Background: Two-thirds of U.S. adult women are overweight or obese. High body mass index (BMI) and adult weight gain are risk factors for a number of chronic diseases, including postmenopausal breast cancer. The higher postmenopausal breast cancer risk in women with elevated BMI is likely to be attributable to related metabolic disturbances including altered circulating sex steroid hormones and adipokines, elevated pro-inflammatory cytokines, and insulin resistance. Metformin is a widely used antidiabetic drug that has demonstrated favorable effects on metabolic disturbances and as such may lead to lower breast cancer risk in obese women. Further, the anti-proliferative effects of metformin suggest it may decrease breast density, an accepted biomarker of breast cancer risk. Methods/design: This is a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have elements of metabolic syndrome. Eligible participants will be randomized to receive metformin 850 mg BID (n=75) or placebo (n=75) for 12 months. The primary endpoint is change in breast density, based on magnetic resonance imaging (MRI) acquired fat-water features. Secondary outcomes include changes in serum insulin levels, serum insulin-like growth factor (IGF)-1 to insulin-like growth factor binding protein (IGFBP)-3 ratio, serum IGF-2 levels, serum testosterone levels, serum leptin to adiponectin ratio, body weight, and waist circumference. Exploratory outcomes include changes in metabolomic profiles in plasma and nipple aspirate fluid. Changes in tissue architecture as well as cellular and molecular targets in breast tissue collected in a subgroup of participants will also be explored. Discussion: The study will evaluate whether metformin can result in favorable changes in breast density, select proteins and hormones, products of body metabolism, and body weight and composition. The study should help determine the potential breast cancer preventive activity of metformin in a growing population at risk for multiple diseases.

Thesis (M.S.)--Boston University

Thesis submitted to the Faculty of Science under the school of Molecular and Cell Biology, University of the Witwatersrand, in partial fulfilment of the requirements for PhD. Gauteng, Johannesburg, 2015 / Cancer is an enormous burden of disease, accounting for millions of deaths annually worldwide. Today, more people are dying from cancer than HIV/AIDS, malaria and tuberculosis combined. According to the American Cancer Society, it is expected that the global cancer burden will double by 2030 if preventative measures are not applied. Breast and gynaecological cancers remains a big scourge in developing countries, with breast cancer being the most common cancer and gynaecological cancers accounting for approximately 25% of all cancers in women in developing countries. Currently, the standard cancer treatments include surgery, radiation and chemotherapy. Adverse toxicities have been associated with these therapies and their effectiveness is also limited to drug resistance. The cost of treatment is another major burden. Limitations associated with these conventional cancer treatments have made discoveries of novel therapeutics which exhibit less toxicity and at a lowered cost of paramount importance. Medicinal plant extracts have recently attracted attention to modern medical science research with their non-lethal activity. Currently, up to 50% of the world drugs including chemotherapeutic drugs such as taxol and camptothecin are made from natural products or their derivatives. In this study we aimed to investigate the anti-cancer properties of the medicinal plant Euphorbia tirucalli. The crude extracts of E. tirucalli extracted using butanol; hexane and methanol solvents were screened for antiproliferative activity in breast (MCF-7 and MDA-MB231), ovarian (RMG-1) and cervical (SiHa) cancer cell lines. MTT assay and Real-Time Cell Analyzer (RTCA), xCELLigence were used to determine cytotoxicity of the extracts and calculate IC50. From MTT and xCELLigence results, we observed that E. tirucalli extracts exhibited dose-dependent inhibition of cell proliferation with RMG-1 and MCF-7 cells being more sensitive than MDA-MB231 and SiHa cells to all three extracts for an unclear reason. The butanol extract appeared to exhibit iv the most cytotoxicity with all cell lines reaching IC50 at low extract concentrations. Most therapies in anticancer treatment, such as chemotherapy, mainly induce cell death by causing either G0/G1 or G2/M cell cycle arrest and then inducing an apoptotic pathway. Therefore, cell cycle arrest and the induction of apoptosis in cancer cells become the major indicators of anticancer effects. Cells were stained with propidium iodide dye to determine if cells were arrested at G0/G1 or G2/M cell cycle stages while annexin V and PI staining were used to determine the type of cell death induced by the extracts. Cell cycle analyses revealed MCF-7, MDA-MB231 and SiHa cancer cells underwent arrest at G0/G1 following treatment with the plant extracts. Annexin V and PI staining revealed different proportions of apoptotic and necrotic populations. The extracts mainly induced apoptosis on MCF-7 and MDA-MB 231 cells, with the butanolic extracts inducing the most apoptosis. RMG-1 and SiHa cells had a high proportion of cells undergoing both late apoptosis and necrosis. The molecular mechanism of cell death induction was investigated using real time PCR and western blot. From the gene expression studies, p21 was observed to be over expressed in all cells following all treatments, in line with the observed cell cycle arrest at G0/G1. The extrinsic pathway of apoptosis was identified as the type of cell death induced with caspase 8 being overexpressed in MDA-MB 231 cells treated with butanol and hexane extracts. Upon further fractionation, flavonoids and especially isorhamnetin were identified as the active compounds in these extracts. Overall, the plant contains compounds that have some activity against cell proliferation and can be a promising tool to treat cancer cells. However, more work needs to be done to verify which compounds are mainly involved.

