Principal Investigator: Caitlin Phillips-Chavez (Honours)



RESEARCH PROJECT PROTOCOLA retrospective cross-sectional cohort trial assessing the implications of MTHFR polymorphisms on DNA methylation and platinum resistance in ovarian cancer patientsPrincipal Investigator: Caitlin Phillips-Chavez (Honours)Chief Investigator: Dr Janet Schloss (PhD)Co-Investigator: Dr Michael Watson (PhD)Co-Investigator: Dr Jim Coward (BSc(Honours) MBBS MRCP (UK) FRACP PhD)Title A retrospective cross-sectional cohort trial assessing the implications of MTHFR polymorphisms on DNA methylation and platinum resistance in ovarian cancer patientsPurposeTo assess the influence of methylene tetrahydrofolate reductase (MTHFR) polymorphisms and diet on platinum responsiveness in ovarian cancer patientsAimsHow might platinum response be affected by the presence of MTHFR polymorphisms.What role does dietary and/or supplementary intake of folate play in platinum resistance.Can we identify a contributor or protective prognostic marker in platinum resistance.DesignRetrospective, cross-sectional cohort (pilot) studyNumber of ParticipantsThe total number of participants in the trial will be n=30 based on the central limit theory, with a power of 48% and confidence level of 95%Types of ParticipantsAdult females aged 18 – 80 yearsKey Inclusion CriteriaDiagnosed with ovarian, fallopian tube, epithelial or peritoneal cancerCompleted first line platinum therapyDiagnosed with refractory/resistant disease or platinum sensitive disease a minimum of 6 months after platinum therapyKey Exclusion CriteriaNon-English speaking Never received a platinum drug for ovarian cancer diagnosisDurationThe trial will run for 8 weeks. There will be a single data collection point for each participant.Outcome measures Primary Outcome will measure; To examine any differences between MTHFR polymorphism presence in platinum resistant versus platinum sensitive patients with ovarian cancer. Secondary Outcomes will measure;To investigate folate intake (epigenetic or direct impact on cancer progression) and difference between platinum resistant and platinum sensitive ovarian cancer patients.Investigate any correlations or predictors of platinum resistance or sensitivity in ovarian cancer patients which may be related to nutrient intake and/or MTHFR statusStudy centre / siteMulti-centre trial located at ICON Cancer Care Southport and Brisbane Day HospitalsEthics Approval Ethics approval will be through ICON Cancer Care HREC and Endeavour College of Natural Health HREC. The trial will be registered on ANZCTRData AnalysisAll data will be analyzed on STATA ?14. Associations between variables such as the presence or absence of MTHFR polymorphisms will be subject to the chi-square test. Logistic regression will be applied to determine the correlation between the existence and/or absence of any of the test variables (folate intake and/or MTHFR polymorphisms) and platinum response. Further analysis may occur once all variables are determined.List of AbbreviationsCPG islandCytosine phosphate guanine islandCRFCase Report FormDQES v3.2Dietary Qestionnaire version 3.2FACT-OFunction Assessment of Cancer Therapy – Ovarian CancerMTHFRMethylene Tetrahydrofolate ReductaseSNPSullivan and Nicolaides PathologyUICUnique Identifier CodePrefaceThis document is a clinical research protocol for a human research study. This study is to be conducted according to the Australian Clinical Trials Guidelines: Australian Government, National Health and Medical Research Council, Department of Industry, Innovation and Science.AimThe research project aims to investigate three significant questions relating to platinum resistance and ovarian cancer.How might platinum response be affected by the presence of MTHFR polymorphisms.What role does dietary and/or supplementary intake of folate play in platinum resistance.Can we identify a contributor or protective prognostic marker in platinum resistance.1.1The hypothesis:The presence of MTHFR polymorphisms may improve response to platinum drug therapy in ovarian cancer.1.2The objectives: To examine whether there is a difference between MTHFR polymorphisms in platinum resistant versus platinum sensitive patients with ovarian cancer.To investigate folate intake (epigenetic or direct impact on cancer progression) and the difference between platinum resistant and sensitive patients with ovarian cancerTo investigate any correlations or predictors of platinum resistance or sensitivity in ovarian cancer patients which may be related to nutrient intake and/or MTHFR status.Research regarding platinum resistance or sensitivity and biomarkers indicates that this area has not been investigated to date.Background2.1Ovarian CancerOvarian cancer is the leading cause of gynecological cancer death world-wide. Highly curable if diagnosed in its early stages, 70% of cases are not diagnosed until the cancer has reached advanced stage ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3892/mmr.2014.2221", "ISSN" : "1791-3004", "PMID" : "24821107", "abstract" : "Genetic alterations alone cannot account for the complexity of ovarian cancer. The potential reversibility of epigenetic mechanisms makes them attractive candidates for the prevention and/or treatment of ovarian carcinoma. Detection of the epigenetic signature of each cancer cell may be useful in the identification of candidate biomarkers for disease detection, classification and monitoring and may also facilitate personalized cancer treatment. In ovarian cancer, in addition to other non\u2011gynaecological cancers, two opposite epigenetic phenomena occur. The first involves an overall global decrease in DNA methylation of heterochromatin leading to demethylation of several oncogenes, while the second involves specific CpG island hypermethylation associated with the promoters of tumor suppressor genes. Early studies focused on the methylation patterns of single genes associated with tumorigenesis. However, newer genome-wide methods have identified a group of genes whose regulation is altered by DNA methylation during ovarian cancer progression.", "author" : [ { "dropping-particle" : "", "family" : "Koukoura", "given" : "Ourania", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spandidos", "given" : "Demetrios A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Daponte", "given" : "Alexandros", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sifakis", "given" : "Stavros", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular medicine reports", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2014", "7" ] ] }, "page" : "3-9", "publisher" : "Spandidos Publications", "title" : "DNA methylation profiles in ovarian cancer: implication in diagnosis and therapy (Review).", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Koukoura, Spandidos, Daponte, & Sifakis, 2014)", "plainTextFormattedCitation" : "(Koukoura, Spandidos, Daponte, & Sifakis, 2014)", "previouslyFormattedCitation" : "(Koukoura, Spandidos, Daponte, & Sifakis, 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Koukoura, Spandidos, Daponte, & Sifakis, 2014). The first-line treatment for this cancer is chemotherapy with a platinum and taxane agent ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S0140", "abstract" : "The standard initial management of epithelial ovarian cancer consists of surgical staging, operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy, and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel. Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes. However, 75% of patients present with advanced (stage III or IV) disease and, although more than 80% of these women benefi t from fi rst-line therapy, tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis. Second-line treatments can improve survival and quality of life but are not curative. Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg, bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes.", "author" : [ { "dropping-particle" : "", "family" : "Hennessy", "given" : "Bryan T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Coleman", "given" : "Robert L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Markman", "given" : "Maurie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Lancet", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "1371-1382", "title" : "Ovarian cancer Epidemiology and risk factors", "type" : "article-journal", "volume" : "374" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Hennessy, Coleman, & Markman, 2009)", "plainTextFormattedCitation" : "(Hennessy, Coleman, & Markman, 2009)", "previouslyFormattedCitation" : "(Hennessy, Coleman, & Markman, 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Hennessy, Coleman, & Markman, 2009). The antitumour activity of platinum compounds is dependent on the platination of DNA strands, causing intra- and interstrand breaks, leading to p53-initiated apoptosis ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.2174/187152007779314044", "ISSN" : "18715206", "author" : [ { "dropping-particle" : "", "family" : "Cepeda", "given" : "Victoria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fuertes", "given" : "Miguel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Castilla", "given" : "Josefina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alonso", "given" : "Carlos", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quevedo", "given" : "Celia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Perez", "given" : "Jose", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Anti-Cancer Agents in Medicinal Chemistry", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2007", "1", "1" ] ] }, "page" : "3-18", "title" : "Biochemical