductase induction assays. Additionally, the tested samples from E. jambolana presented antimalarial, antiacetylcholinesterase and antifungal activities towards human pathogenic fungi

Resumo: O presente estudo foi delineado para investigar a possível ação quimioprotetora do quelato de zinco (ZnGly), na etapa de iniciação da carcinogênese do cólon, induzida pela 1,2- dimetilhidrazina (DMH) em ratos Wistar machos. Os animais foram distribuídos em quatro grupos experimentais e receberam três doses de 40mg/Kg, via subcutânea (sc) de DMH ou EDTA (veiculo da DMH) e 15mg/Kg de quelato de zinco (ZnGly) por gavagem durante quatro semanas. Após a narcose foram coletadas amostras de sangue e, em seguida fragmentos do cólon para dosagens de zinco. O cólon foi removido inteiro, fixado em formalina tamponada a 10%, corado com azul de metileno para análise de incidência de focos de criptas aberrantes (FCAs) e processado histologicamente para análise dos índices de proliferação celular e apoptose. A exposição à DMH aumentou significativamente os índices de proliferação celular e apoptose na mucosa do cólon. A administração do quelato de zinco (ZnGly) não alterou o número e multiplicidade de FCAs e não modificou as taxas de proliferação celular e de apoptose da mucosa do cólon, tanto no grupo tratado com DMH como no respectivo grupo controle. Os resultados deste estudo indicam o zinco não mostrou ação protetora na etapa de iniciação da carcinogênese do cólon induzida pela DMH em ratos Wistar machos / Abstract: The present study was designed to investigate the possible chemopreventive action of zinc gluconate (ZnGly) on the initiation step of colon carcinogenesis induced by 1,2- dimethylhydrazine (DMH) in male Wistar rats. The animals were divided into four groups and received three doses of DMH (40 mg/Kg, s.c) or EDTA (DMH vehicle) and 15 mg/Kg of zinc glycine (ZnGly) administered by gavage for four weeks. After the narcosis, blood and colon fragments samples were collected for zinc dosage. The entire colon was removed, fixed in buffered formalin 10%, stained with methylene blue for the analysis of ACF formation. The rates of cell proliferation and apoptosis were also analyzed in epithelial crypt cells. The exposure to DMH significantly increased the rates of cell proliferation and apoptosis in epithelial cript cells. Treatment with zinc glycine (ZnGly) did not alter the number and multiplicity of ACFs, as well as apoptosis and cell proliferation indices in both DMH-treated and control group. The present findings indicate that zinc did not present chemopreventive effects on the initiation step of DMH-induced colon carcinogenesis in male Wistar rats / Orientador: Maria Aparecida Marchesan Rodrigues / Coorientador: Luis Fernando Barbisan / Banca: Daniel Araki Ribeiro / Banca: Alaor Aparecido Almeida / Mestre

Philosophiae Doctor - PhD / Lung cancer is the most common fatal cancer in terms of both incidence and mortality in the world. The most important cause of lung cancer is exposure to tobacco smoke through active or passive smoking. Nicotine which is a major component of tobacco could be assumed to be a tumour promoter since it had been indicated to stimulate tumour growth. Over expression of Bcl-2 in human lung cancer cells blocked the induction pathways (type I and II) of apoptosis. The increase in Bcl-2 in patients with lung cancer had also been linked to nicotine. In recent years nicotine replacement therapy has become a therapeutic method to treat smoker’s withdrawal symptoms and to advise cancer patients to stop smoking because, numerous cancer patients continue to smoke after their diagnosis. Non small cell lung carcinomas constitutes for approximately 80% of lung cancer cases. However, even with the development and improvement in conventional treatments of surgery, radiation and chemotherapy, the 5 year survival rate for these patients remains less than 15%. Chemoprevention, an approach to control cancer, is the use of specific natural or synthetic substances with the objective of delaying, reversing, suppressing or preventing carcinogenic progression to invasive cancer. A promising tool for chemoprevention against lung cancer could be prostaglandin A2 (PGA2), since it had been shown to have inhibitory effects on various cancer cell growth. The search for more effective agents, or combination therapies that could induce apoptosis in lung cancer are currently under investigation as a therapeutic target for the treatment of lung cancer. In order to elucidate the effect of nicotine and PGA2 on lung cancer cell proliferation in this study, an over view of the following was given;the cell cycle, tubulin, nucleoli, apoptosis, lung cancer, the etiology of cancer with reference to tobacco smoke and nicotine, the nutritional influence on carcinogenesis with reference to essential fatty acids and prostaglandins and chemoprevention.The supplements nicotine and PGA2 were administered to the NCI-H157 lung cancer cell line at the concentrations of 1 mM, 1 μM and 1 nM for nicotine and 5, 10 and 20 μg/ml PGA2. The effect of combinations of nicotine and PGA2 on the proliferation and survival was also tested. 5 μg/ml PGA2 was added to 1 mM, 1 μM and 1 nM nicotine respectively. This was also done for 10 and 20 μg/ml PGA2.These concentrations were administered to the cell culture and exposed for three different time exposures, namely 24, 48 and 72 hours. The objectives were: 1) To determine the effect of nicotine and PGA2 and combinations thereof on the growth(proliferation) of the NCI-H157 cells, where early results indicative of apoptosis lead to the investigation of the influence of nicotine and PGA2 on apoptosis. The effect of nicotine and PGA2 and their combinations on the morphology of interphase and dividing cells, as well as on the morphology of the dying cells were compared and quantified. 2) To study the effects of nicotine and PGA2 and their combinations on the nucleolar organizer region using silver stain. 3) To study the effects of nicotine and PGA2 or combinations thereof on the cytoskeleton (α-tubulin) of the cancer cells with aid of indirect immunofluorescence and to identify apoptotic cells using Hoechst 33342. 4) To determine the effect of nicotine and PGA2 and their combinations on cell cycle progression and apoptosis induction in the transformed cells using flow cytometry (DNA propidium iodide stain, Annexin V and caspase-3).In order to verify the effects of nicotine and PGA2 and their combinations on protein synthesis, SDS-PAGE and immunoblotting was employed.This study indicated the anti-apoptotic effects of nicotine. It maintained and stimulated cell proliferation of the NCI-H157 cell line. PGA2 demonstrated that it has a pro-apoptotic effect. The concentrations of 10 and 20 μg/ml PGA2 decreased cell proliferation and demonstrated its pro-apoptotic effects more effectively than 5 μg/ml PGA2. The combination of 10 and 20 μg/ml PGA2 and nicotine (1 mM, 1 μM and 1 nM) also showed a more pronounced induction of apoptosis than 5 μg/ml PGA2 and nicotine (1 mM, 1 μM and 1 nM). PGA2 therefore demonstrated that it blocked the mitogenic and anti-apoptotic effects of nicotine. With its pro-apoptotic effects, PGA2 could therefore be assumed to be a chemopreventive agent. However,it was evident that apoptotic induction was stimulated via both a dependent and an independent caspase-3 pathway and therefore further investigation is needed to indicate which pathway was activated. This study identified PGA2 as a chemopreventive agent for in vitro conditions; however, further studies are also needed to investigate the effect of in vivo conditions.