Master of Science / Department of Human Nutrition / Weiqun Wang / Exercise has been previously reported to lower cancer risk through reducing circulating IGF-1 and IGF-1-dependent signaling in mouse skin cancer models. This study is to investigate the underlying mechanisms by which exercise might impact IGF-1 pathway regulated by p53 and p53-related proteins in mouse skin epidermis. Female SENCAR mice were pair fed an AIN-93 diet with or without 10-week treadmill exercise at 20 m/min for 60 min daily. Animals were topically treated with TPA or vehicle control 2 hours before sacrifice and the target proteins in the epidermis were assessed by immunohistochemistry and Western blotting. Under TPA or vehicle treatment, MDM2 was significantly reduced in exercised mice compared with sedentary control. Meanwhile, p53 was significantly increased. In addition, p53 transcription target proteins p21, IGFBP-3, and PTEN were elevated in response to exercise. An interaction between exercise and TPA was observed on the decrease of MDM2 and increase of p53, but not p53 down-regulated proteins. Taken together, exercise appears to activate p53 by reducing MDM2 suppression, resulting in enhanced expression of p21, IGFBP-3 and PTEN that might further induce a negative regulation of IGF-1 pathway and therefore contribute to the observed cancer prevention by exercise in this mouse skin cancer model.

Made available in DSpace on 2016-06-07T17:12:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-05-05. Added 1 bitstream(s) on 2016-06-07T17:16:49Z : No. of bitstreams: 1 000866233.pdf: 1190225 bytes, checksum: 8cd962d8b89cea674232321366f482ca (MD5) / O câncer de esôfago é um dos menos estudados e mais mortais cânceres do mundo. A despeito de avanços tecnológicos, sua sobrevida global permanece próxima a 10% em 5 anos. No entanto, o diagnóstico precoce muda radicalmente seu prognóstico, visto que o tumor in situ tem sobrevida em 5 anos maior que 95%. O carcinoma espinocelular (CEC) é o principal subtipo no Brasil (96% dos casos) e no mundo (93% dos casos). Os principais fatores de risco para o CEC de esôfago, bem como para todos os cânceres do trato aerodigestivo alto são o uso de álcool e tabaco. Assim realizou-se rastreamento de neoplasias em indivíduos etilistas e tabagistas, oriundos de duas cidades de 15 mil habitantes cada, através da realização de endoscopia do trato aerodigestivo, com o uso de Lugol. Em 164 exames diagnosticou-se 13 neoplasias (1 faríngea, 3 laríngeas, 3 esofágicas, 5 gástricas e 1 duodenal) e um caso indefinido para neoplasia na faringe. Houve diferença estatisticamente significante (p=0,02106) na prevalência de neoplasias quando se examina somente o esôfago em comparação com o exame de laringe, faringe, esôfago, estômago e duodeno. O consumo de 60g/dia de etanol ou mais aumentou a razão de chances em 5,2 [1,27 : 21,19] e o uso simultâneo de álcool e tabaco aumentou a razão de chances em 5,82 [1,55 : 21,73] para se ter um rastreamento positivo. O sexo masculino teve 12,5x [1,53 : 94,06] maior a razão de chances de seu rastreamento ser positivo em relação ao sexo feminino. Fato explicado, nesta amostra, pelo maior consumo de médio de álcool (p<0,001) e fumo (p<0,001) dos homens em relação às mulheres e também maior uso concomitante de álcool e tabaco entre os homens quando comparado com as mulheres (p<0,001). Conclui-se, com esta amostra, que ao utilizar a endoscopia para o rastreamento de todos os órgãos passíveis de serem examinados endoscopicamente, há um aumento considerável na prevalência de neoplasias...