Mechanisms of Cisplatin Cytotoxicity", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Cepeda et al., 2007)", "plainTextFormattedCitation" : "(Cepeda et al., 2007)", "previouslyFormattedCitation" : "(Cepeda et al., 2007)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Cepeda et al., 2007). Certain patients have been found to be resistant to platinum therapies and prognostic biomarkers may be predictive of chemotherapy response. It is also predicted that up to 20% of all ovarian cancer patients are intrinsically resistant to platinum-based therapies significantly increasing toxicities and reducing overall survival ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.ctrv.2017.10.001", "abstract" : "a b s t r a c t Background: The potential predictive value of genetic polymorphisms in ovarian cancer first-line treat-ment is inconsistently reported. We aimed to review ovarian cancer pharmacogenetic studies to update and summarize the available data and to provide directions for further research. Methods: A systematic review followed by a meta-analysis was conducted on cohort studies assessing the involvement of genetic polymorphisms in ovarian cancer first-line treatment response retrieved through a MEDLINE database search by November 2016. Studies were pooled and summary estimates and 95% confidence intervals (CI) were calculated using random or fixed-effects models as appropriate. Results: One hundred and forty-two studies gathering 106871 patients were included. Combined data suggested that GSTM1-null genotype patients have a lower risk of death compared to GSTM1-wt carriers, specifically in advanced stages (hazard ratio (HR), 0.68; 95% CI, 0.48\u20130.97) and when submitted to platinum-based chemotherapy (aHR, 0.61; 95% CI, 0.39\u20130.94). ERCC1 rs11615 and rs3212886 might have also a significant impact in treatment outcome (aHR, 0.67; 95% CI, 0.51\u20130.89; aHR, 1.28; 95% CI, 1.01\u2013 1.63, respectively). Moreover, ERCC2 rs13181 and rs1799793 showed a distinct ethnic behavior (Asians: aHR, 1.41; 95% CI, 0.80\u20132.49; aHR, 1.07; 95% CI, 0.62\u20131.86; Caucasians: aHR, 0.10; 95% CI, 0.01\u20130.96; aHR, 0.18; 95% CI, 0.05\u20130.68, respectively). Conclusion(s): The definition of integrative predictive models should encompass genetic information, especially regarding GSTM1 homozygous deletion. Justifying additional pharmacogenetic investigation are variants in ERCC1 and ERCC2, which highlight the DNA Repair ability to ovarian cancer prognosis. Further knowledge could aid to understand platinum-treatment failure and to tailor chemotherapy strategies.", "author" : [ { "dropping-particle" : "", "family" : "Assis", "given" : "Joana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pereira", "given" : "Carina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nogueira", "given" : "Augusto", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pereira", "given" : "Deolinda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carreira", "given" : "Rafael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Medeiros", "given" : "Rui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer Treatment Reviews", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2017" ] ] }, "page" : "35-52", "title" : "Systematic or Meta-analysis Studies Genetic variants as ovarian cancer first-line treatment hallmarks: A systematic review and meta-analysis", "type" : "article-journal", "volume" : "61" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1210/en.2009-0404", "abstract" : "Epigenetic aberrations, including DNA methylation, histone modifications, and micro-RNA dysregulation, are now well established in the development and progression of ovarian cancer, and their gradual accumulation is associated with advancing disease stage and grade. Epige-netic aberrations are relatively stable, associated with distinct disease subtypes, and present in circulating serum, representing promising diagnostic, prognostic, and pharmacodynamic biomar-kers. In contrast to DNA mutations and deletions, aberrant gene-repressive epigenetic modifica-tions are potentially reversible by epigenetic therapies, including inhibitors of DNA methylation or histone-modifying enzymes. Although epigenetic monotherapies have not shown activity against solid tumors, including ovarian cancer, preclinical studies suggest they will be effective when used in combination with one another or with conventional chemotherapeutics, and combinatorial epigenetic therapy regiments are being examined in cancer clinical trials. A greater understanding of the role of epigenetics in ovarian neoplasia will provide for improved interventions against this devastating malignancy. (Endocrinology 150: 4003\u2013 4011, 2009)", "author" : [ { "dropping-particle" : "", "family" : "Balch", "given" : "Curt", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fang", "given" : "Fang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matei", "given" : "Daniela E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "H-M Huang", "given" : "Tim", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nephew", "given" : "Kenneth P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Endocrinology", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "4003 - 4011", "title" : "Minireview: Epigenetic Changes in Ovarian Cancer", "type" : "article-journal", "volume" : "150" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Assis et al., 2017; Balch, Fang, Matei, H-M Huang, & Nephew, 2009)", "plainTextFormattedCitation" : "(Assis et al., 2017; Balch, Fang, Matei, H-M Huang, & Nephew, 2009)", "previouslyFormattedCitation" : "(Assis et al., 2017; Balch, Fang, Matei, H-M Huang, & Nephew, 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Assis et al., 2017; Balch, Fang, Matei, H-M Huang, & Nephew, 2009). Platinum resistance poses a significant challenge to the clinical approach in affectively treating ovarian cancer patients. Since platinum-therapy inception very little advancement has been made in combating resistance in a population where 5-year overall survival is as low as 30% ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Aberrant epigenetic regulation, such as CpG island methylation and associated transcriptional silencing of genes, has been implicated in a variety of human diseases, including cancer. Methylation of genes involved in apopto-sis, including the DNA mismatch repair (MMR) gene hMLH1, can occur in tumor models of resistance to chemo-therapeutic drugs. However, the relevance for acquired re-sistance to chemotherapy of patients' tumors remains un-substantiated. Plasma DNA from cancer patients, including those with ovarian cancer, often contains identical DNA changes as the tumor and provides a means to monitor CpG island methylation changes. We have examined plasma DNA of patients with epithelial ovarian cancer enrolled in the SCOTROC1 Phase III clinical trial for methylation of the hMLH1 CpG island before carboplatin/taxoid chemother-apy and at relapse. Methylation of hMLH1 is increased at relapse, and 25% (34 of 138) of relapse samples have hMLH1 methylation that is not detected in matched preche-motherapy plasma samples. Furthermore, hMLH1 methyl-ation is significantly associated with increased microsatellite instability in plasma DNA at relapse, providing an inde-pendent measure of function of the MMR pathway. Acqui-sition of hMLH1 methylation in plasma DNA at relapse predicts poor overall survival of patients, independent from time to progression and age (hazard ratio, 1.99; 95% confi-dence interval, 1.20 \u20133.30; P \u202b\u060d\u202c 0.007). These data support the clinical relevance of acquired hMLH1 methylation and concomitant loss of DNA MMR after chemotherapy of ovar-ian cancer patients. DNA methylation changes in plasma provide the potential to define patterns of methylation dur-ing therapy and identify those patient populations who would be suitable for novel epigenetic therapies.", "author" : [ { "dropping-particle" : "", "family" : "Gifford", "given" : "Gillian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paul", "given" : "Jim", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vasey", "given" : "Paul A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kaye", "given" : "Stanley B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brown", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical Cancer Research", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2004" ] ] }, "page" : "4420 - 4426", "title" : "The Acquisition of hMLH1 Methylation in Plasma DNA after Chemotherapy Predicts Poor Survival for Ovarian Cancer Patients", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Gifford, Paul, Vasey, Kaye, & Brown, 2004)", "plainTextFormattedCitation" : "(Gifford, Paul, Vasey, Kaye, & Brown, 2004)", "previouslyFormattedCitation" : "(Gifford, Paul, Vasey, Kaye, & Brown, 2004)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Gifford, Paul, Vasey, Kaye, & Brown, 2004). 2.2MTHFR, Folic Acid and DNA methylationIt is estimated that up to 70% of the world’s population has one or more alleles affected by polymorphisms in the MTHFR enzyme, resulting in a reduction of enzyme activity, thereby impacting folate utilisation and conversion, homocysteine and methionine recirculation and potentially cellular antioxidant status, DNA synthesis and methylation specific epigenetic changes in cellular activity ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Long", "given" : "Sarah", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goldblatt", "given" : "Jack", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2016" ] ] }, "title" : "MTHFR genetic testing: Controversy and clinical implications", "type" : "article-journal", "volume" : "45" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Long & Goldblatt, 2016)", "plainTextFormattedCitation" : "(Long & Goldblatt, 2016)", "previouslyFormattedCitation" : "(Long & Goldblatt, 2016)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Long & Goldblatt, 2016).Methylene tetrahydrofolate is an essential contributor to DNA synthesis ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "The common 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism causes decreased activity of this enzyme and can be associated with mild-to-moderate hyperhomocysteinemia in homozygotes, particularly when there is folic acid deficiency, as well as with vascular dementia, arterial thrombosis, venous thrombosis, neural-tube defects, and fetal loss. When folic acid intake is sufficient, homozygotes for MTHFR 677T appear to be protected against colon cancer and acute lymphatic leukemia, and fetuses bearing this genotype have an augmented survival. The distribution of MTHFR 677T is worldwide, but its frequency in different populations varies exten-sively. In the present study, we addressed the question of whether the MTHFR 677T alteration has an ancestral origin or has occurred repeatedly. We analyzed the frequency distribution of the previously described polymorphism A1298C in exon 7 and of three intronic dimorphisms, in white Israelis (Jews and Arabs), Japanese, and Ghanaian Africans. The 677T allele was, remarkably, associated with one haplotype, G-T-A-C, in white and Japanese ho-mozygotes. Among the Africans, analysis of maximum likelihood also disclosed an association with the G-T-A-C haplotype, although none of the 174 subjects examined was homozygous for MTHFR 677T. These results suggest that the MTHFR 677T alteration occurred on a founder haplotype that may have had a selective advantage. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR [MIM 236250]) catalyzes the conversion of 5,10-methylenetetrahydrofolate (methylene-THF) to 5-methyltetrahydrofolate, which is the carbon donor for methylation of homocysteine to methionine (Rosenblatt and Fenton 2001). The human gene for MTHFR has been mapped to chromosomal region 1p36.3 and con-sists of \u223c17 kb, which include 11 exons spanning 2.2 kb (cDNA GenBank accession number U09806) (Goy-ette et al. 1994, 1998). A common alteration in the MTHFR gene, C677T (dbSNP cluster ID rs1801133), converts an alanine to a valine at position 222 and is associated with reduced specific activity and increased", "author" : [ { "dropping-particle" : "", "family" : "Rosenberg", "given" : "Nurit", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Murata", "given" : "Mitsuru", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ikeda", "given" : "Yasuo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Opare-Sem", "given" : "Ohene", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zivelin", "given" : "Ariella", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Geffen", "given" : "Eli", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Seligsohn", "given" : "Uri", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Human Genetics", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2002" ] ] }, "page" : "758-762", "title" : "The Frequent 5,10-Methylenetetrahydrofolate Reductase C677T Polymorphism Is Associated with a Common Haplotype in Whites, Japanese, and Africans", "type" : "article-journal", "volume" : "70" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Rosenberg et al., 2002)", "plainTextFormattedCitation" : "(Rosenberg et al., 2002)", "previouslyFormattedCitation" : "(Rosenberg et al., 2002)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Rosenberg et al., 2002). Likewise, folic acid is crucial for genome stability and preventing the hypomethylation of DNA ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S0027-5107(01)00079-3", "ISSN" : "0027-5107", "abstract" : "Folic acid plays a critical role in the prevention of chromosome breakage and hypomethylation of DNA. This activity is compromised when Vitamin B12 (B12) concentration is low because methionine synthase activity is reduced, lowering the concentration of S-adenosyl methionine (SAM) which in turn may diminish DNA methylation and cause folate to become unavailable for the conversion of dUMP to dTMP. The most plausible explanation for the chromosome-breaking effect of low folate is excessive uracil misincorporation into DNA, a mutagenic lesion that leads to strand breaks in DNA during repair. Both in vitro and in vivo studies with human cells clearly show that folate deficiency causes expression of chromosomal fragile sites, chromosome breaks, excessive uracil in DNA, micronucleus formation and DNA hypomethylation. In vivo studies show that Vitamin B12 deficiency and elevated plasma homocysteine are significantly correlated with increased micronucleus formation. In vitro experiments indicate that genomic instability in human cells is minimised when folic acid concentration in culture medium is >227nmol/l. Intervention studies in humans show: (a) that DNA hypomethylation, chromosome breaks, uracil misincorporation and micronucleus formation are minimised when red cell folate concentration is >700nmol/l folate; and (b) micronucleus formation is minimised when plasma concentration of Vitamin B12 is >300pmol/l and plasma homocysteine is <7.5umol/l. These concentrations are achievable at intake levels in excess of current RDIs i.e. more than 200\u2013400ug folic acid per day and more than 2ug Vitamin B12 per day. A placebo-controlled study with a dose\u2013response suggests that based on the micronucleus index in lymphocytes, an RDI level of 700ug/day for folic acid and 7ug/day for Vitamin B12 would be appropriate for genomic stability in young adults. Dietary intakes above the current RDI may be particularly important in those with extreme defects in the absorption and metabolism of these Vitamins, for which ageing is a contributing factor.", "author" : [ { "dropping-particle" : "", "family" : "Fenech", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis", "id" : "ITEM-1", "issue" : "1-2", "issued" : { "date-parts" : [ [ "2001", "4", "18" ] ] }, "page" : "57-67", "publisher" : "Elsevier", "title" : "The role of folic acid and Vitamin B12 in genomic stability of human cells", "type" : "article-journal", "volume" : "475" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Fenech, 2001)", "plainTextFormattedCitation" : "(Fenech, 2001)", "previouslyFormattedCitation" : "(Fenech, 2001)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Fenech, 2001). MTHFR enzyme is essential in the conversion of dietary and supplemental folates into active folate for use in one-carbon transfer reactions associated with the methylation of homocysteine to methionine, DNA replication, neurotransmitter synthesis and intracellular antioxidant status (Gropper & Smith 2013, pp. 344 – 350). In 2009 it became mandatory in Australia, for foods such as breads and cereals, to be fortified with a synthetic form of folate, folic acid to aid in the reduction of neural tube defects in children ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3390/nu3030370", "ISSN" : "2072-6643", "abstract" : "Periconceptional intake of folic acid is known to reduce a woman's risk of having an infant affected by a neural tube birth defect (NTD). National programs to mandate fortification of food with folic acid have reduced the prevalence of NTDs worldwide. Uncertainty surrounding possible unintended consequences has led to concerns about higher folic acid intake and food fortification programs. This uncertainty emphasizes the need to continually monitor fortification programs for accurate measures of their effect and the ability to address concerns as they arise. This review highlights the history, effect, concerns, and future directions of folic acid food fortification programs.", "author" : [ { "dropping-particle" : "", "family" : "Crider", "given" : "Krista S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bailey", "given" : "Lynn B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berry", "given" : "Robert J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nutrients", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "370-384", "title" : "Folic Acid Food Fortification\u2014Its History, Effect, Concerns, and Future Directions", "type" : "article-journal", "volume" : "3" }, "locator" : "377", "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Crider, Bailey, & Berry, 2011, p. 377)", "plainTextFormattedCitation" : "(Crider, Bailey, & Berry, 2011, p. 377)", "previouslyFormattedCitation" : "(Crider, Bailey, & Berry, 2011, p. 377)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Crider, Bailey, & Berry, 2011, p. 377). From a holistic perspective, it is well understood that isolated vitamins and minerals may lack the synergistic benefit that whole food forms provide in the body. However, from a biomedical perspective, the synergistic effects of foods are only now being considered. The impact of these isolated forms compared to synergistic nutrients on human health is yet to be completely understood ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Jacobs Jr.", "given" : "David R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of Nutrition", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "543s - 546s", "title" : "What Comes First: The Food or the Nutrient? Executive Summary of a Symposium", "type" : "article-journal", "volume" : "144" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.3945/an.115.011718", "abstract" : "Dietary guidelines provide