Orientador: Érika Veruska Paiva Ortolan / Banca: Walmar Kerche de Oliveira / Banca: Cássio Vieira de Oliveira / Banca: Cláudio Lyoiti Hashimoto / Banca: Gilberto Fava / Resumo: O câncer de esôfago é um dos menos estudados e mais mortais cânceres do mundo. A despeito de avanços tecnológicos, sua sobrevida global permanece próxima a 10% em 5 anos. No entanto, o diagnóstico precoce muda radicalmente seu prognóstico, visto que o tumor "in situ" tem sobrevida em 5 anos maior que 95%. O carcinoma espinocelular (CEC) é o principal subtipo no Brasil (96% dos casos) e no mundo (93% dos casos). Os principais fatores de risco para o CEC de esôfago, bem como para todos os cânceres do trato aerodigestivo alto são o uso de álcool e tabaco. Assim realizou-se rastreamento de neoplasias em indivíduos etilistas e tabagistas, oriundos de duas cidades de 15 mil habitantes cada, através da realização de endoscopia do trato aerodigestivo, com o uso de Lugol. Em 164 exames diagnosticou-se 13 neoplasias (1 faríngea, 3 laríngeas, 3 esofágicas, 5 gástricas e 1 duodenal) e um caso indefinido para neoplasia na faringe. Houve diferença estatisticamente significante (p=0,02106) na prevalência de neoplasias quando se examina somente o esôfago em comparação com o exame de laringe, faringe, esôfago, estômago e duodeno. O consumo de 60g/dia de etanol ou mais aumentou a razão de chances em 5,2 [1,27 : 21,19] e o uso simultâneo de álcool e tabaco aumentou a razão de chances em 5,82 [1,55 : 21,73] para se ter um rastreamento positivo. O sexo masculino teve 12,5x [1,53 : 94,06] maior a razão de chances de seu rastreamento ser positivo em relação ao sexo feminino. Fato explicado, nesta amostra, pelo maior consumo de médio de álcool (p<0,001) e fumo (p<0,001) dos homens em relação às mulheres e também maior uso concomitante de álcool e tabaco entre os homens quando comparado com as mulheres (p<0,001). Conclui-se, com esta amostra, que ao utilizar a endoscopia para o rastreamento de todos os órgãos passíveis de serem examinados endoscopicamente, há um aumento considerável na prevalência de neoplasias... / Abstract: Not available / Doutor

Breast cancer is the most frequently diagnosed cancer in women worldwide.A treatment regime, both effective and safe and can only be achieved once more effective chemotherapeutic agents are discovered or identified. These “drugs” must selectively induce cell death such as apoptosis or necroptosis in the cancer cells. Apoptotic cell death allows a cell to “commit suicide” in genetically- controlled or programmed mechanism(s). The microenvironment of the tumour is important since a nurturing malignant environment is required for tumour maintenance, progression and ultimately the development of metastasis. Due to the correlation of the tumour microenvironment to aggressive tumour progression, emphasis should be placed on the constituents of the tumour’s microenvironment. In recent years, the understanding of intracellular pathways in cancer cells has increased rapidly, contributing to the development of drugs with more specific targets such as growth factors, signalling molecules, cell adhesion proteins, proteases, cell-cycle proteins, modulators of apoptosis and molecules that promote angiogenesis and metastasis. The main aim of this study was thus to identify a few potential or active compounds from a library of synthetically-derived compounds as possible alternative breast cancer treatment candidates.

Doctor of Philosophy / Department of Human Nutrition / Weiqun Wang / Body weight control via increasing exercise and/or decreasing calorie intake has been linked to a reduced cancer risk in animal models. However, the underlying mechanisms are not clear. This study assessed the impact of exercise with or without limited dietary calorie intake on the overview profiling of phospholipids and gene expression in the skin tissues of weight controlled-mice. Mice were randomly assigned to three groups: ad libitum-fed sedentary control, ad libitum-fed treadmill exercise at 13.4 m/min for 60 min/d, 5 d/wk (Ex+AL), and exercise but pair-fed with the sedentary control (Ex+PF). After 10 wks, Ex+PF but not Ex+AL mice demonstrated a significant decrease in both body weight and percentage of body fat when compared to the sedentary controls. Among 338 phospholipids measured in the skin samples by electrospray ionization mass spectrometry, most classes of phosphatidylinositol (PI), phosphatidylcholine-containing lipids with ether linkage (ePC), and some lysophosphatidylcholine (lysoPC) significantly decreased in Ex+PF mice when compared to the controls. Furthermore, some species of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) containing omega-3 18:0-22:6 fatty acyl combinations increased significantly in Ex+PF mice. A total of 25 significantly-changed phospholipids were distinguishable between diet and exercise treatments by discriminant analysis. The reduced PI in Ex+PF mice was observed concomitantly with a significant reduction of PI3K protein expression. Among the 45,101 probe sets tested in skin tissues, expression of 839 genes was significantly changed by exercise with or without limited dietary calorie intake. The genes with impacted expression were involved in oxidative stress, inflammatory response, lipolysis, protein synthesis, and signaling pathway. Up-regulated expression of genes involved in elongation of long chain fatty acids in Ex+PF but not Ex+AL mice appears to partially account for increased level of 18:0-22:5PC/PE and 18:0-22:6 PC/PE. Taken together, these data indicate that controlling body weight via exercise with limited dietary calorie intake rather than exercise alone significantly modified phospholipid and gene expression profiles. The altered profiles may be associated with cancer preventive mechanisms; in particular, reduced PI and PI-related PI3K expression and altered expression of genes involved in protein kinase activity and lipid metabolism may prevent cancer.