evidence-based statements on food choices to meet nutritional requirements and reduce the risk of prevailing chronic disease. They involve a substantial amount of research translation, and their implementation has important health consequences. Foods, however, are complex combinations of nutrients and other compounds that act synergistically within the food and across food combinations. In addition, the evidence base underpinning dietary guidelines accesses research that reflects different study designs, with inherent strengths and limitations. We propose a systematic approach for the review of evidence that begins with research on dietary patterns. This research will identify the combinations of foods that best protect, or appear deleterious to, health. Next, we suggest that evidence be sought from research that focuses on the effects of individual foods. Finally, nutrient-based research should be considered to explain the mechanisms by which these foods and dietary patterns exert their effects, take into account the effects of ingredients added to the food supply, and enable assessments of dietary sufficiency. The consideration of individual nutrients and food components (e.g., upper limits for saturated fat, added sugar, and sodium) provides important benchmarks for evaluating overall diet quality. The concepts of core and discretionary foods (nutrient-rich and nutrient-poor foods, respectively) enable distinctions between foods, and this has implications for the relation between food policy and food manufacturing. In summary, evidence supporting healthy dietary patterns provides the foundation for the development of dietary guidelines. Further reference to individual foods and nutrients follows from the foundation of healthy dietary patterns. Adv Nutr 2016;7:445\u201354.", "author" : [ { "dropping-particle" : "", "family" : "Tapsell", "given" : "Linda C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Neale", "given" : "Elizabeth P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Satija", "given" : "Ambika", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hu", "given" : "Frank B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Advances in Nutrition", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2016" ] ] }, "page" : "445-454", "title" : "Foods, Nutrients, and Dietary Patterns: Interconnections and Implications for Dietary Guidelines 1,2", "type" : "article-journal", "volume" : "7" }, "locator" : "445", "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Jacobs Jr., 2014; Tapsell, Neale, Satija, & Hu, 2016, p. 445)", "plainTextFormattedCitation" : "(Jacobs Jr., 2014; Tapsell, Neale, Satija, & Hu, 2016, p. 445)", "previouslyFormattedCitation" : "(Jacobs Jr., 2014; Tapsell, Neale, Satija, & Hu, 2016, p. 445)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Jacobs Jr., 2014; Tapsell, Neale, Satija, & Hu, 2016, p. 445).Low folate status has been implicated in the development of some cancers, however current research identifying tumour folate receptors suggest that whilst folate status may play a protective role against cancer in healthy populations, unmetabolised folic acid may be associated with the promotion of cancer cell growth and drug resistance ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Baldauff", "given" : "Regine L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "title" : "The Relationship Between Unmetabolized Folic Acid and Serum Folate Concentrations and Cancer Risk in Older US Adults", "type" : "article-journal" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1093/jnci/djv260", "abstract" : "Higher folate has been associated with a reduced colorectal cancer (CRC) risk, but excessive folate may promote tumor progression. The role of unmetabolized folic acid (UFA) from high folic acid consumption in carcinogenesis is largely unexplored. We evaluated prediagnostic plasma levels of UFA in relation to CRC risk in nested case-control studies (618 CRC case patients and 1207 matched control) with blood samples collected prior to folic acid fortification. UFA was detected in 21.4% of control UFA levels were not associated with CRC risk. Compared with undetectable levels, the multivariable relative risks (RRs) of CRC were 1.03 (95% confidence interval [CI] = 0.73 to 1.46) for less than 0.5 nmol/L and 1.12 (95% CI = 0.81 to 1.55) for 0.5 nmol/L or more (P trend = .32). A positive association between UFA levels and CRC risk was observed among men (RR = 1.57, 95% CI = 0.99 to 2.49 for \u22650.5 nmol/L vs undetectable, P interaction = .04), and a positive association was also observed among those with the methylene-tetrahydrofolate reductase (MTHFR) CT/TT genotype (RR = 2.20, 95% CI = 1.22 to 3.94 for \u22650.5 nmol/L vs undetectable, P interaction =0.02). In conclusion, prediagnostic plasma levels of UFA from the prefortification period were not associated with risk of CRC.", "author" : [ { "dropping-particle" : "", "family" : "Cho", "given" : "Eunyoung", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Xuehong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Townsend", "given" : "Mary K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Selhub", "given" : "Jacob", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paul", "given" : "Ligi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rosner", "given" : "Bernard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fuchs", "given" : "Charles S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Willett", "given" : "Walter C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Giovannucci", "given" : "Edward L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the National Cancer Institute", "id" : "ITEM-2", "issue" : "12", "issued" : { "date-parts" : [ [ "2015" ] ] }, "title" : "Unmetabolized Folic Acid in Prediagnostic Plasma and the Risk for Colorectal Cancer", "type" : "article-journal", "volume" : "107" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.3892/mmr.2014.2221", "ISSN" : "1791-3004", "PMID" : "24821107", "abstract" : "Genetic alterations alone cannot account for the complexity of ovarian cancer. The potential reversibility of epigenetic mechanisms makes them attractive candidates for the prevention and/or treatment of ovarian carcinoma. Detection of the epigenetic signature of each cancer cell may be useful in the identification of candidate biomarkers for disease detection, classification and monitoring and may also facilitate personalized cancer treatment. In ovarian cancer, in addition to other non\u2011gynaecological cancers, two opposite epigenetic phenomena occur. The first involves an overall global decrease in DNA methylation of heterochromatin leading to demethylation of several oncogenes, while the second involves specific CpG island hypermethylation associated with the promoters of tumor suppressor genes. Early studies focused on the methylation patterns of single genes associated with tumorigenesis. However, newer genome-wide methods have identified a group of genes whose regulation is altered by DNA methylation during ovarian cancer progression.", "author" : [ { "dropping-particle" : "", "family" : "Koukoura", "given" : "Ourania", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spandidos", "given" : "Demetrios A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Daponte", "given" : "Alexandros", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sifakis", "given" : "Stavros", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular medicine reports", "id" : "ITEM-3", "issue" : "1", "issued" : { "date-parts" : [ [ "2014", "7" ] ] }, "page" : "3-9", "publisher" : "Spandidos Publications", "title" : "DNA methylation profiles in ovarian cancer: implication in diagnosis and therapy (Review).", "type" : "article-journal", "volume" : "10" }, "locator" : "6", "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1097/MCO.0b013e32831cec62", "abstract" : "Purpose of review\u2014The intent of this evidence-based review is to analyze the role of folate in chronic diseases, focusing on cancer and cardiovascular disease. Recent findings\u2014Low folate status has been shown to be a risk factor for cancer and cardiovascular disease. While epidemiological data suggest an inverse association between folate status and disease risk, intervention studies give equivocal results, suggesting the response to folate intake does not follow a linear continuum. Moreover, recent folate intervention trials raise concern about possible adverse effects of folate supplementation and suggest that too much folate in inopportune settings may be potentially harmful in individuals at higher risk for cardiovascular disease and cancer. Summary\u2014Although folate intake at sufficient levels appears to be an effective cancer chemopreventive strategy, high dose supplementation of folate has not been effective in reducing recurrence of cardiovascular events or colorectal adenomas in clinical intervention trials. Although controversial, high folate status achieved through folate fortification or supplementation may increase the risk of certain chronic diseases among certain individuals, possibly by interfering with the homeostasis of one-carbon metabolism. Further research is urgently needed to accurately define the relationship between supraphysiological intake of folate and chronic diseases.", "author" : [ { "dropping-particle" : "", "family" : "Sauer", "given" : "Julia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mason", "given" : "Joel B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Choi", "given" : "Sang-Woon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current Opinion in Clinical Nutrition and Metabolic Care", "id" : "ITEM-4", "issue" : "1", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "30-36", "title" : "Too much folate \u2013 a risk factor for cancer and cardiovascular disease?", "type" : "article-journal", "volume" : "12" }, "locator" : "5", "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Baldauff, 2013; Cho et al., 2015; Koukoura et al., 2014, p. 6; Sauer, Mason, & Choi, 2009, p. 5)", "plainTextFormattedCitation" : "(Baldauff, 2013; Cho et al., 2015; Koukoura et al., 2014, p. 6; Sauer, Mason, & Choi, 2009, p. 5)", "previouslyFormattedCitation" : "(Baldauff, 2013; Cho et al., 2015; Koukoura et al., 2014, p. 6; Sauer, Mason, & Choi, 2009, p. 5)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Baldauff, 2013; Cho et al., 2015; Koukoura et al., 2014, p. 6; Sauer, Mason, & Choi, 2009, p. 5).Furthermore, ovarian tumours contain increased intracellular levels of glutathione (GSH) a potent antioxidant, that may play a role in the resistance of platinum drug therapy and is reliant on the availability of amino acids cysteine, glycine and glutamate ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/1476-4598-12-138", "ISSN" : "1476-4598", "PMID" : "24238102", "abstract" : "BACKGROUND Ovarian cancer is characterized by high rates of metastasis and therapeutic resistance. Many chemotherapeutic agents rely on the induction of oxidative stress to cause cancer cell death, thus targeting redox regulation is a promising strategy to overcome drug resistance. METHODS We have used a tetracycline-inducible Ets-1 overexpression model derived from 2008 ovarian cancer cells in the present study. To examine the role of Ets-1 in glutathione regulation we have measured intracellular reactive oxygen species and glutathione levels, as well as glutathione peroxidase enzyme activity. Glutathione synthesis was limited using transsulfuration or Sx(c)- pathway blocking agents, and glutamate release was measured to confirm Sx(c)- blockade. Cell viability following drug treatment was assessed via crystal violet assay. Oxidative stress was induced through glucose oxidase treatment, which produces hydrogen peroxide by glucose oxidation. The protein expressions of redox-related factors were measured through western blotting. RESULTS Overexpression of Ets-1 was associated with decreased intracellular ROS, concomitantly with increased intracellular GSH, GPX antioxidant activity, and Sx(c)- transporter activity. Under basal conditions, inhibition of the transsulfuration pathway resulted in decreased GSH levels and GPX activity in all cell lines, whereas inhibition of Sx(c)- by sulfasalazine decreased GPX activity in Ets-1-expressing cells only. However, under oxidative stress the intracellular GSH levels decreased significantly in correlation with increased Ets-1 expression following sulfasalazine treatment. CONCLUSIONS In this study we have identified a role for proto-oncogene Ets-1 in the regulation of intracellular glutathione levels, and examined the effects of the anti-inflammatory drug sulfasalazine on glutathione depletion using an ovarian cancer cell model. The findings from this study show that Ets-1 mediates enhanced Sx(c)- activity to increase glutathione levels under oxidative stress, suggesting that Ets-1 could be a promising putative target to enhance conventional therapeutic strategies.", "author" : [ { "dropping-particle" : "", "family" : "Verschoor", "given" : "Meghan L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Singh", "given" : "Gurmit", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular cancer", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013", "11", "15" ] ] }, "page" : "138", "publisher" : "BioMed Central", "title" : "Ets-1 regulates intracellular glutathione levels: key target for resistant ovarian cancer.", "type" : "article-journal", "volume" : "12" }, "locator" : "141", "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Verschoor & Singh, 2013, p. 141)", "plainTextFormattedCitation" : "(Verschoor & Singh, 2013, p. 141)", "previouslyFormattedCitation" : "(Verschoor & Singh, 2013, p. 141)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Verschoor & Singh, 2013, p. 141). GSH is recycled through the methionine pathway by the folate dependent methylation cycle.It is currently unclear whether DNA methylation among humans can be altered by folate intake, or whether the patterns in methylation change, dependant on the timing and extent of exposure ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3390/nu3030370", "ISSN" : "2072-6643", "abstract" : "Periconceptional intake of folic acid is known to reduce a woman's risk of having an infant affected by a neural tube birth defect (NTD). National programs to mandate fortification of food with folic acid have reduced the prevalence of NTDs worldwide. Uncertainty surrounding possible unintended consequences has led to concerns about higher folic acid intake and food fortification programs. This uncertainty emphasizes the need to continually monitor fortification programs for accurate measures of their effect and the ability to address concerns as they arise. This review highlights the history, effect, concerns, and future directions of folic acid food fortification programs.", "author" : [ { "dropping-particle" : "", "family" : "Crider", "given" : "Krista S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bailey", "given" : "Lynn B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berry", "given" : "Robert J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nutrients", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "370-384", "title" : "Folic Acid Food Fortification\u2014Its History, Effect, Concerns, and Future Directions", "type" : "article-journal", "volume" : "3" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Crider et al., 2011)", "plainTextFormattedCitation" : "(Crider et al., 2011)", "previouslyFormattedCitation" : "(Crider et al., 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Crider et al., 2011). 2.3Literature ReviewA review of the current literature revealed a large number of biomarkers related to platinum therapy response in ovarian cancer patients and that some of these biomarkers may be used as prognostic indicators. It is further revealed that methylation and histone modifications may play a role in the association with biomarkers, such as BRCA1, hMLH1 and LINE-1, chemoresponse and subsequent clinical outcome ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3892/mmr.2014.2221", "ISSN" : "1791-3004", "PMID" : "24821107", "abstract" : "Genetic alterations alone cannot account for the complexity of ovarian cancer. The potential reversibility of epigenetic mechanisms makes them attractive candidates for the prevention and/or treatment of ovarian carcinoma. Detection of the epigenetic signature of each cancer cell may be useful in the identification of candidate biomarkers for disease detection, classification and monitoring and may also facilitate personalized cancer treatment. In ovarian cancer, in addition to other non\u2011gynaecological cancers, two opposite epigenetic phenomena occur. The first involves an overall global decrease in DNA methylation of heterochromatin leading to demethylation of several oncogenes, while the second involves specific CpG island hypermethylation associated with the promoters of tumor suppressor genes. Early studies focused on the methylation patterns of single genes associated with tumorigenesis. However, newer genome-wide methods have identified a group of genes whose regulation is altered by DNA methylation during ovarian cancer progression.", "author" : [ { "dropping-particle" : "", "family" : "Koukoura", "given" : "Ourania", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spandidos", "given" : "Demetrios A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Daponte", "given" : "Alexandros", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sifakis", "given" : "Stavros", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular medicine reports", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2014", "7" ] ] }, "page" : "3-9", "publisher" : "Spandidos Publications", "title" : "DNA methylation profiles in ovarian cancer: implication in diagnosis and therapy (Review).", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Koukoura et al., 2014)", "plainTextFormattedCitation" : "(Koukoura et al., 2014)", "previouslyFormattedCitation" : "(Koukoura et al., 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Koukoura et al., 2014). Moreover, epigenetic changes may also contribute to the relationship between biomarkers and chemoresponse rate, as well as variability in individual responses to therapy ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1210/en.2009-0404", "abstract" : "Epigenetic aberrations, including DNA methylation, histone modifications, and micro-RNA dysregulation, are now well established in the development and progression of ovarian cancer, and their gradual accumulation is associated with advancing disease stage and grade. Epige-netic aberrations are relatively stable, associated with distinct disease subtypes, and present in circulating serum, representing promising diagnostic, prognostic, and pharmacodynamic biomar-kers. In contrast to DNA mutations and deletions, aberrant gene-repressive epigenetic modifica-tions are potentially reversible by epigenetic therapies, including inhibitors of DNA methylation or histone-modifying enzymes. Although epigenetic monotherapies have not shown activity against solid tumors, including ovarian cancer, preclinical studies suggest they will be effective when used in combination with one another or with conventional