Ovarian cancer is a deadly gynecological disease that ranks fifth in all cancer-related deaths inwomen. The disease is often detected at an advanced stage and lack of sensitive predictive biomarkerscontribute to its poor prognosis, which is also responsible for the current five-year survival rate of only47%. Our laboratory has previously shown that a whole flaxseed supplemented diet decreases the onsetand severity of ovarian cancer in the laying hen, the only known animal model of spontaneous ovariancancer. Flaxseed is rich in omega-3 fatty acids (OM3FA), mostly α-Linoleic acid (ALA), which getsconverted to Docosahexaenoic acid (DHA) by the action of delta-6 desaturase enzyme. We have also shownthat the flaxseed diet in hens induces CYP1A1 expression in the liver while suppressing both CYP1B1 andCYP3A4 expressions. The upregulation of CYP1A1 parallels the increase in 2-hydroxyestradiol and the 2-methoxyestradiol (2MeOE2) level in the serum of the chickens. Flaxseed diet induces apoptosis to ovariantumors and not in the normal ovarian tissues. The current work explores the pro-apoptotic actions of oneof the biologically derived compounds of flaxseed diet, 2MeOE2, and describes one of its novel molecularactions. Our results indicate that 2MeOE2 -mediated pro-apoptotic actions are partly dependent on thecatalytic activation of protein kinase C delta (PKCd), which is responsible for key apoptotic histonemodifications and p38 MAPK (MAPK14) phosphorylation. Phosphorylated MAPK14, in turn, results inmore caspase-3 cleavage which activates more PKCd, therefore amplifying the apoptotic signal.The other part of this work explains one of the key anti-cancer actions of a flaxseed diet. Flaxseedreduces the number of endothelial cells and increases pericytes to endothelial cell ratio in ovarian tumorscompared to control diet-fed birds, indicating a reduction in tumor angiogenesis and an improvement inblood vessel maturation. Flaxseed decreases a-smooth muscle actin expression in ovarian tumors, whichmarks a decrease in cancer-associated fibroblasts (CAFs) in the tumor stroma. Flaxseed also reduces fibrosisin ovarian tumors. Flax -mediated reduction of ovarian fibrosis parallels an increased infiltration ofimmune cells in the preneoplastic ovaries and ovarian tumors. Therefore, this work describes how the flaxdiet differentially targets the ovarian tumor cells and the tumor stroma in preventing the incidence andseverity of ovarian cancer. Dietary supplementation with flaxseed can, therefore, be a healthy lifestylechoice as well as a potential adjuvant therapy for immunotherapy-based treatment modalities.

Twitter may be useful for learning about indoor tanning behavior and attitudes. The objective of this study was to analyze the content of tweets about indoor tanning to determine the extent to which tweets are posted by people who tan, and to characterize the topics of tweets. We extracted 4,691 unique tweets from Twitter using the terms “tanning bed” or “tanning salon” over 7 days in March 2016. We content analyzed a random selection of 1,000 tweets, double-coding 20% of tweets (κ = 0.74, 81% agreement). Most tweets (71%) were by tanners (n = 699 individuals) and included tweets expressing positive sentiment about tanning (57%), and reports of a negative tanning experience (17%), burning (15%), or sleeping in a tanning bed (9%). Four percent of tweets were by tanning salon employees. Tweets posted by people unlikely to be tanners (15%) included tweets mocking tanners (71%) and health warnings (29%). The term “tanning bed” had higher precision for identifying individuals who engage in indoor tanning than “tanning salon”; 77% versus 45% of tweets captured by these search terms were by individuals who engaged in indoor tanning, respectively. Extrapolating to the full data set of 4,691 tweets, findings suggest that an average of 468 individuals who engage in indoor tanning can be identified by their tweets per day. The majority of tweets were from tanners and included reports of especially risky habits (e.g., burning, falling asleep). Twitter provides opportunity to identify indoor tanners and examine conversations about indoor tanning.