chemotherapeutics, and combinatorial epigenetic therapy regiments are being examined in cancer clinical trials. A greater understanding of the role of epigenetics in ovarian neoplasia will provide for improved interventions against this devastating malignancy. (Endocrinology 150: 4003\u2013 4011, 2009)", "author" : [ { "dropping-particle" : "", "family" : "Balch", "given" : "Curt", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fang", "given" : "Fang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matei", "given" : "Daniela E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "H-M Huang", "given" : "Tim", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nephew", "given" : "Kenneth P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Endocrinology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "4003 - 4011", "title" : "Minireview: Epigenetic Changes in Ovarian Cancer", "type" : "article-journal", "volume" : "150" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Balch et al., 2009)", "plainTextFormattedCitation" : "(Balch et al., 2009)", "previouslyFormattedCitation" : "(Balch et al., 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Balch et al., 2009).Epigenetic regulation of DNA in cancer includes DNA methylation of CpG islands and histone modifications, changes in genetic behaviour without altering the sequence of DNA ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nm.2305", "ISSN" : "1078-8956", "abstract" : "Cancer epigenetics reaches mainstream oncology", "author" : [ { "dropping-particle" : "", "family" : "Rodr\u00edguez-Paredes", "given" : "Manuel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Esteller", "given" : "Manel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Medicine", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "3", "1" ] ] }, "page" : "330-339", "publisher" : "Nature Publishing Group", "title" : "Cancer epigenetics reaches mainstream oncology", "type" : "article-journal", "volume" : "17" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Rodr\u00edguez-Paredes & Esteller, 2011)", "plainTextFormattedCitation" : "(Rodr\u00edguez-Paredes & Esteller, 2011)", "previouslyFormattedCitation" : "(Rodr\u00edguez-Paredes & Esteller, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Rodríguez-Paredes & Esteller, 2011). Since genetic alterations are nearly impossible to correct and cannot alone account for the complexities of platinum resistance ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3892/mmr.2014.2221", "ISSN" : "1791-3004", "PMID" : "24821107", "abstract" : "Genetic alterations alone cannot account for the complexity of ovarian cancer. The potential reversibility of epigenetic mechanisms makes them attractive candidates for the prevention and/or treatment of ovarian carcinoma. Detection of the epigenetic signature of each cancer cell may be useful in the identification of candidate biomarkers for disease detection, classification and monitoring and may also facilitate personalized cancer treatment. In ovarian cancer, in addition to other non\u2011gynaecological cancers, two opposite epigenetic phenomena occur. The first involves an overall global decrease in DNA methylation of heterochromatin leading to demethylation of several oncogenes, while the second involves specific CpG island hypermethylation associated with the promoters of tumor suppressor genes. Early studies focused on the methylation patterns of single genes associated with tumorigenesis. However, newer genome-wide methods have identified a group of genes whose regulation is altered by DNA methylation during ovarian cancer progression.", "author" : [ { "dropping-particle" : "", "family" : "Koukoura", "given" : "Ourania", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spandidos", "given" : "Demetrios A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Daponte", "given" : "Alexandros", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sifakis", "given" : "Stavros", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular medicine reports", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2014", "7" ] ] }, "page" : "3-9", "publisher" : "Spandidos Publications", "title" : "DNA methylation profiles in ovarian cancer: implication in diagnosis and therapy (Review).", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Koukoura et al., 2014)", "plainTextFormattedCitation" : "(Koukoura et al., 2014)", "previouslyFormattedCitation" : "(Koukoura et al., 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Koukoura et al., 2014), epigenetic modifications in cancer makes them the target for prevention and/or treatment strategies. MethodologyStudy designThe research project is a retrospective cross-sectional cohort observational trial. Participants will be selected based on ovarian cancer diagnosis and response to chemotherapy, placed in one of two groups, platinum resistant or platinum sensitive. Platinum refractory disease patients, whose tumours continued to grow throughout primary therapy will be included in the platinum resistant group. The two groups will be compared for the presence or absence of MTHFR polymorphisms, dietary and supplementary intake of folate prior to diagnosis and during chemotherapy and serum active B12, homocysteine, and serum folate levels in a one-off blood test conducted by SNP.3.2ParticipantsThe target population for this study will be female adults aged 18 to 80 years old and meet the inclusion criteria as outlined below. Participation in this clinical trial is sought to identify possible contributors and/or biomarker for platinum drug response in ovarian cancer patients.3.3Sample size By selecting a sample size of 30 participants for the study with a 95% confidence level, this would reflect a CI of 17.89%. In the event that 70% of participants have an MTHFR mutation, as has been suggested by world-wide population estimates, the investigators can be confident that between 52.11% and 87.89% of the sample will contain an accurate reflection of possibility, equating to between 16 and 26 participants showing some correlation (Figure 1).Figure 1. Sample Size Calculation: n= sample size, z score is based on confidence level (being ±1.96 based on 95%), p= population proportion and N= population size ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.4103/0974-7788.59946", "ISSN" : "0974-925X", "PMID" : "20532100", "author" : [ { "dropping-particle" : "", "family" : "Kadam", "given" : "Prashant", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bhalerao", "given" : "Supriya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International journal of Ayurveda research", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2010", "1" ] ] }, "page" : "55-7", "publisher" : "Wolters Kluwer -- Medknow Publications", "title" : "Sample size calculation.", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Kadam & Bhalerao, 2010)", "plainTextFormattedCitation" : "(Kadam & Bhalerao, 2010)", "previouslyFormattedCitation" : "(Kadam & Bhalerao, 2010)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Kadam & Bhalerao, 2010).3.4Inclusion and Exclusion Criteria 3.4.1Inclusion criteriaDiagnosed with ovarian, fallopian tube, epithelial or peritoneal cancerCompleted first line platinum therapyDiagnosed with refractory/resistant disease or platinum sensitive disease.3.4.2Exclusion criteria Non-English speaking Never received platinum drug therapy for ovarian cancer 3.5Recruitment Recruitment of participants will take place through day hospital units located on the Gold Coast and Brisbane, Australia through day oncology hospitals belonging to ICON Cancer Care. Recruitment will be supervised by medical oncologist, Dr. Jim Coward (BSc(Honours) MBBS MRCP (UK) FRACP PhD). Prospective participants will be identified using ICON’s patient database and will be notified of the trial by mail and on-site. An information session outlining the trial will be provided to all interested participants and an information and consent form provided for perusal. Consent will be sought to access medical records, the provision of a single blood test and the use of blood serum for future use in this trial if necessary (Appendix A). Participants will be deidentified using a UIC generated by Totalcare? software.3.6 Consent and Procedures3.6.1Pre-trialThe formal consent will be signed after the following criteria have been met; the researcher is satisfied the participant has an individual understanding of the trial, and the Patient Information Sheet has been read thoroughly by the participant and any supporting family members if the participant requests their attendance. A consent form for the participant to sign together with the Researcher’s signature is to be kept by the participant as their copy of the consent. A second consent signed by both the participant and the Researcher is the Researcher’s copy of the consent and is to be filed in a locked filing cabinet, in the Researcher’s locked office. An electronic copy of both these consent forms will be generated into a PDF format and stored electronically with password protected signature to maintain confidentiality and anonymity of the participant.3.6.2SettingThe research setting is ICON Cancer Care Day Hospital Southport, Level 9, 39 White Street Southport, Gold Coast and The Mater Medical Centre (ICON Cancer Care South Brisbane), level 5, 293 Vulture Street, South Brisbane. ICON research committee have verbally agreed to a reciprocal ethics agreement between Endeavour College of Natural Health and ICON Cancer Care. A hardcopy of this protocol will be provided to ICON Cancer Care ethics committee once available.3.7 Data collection3.7.1MTHFR PolymorphismsMTHFR analysis will be based on three criteria:?Presence of mutation – positive or negative?SNP (single nucleotide polymorphism) variation – heterozygous or homozygous?Call letter and location variation – A/C/TCollection will be performed by trained nurse collection staff at SNP and analysed as per SNP procedures and protocols by their pathologists.3.7.2InstrumentsThere will be two instruments that will be used in this trial for quality of life, the FACT-O (Functional Assessment of Cancer Therapy – Ovarian Cancer)(Appendix B) and nutrient intake assessment, DQES v.3 (dietary questionnaire version 3.2)(Appendix C). Permission has been granted from the authors for the use of the FACT-O (Appendix D) and the DQES v3.2 will be purchased through the Cancer Council Victoria. The participant will complete the FACT-O and DQES v3.2 at the single data collection point, to assess the impact of their chemotherapy regime on quality of life, and their nutrient intake throughout the past 12 months of treatment.3.7.3Medical RecordsThe extraction of key data from medical records is an essential factor in the study. Collecting data on age, tumour stage and grade at diagnosis, the presence of metastasis, surgical history including the presence of residual disease at the commencement of chemotherapy, time to relapse, family and subsequent genetic history, and existing comorbidities and medication history. All patient data will be collected using an extensive CRF allowing for data to be confidentially and thoroughly compiled without the risk of a data breach resulting in sensitive information being leaked or accessed by any external parties (Appendix E). CRF’s will be identifiable only through the UIC.3.8 Data managementAll participant hard copy files which include; CRF, PISCF, DQES v3.2 and FACT-O will be kept in individual files in plastic sleeves in the participants medical file located in the medical records department. This is inside the locked ICON Cancer Care Southport Day Hospital, which is located at Level 9, 39 White Street Southport, Queensland. The only people accessible to this office are the staff and doctors employed by ICON Cancer Care. Electronic forms and logs will be maintained as password protected files on the computers of the primary investigator (Caitlin Phillips-Chavez) which are only accessible by the researcher named. These password protected computers are in a locked office within ICON Cancer Care Southport.The hard copy data files will be stored in a locked medical records department of ICON Cancer Care Southport Day Hospital for fifteen (15) years, then destroyed permanently. 3.9WithdrawalParticipants are free to withdraw from the trial at any point without question or penalty. This is verbalised by the participant when they either contact the researcher via email or phone. There is allocated space on the CRF for the participant to complete the withdrawal of consent. If the parent withdraws consent over phone or email, it will be noted in the CRF, located on the last page of the document. 3.10Data analysisAll data will be analysed on STATA ?14. All data will be analysed on STATA ?14. Associations between variables such as the presence or absence of MTHFR polymorphisms will be subject to the chi-square test. Logistic regression will be applied to determine the correlation between the existence and/or absence of any of the test variables (folate intake and/or MTHFR polymorphisms) and platinum response. Further analysis may occur once all variables are determined.3.11Outcome Measures3.11.1Primary Outcome MeasuresThe Primary outcome measure will be to examine any differences between MTHFR polymorphism presence in platinum resistant versus platinum sensitive patients with ovarian cancer. 3.11.2Secondary Outcome Measures1 – The secondary outcome measures will investigate folate intake (epigenetic or direct impact on cancer progression) and difference between platinum resistant and platinum sensitive ovarian cancer patients and;2 - Investigate any correlations or predictors of platinum resistance or sensitivity in ovarian cancer patients which may be related to nutrient intake and/or MTHFR statusQuantitative assessment of the possible impact of folate intake during treatment will be conducted using the DQES_v3.2? from the Cancer Council Victoria. Case reporting will include supplement use prior to and during diagnosis and chemotherapy, as well as medications that may impact nutrient intake. Validated FFQ have been significantly correlated with serum folate levels (p=<0.01) in previous studies, qualifying their usefulness in appropriately assessing dietary folate intake ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/J.NUTRES.2010.12.004", "ISSN" : "0271-5317", "abstract" : "Folate, vitamin B12, iron, and zinc are particularly important nutrients for women of childbearing age. We tested the hypothesis that an electronic, 235-item, semiquantitative food frequency questionnaire (FFQ) is a valid measure of dietary intake when compared with repeat dietary 24-hour recalls. Biomarkers of folate, vitamin B12, iron, and zinc were determined because their measurement errors are unrelated to errors in dietary questionnaires. Female adults (N = 256) aged 18 to 35 years completed the FFQ, and a representative subset (n = 53) completed repeat dietary 24-hour recalls. The FFQ estimates (mean \u00b1 SD) were 315 \u00b1 132 \u03bcg for folate, 3.1 \u00b1 2.1 \u03bcg for vitamin B12, 15.4 \u00b1 5.6 mg for iron, and 15.1 \u00b1 6.4 mg for zinc. The percentage of women classified within the same \u00b11 quartile for energy intake by the 2 methods was 77.3%. There was moderate agreement between the 2 dietary methods, and no systematic bias was noted for energy, folate, vitamin B12, and zinc. The deattenuated energy-adjusted correlation coefficients ranged from 0.41 (dietary folate equivalents) to 0.60 (folate). Significant correlations between biomarker and nutrient intakes were found for folate (r = 0.37, P < .01) and vitamin B12 (r = 0.27, P < .01). The electronic FFQ developed in the present study is a relatively valid tool that was able to adequately assess and rank individuals according to their nutrient intakes.", "author" : [ { "dropping-particle" : "", "family" : "Fayet", "given" : "Flavia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flood", "given" : "Victoria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petocz", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Samman", "given" : "Samir", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nutrition Research", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2011", "1", "1" ] ] }, "page" : "14-20", "publisher" : "Elsevier", "title" : "Relative and biomarker-based validity of a food frequency questionnaire that measures the intakes of vitamin B12, folate, iron, and zinc in young women", "type" : "article-journal", "volume" : "31" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1079/BJN2002518", "ISSN" : "0007-1145", "author" : [ { "dropping-particle" : "", "family" : "Pufulete", "given" : "Maria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Emery", "given" : "Peter W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nelson", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Thomas A. B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "British Journal of Nutrition", "id" : "ITEM-2", "issue" : "04", "issued" : { "date-parts" : [ [ "2002", "4", "9" ] ] }, "page" : "383", "publisher" : "Cambridge University Press", "title" : "Validation of a short food frequency questionnaire to assess folate intake", "type" : "article-journal", "volume" : "87" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Fayet, Flood, Petocz, & Samman, 2011; Pufulete, Emery, Nelson, & Sanders, 2002)", "plainTextFormattedCitation" : "(Fayet, Flood, Petocz, & Samman, 2011; Pufulete, Emery, Nelson, & Sanders, 2002)", "previouslyFormattedCitation" : "(Fayet, Flood, Petocz, & Samman, 2011; Pufulete, Emery, Nelson, & Sanders, 2002)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Fayet, Flood, Petocz, & Samman, 2011; Pufulete, Emery, Nelson, & Sanders, 2002).Quality of life will also be assessed using the FACT-O? ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2018", "4", "30" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2017" ] ] }, "title" : "FACT-O - Functional Assessment of Cancer Therapy - Ovarian Cancer", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(, 2017)", "plainTextFormattedCitation" : "(, 2017)", "previouslyFormattedCitation" : "(, 2017)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(, 2017) tool to quantify how treatment has affected the target population and may further substantiate the need for biomarker research to be undertaken in this particularly vulnerable group of resistant patients. Previous research highlights the impact of side effects related to diagnosis and treatment has on well-being and overall functioning ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/1757-2215-6-17", "ISSN" : "1757-2215", "author" : [ { "dropping-particle" : "", "family" : "Gupta", "given" : "Digant", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Braun", "given" : "Donald P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Staren", "given" : "Edgar D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Markman", "given" : "Maurie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Ovarian Research", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "17", "title" : "Longitudinal health-related quality of life assessment: implications for prognosis in ovarian cancer", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Gupta, Braun, Staren, & Markman, 2013)", "plainTextFormattedCitation" : "(Gupta, Braun, Staren, & Markman, 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Gupta, Braun, Staren, & Markman, 2013).LimitationsICON Cancer Care is a ‘referral centre’ that attracts patients from a higher socioeconomic demographic. It has been reported that the purchasing and consumption of unhealthy diets including the intake of lesser fruits and vegetables, is strongly correlated with socioeconomic status and that higher diet quality is associated with higher cost ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/J.APPET.2014.10.022", "ISSN" : "0195-6663", "abstract" : "Background: Those of lower socioeconomic status (SES) tend to have less healthy diets than those of higher SES. This study aimed to assess whether differences in motivations for particular foods might contribute to socioeconomic differences in consumption. Methods: Participants (n\u2009=\u2009732) rated their frequency of consumption and explicit liking of fruit, cake and cheese. They reported eating motivations (e.g., health, hunger, price) and related attributes of the investigated foods (healthiness, expected satiety, value for money). Participants were randomly assigned to an implicit liking task (Single Category Implicit Association Task) for one food category. Analyses were conducted separately for different SES measures (income, education, occupational group). Results: Lower SES and male participants reported eating less fruit, but no SES differences were found for cheese or cake. Analyses therefore focused on fruit. In implicit liking analyses, results (for income and education) reflected patterning in consumption, with lower SES and male participants liking fruit less. In explicit liking analyses, no differences were found by SES. Higher SES participants (all indicators) were more likely to report health and weight control and less likely report price as motivators of food choices. For perceptions of fruit, no SES-based differences were found in healthiness whilst significant interactions (but not main effects) were found (for income and education) for expected satiety and value for money. Neither liking nor perceptions of fruit were found to mediate the relationship between SES and frequency of fruit consumption. Conclusions: There is evidence for social patterning in food motivation, but differences are modified by the choice of implicit or explicit measures. Further work should clarify the extent to which these motivations may be contributing to the social and gender patterning in diet.", "author" : [ { "dropping-particle" : "", "family" : "Pechey", "given" : "Rachel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monsivais", "given" : "Pablo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ng", "given" : "Yin-Lam", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marteau", "given" : "Theresa M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Appetite", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "1", "1" ] ] }, "page" : "271-279", "publisher" : "Academic Press", "title" : "Why don't poor men eat fruit? Socioeconomic differences in motivations for fruit consumption", "type" : "article-journal", "volume" : "84" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.ypmed.2015.01.019", "ISSN" : "00917435", "PMID" : "25625693", "abstract" : "BACKGROUND Food prices may be one reason for the growing socioeconomic disparities in diet quality. OBJECTIVE To evaluate the association between diet costs and the Healthy Eating Index-2010 (HEI-2010). METHODS Cross-sectional study based on 11,181 adults from the 2007-2010 National Health and Nutrition Examination Survey, analyzed in spring 2014. Diet cost was estimated by linking dietary data with a national food price database. The HEI-2010, a measure of adherence to the dietary guidelines, was the outcome. The population ratio method was used to estimate the average HEI-2010 scores by quintile of energy-adjusted diet cost. Additional analyses evaluated the association between cost and HEI-2010 components. RESULTS There was a strong positive association between lower energy-adjusted diet costs and lower HEI-2010 scores. The association was stronger among women (p-interaction=0.003). Lower diet costs were associated with lower consumption of vegetables, fruits, whole grains, and seafood, and higher consumption of refined grains and solid fat, alcohol and added sugars. CONCLUSIONS Lower energy-adjusted diet costs were associated with lower-quality diets. Future efforts to improve the nutritional status of the US public should take food prices and diet costs into account.", "author" : [ { "dropping-particle" : "", "family" : "Rehm", "given" : "Colin D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monsivais", "given" : "Pablo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Drewnowski", "given" : "Adam", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Preventive Medicine", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2015", "4" ] ] }, "page" : "70-75", "title" : "Relation between diet cost and Healthy Eating Index 2010 scores among adults in the United States 2007\u20132010", "type" : "article-journal", "volume" : "73" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Pechey, Monsivais, Ng, & Marteau, 2015; Rehm, Monsivais, & Drewnowski, 2015)", "plainTextFormattedCitation" : "(Pechey, Monsivais, Ng, & Marteau, 2015; Rehm, Monsivais, & Drewnowski, 2015)", "previouslyFormattedCitation" : "(Pechey, Monsivais, Ng, & Marteau, 2015; Rehm, Monsivais, & Drewnowski, 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Pechey, Monsivais, Ng, & Marteau, 2015; Rehm, Monsivais, & Drewnowski, 2015).Study Procedures4.1 Participant AttendanceParticipants will be asked to attend an information session run by the Primary investigator on the trial for information and to be provided with consent forms to take home for consideration. Participants will then be asked to return their consent forms to their participating ICON site, where the Primary investigator and oncologist can run through the details of the trial and to clarify the participant’s intent to consent. At the stage of consent, the participant will be provided with their blood test request form, and DQES v3.2 log in details. The Primary investigator will run through the CRF with the participant to capture all the necessary information. The time required of the participant is estimated at one hour to complete the CRF. There is only one point of contact necessary for the participant to attend ICON for the trial which can completed at any point within the trial period, allowing for the required 2 weeks for Cancer Council Victoria to analyse DQES v3.2 data. Blood tests can be actioned onsite on the same day or on any day that is convenient for the participant. Results and analysis of the DQES v3.2 are electronically provided to the Primary investigator as are the blood serum results, which are electronically matched and uploaded into participant files based on their UIC. The FACT-O should be completed at the time of the CRF, however participants can be given a private space and time for its completion if they feel it’s necessary. Information regarding support services can also be provided to the participant if they are feeling distressed by the FACT-O.4.2 Medical RecordsAny information missing from the CRF due to participants not being able to provide it can be retrieved from the participants charts, as per consent. Further data will be collected to satisfy information regarding tumour stage and grade, residual disease, comorbidities or past blood and genetic testing that have been done, from participant medical records, as per consent. All further information will be filled out in the participants corresponding CRF which is identified only by UIC (figure 2).Figure 2: Project Plan: Schematic representation of the project plan from recruitment to data collection and analysis.Finance and Insurance5.1Funding SourceFunds will be sourced from the Endeavour College of Natural Health for the Honours project to the worth of $1000. All other funds will be through the Chief investigator and Primary supervisor, Dr Janet Schloss, Endeavour research funds.5.2 Conflict of InterestAll investigators declare no conflict of interest in relation to this study.5.3InsuranceClinical trial insurance will be provided by Endeavour College of Natural Health by Mackenzie Ross.Publication PlanLiterature Review: First author, Caitlin Phillips-ChavezResults: First author, Caitlin Phillips-ChavezReferencesADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY Assis, J., Pereira, C., Nogueira, A., Pereira, D., Carreira, R., & Medeiros, R. (2017). Systematic or Meta-analysis Studies Genetic variants as ovarian cancer first-line treatment hallmarks: A systematic review and meta-analysis. Cancer Treatment Reviews, 61, 35–52. , C., Fang, F., Matei, D. E., H-M Huang, T., & Nephew, K. P. (2009). Minireview: Epigenetic Changes in Ovarian Cancer. Endocrinology, 150, 4003–4011. , R. L. (2013). The Relationship Between Unmetabolized Folic Acid and Serum Folate Concentrations and Cancer Risk in Older US Adults. Retrieved from , V., Fuertes, M., Castilla, J., Alonso, C., Quevedo, C., & Perez, J. (2007). Biochemical Mechanisms of Cisplatin Cytotoxicity. Anti-Cancer Agents in Medicinal Chemistry, 7(1), 3–18. , E., Zhang, X., Townsend, M. K., Selhub, J., Paul, L., Rosner, B., … Giovannucci, E. L. (2015). Unmetabolized Folic Acid in Prediagnostic Plasma and the Risk for Colorectal Cancer. Journal of the National Cancer Institute, 107(12). , K. S., Bailey, L. B., & Berry, R. J. (2011). 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