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Sousa, Cristovao. "Huntington disease and breast cancer." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA114823/document.
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La maladie de Huntington (MH) est une maladie neurodégénérative autosomale dominante causée par une expansion anormale de CAG dans le gène codant la huntingtine (HTT) qui se traduit dans la protéine HTT par une répétition de polyglutamine, entrainant la mort neuronale. Néanmoins, la MH entraine aussi le développement de symptômes périphériques comme la HTT est une protéine exprimée de façon ubiquitaire. Notamment, la MH a été associé à une plus faible incidence des cancers, mais les mécanismes sous-jacents ne sont pas décrits. Nous avons étudié le rôle de HTT mutée et sauvage dans le cancer du sein, où la protéine est fortement exprimée. Des modèles murins de cancer du sein (MMTV-PyVT et MMTV-ErbB2) exprimant la HTT mutée (souris knock-in transportant 111 GAC) développent des tumeurs mammaires agressives par rapport aux souris exprimant la HTT sauvage. La transition épithéliale-mésenchymateuse est accélérée avec une augmentation de la motilité cellulaire ainsi que de la formation de métastases. Ces tumeurs accumulent le récepteur tyrosine-kinase HER2 à la membrane, en raison d'un défaut d'endocytose dynamine-dépendante en présence de la HTT mutée. La signalisation accrue de HER2 est responsable de l'agressivité des tumeurs exprimant la HTT mutée, comme en témoigne le traitement trastuzumab, un anticorps dirigé contre HER2 qui restaure la motilité et l'invasion des cellules tumorales porteuses de la mutation responsable de la MH. La HTT sauvage a elle-même un rôle protecteur dans le cancer, retardant l’apparition des métastases en raison d'un potentiel rôle dans l’adhésion intercellulaire. Ainsi, notre travail met en évidence des rôles clés de la HTT mutée et sauvage au cours de la progression du cancer du seinHuntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormal CAG expansion in the huntingtin (HTT) gene. The corresponding polyglutamine expansion in the HTT protein causes specific neuronal death, but the consequences of HTT mutation in other tissues are less well understood. Nevertheless, HD mutation causes peripheral symptoms as HTT is an ubiquitous protein. HD was associated to lower cancer incidence, however, the mechanisms behind this effect were not described. Here we have studied the role of wild-type and mutant HTT in breast cancer, where we found the protein to be highly expressed. We demonstrate that mouse breast cancer models (MMTV-PyVT and MMTV-ErbB2) expressing mutant HTT (knock-in mice carrying 111 CAGs) develop aggressive mammary tumors as compared to control mice. Epithelial-to-mesenchymal transition is enhanced with subsequent increased cell motility and metastasis. These tumors accumulate tyrosine-kinase receptor HER2 at the membrane, due to a dynamin-dependent endocytosis defect in the presence of mutant HTT. HER2 enhanced signaling is responsible for the aggressiveness of the mutant HTT expressing tumors, as demonstrated by Trastuzumab treatment, an antibody against HER2 that restores motility and invasion in tumor cells carrying HD mutation. The wild-type HTT has itself a protective role in cancer, inhibiting metastasis due to a possible role in cellular junction maintenance. Thus, our work unravels a key role of HTT in breast cancer progression, with the mutant HTT triggering the development of aggressive and metastatic tumors
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Taylor, Carolyn W. "Breast cancer radiotherapy and heart disease." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:c9dda3ca-8cb3-4a38-938d-0b75b4f6471d.
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Introduction: Some past breast cancer radiotherapy regimens led to an increased risk of death from heart disease. Although heart dose from breast cancer radiotherapy has generally reduced over the past few decades, there may still be some cardiac risk. Estimation of future risk for women irradiated today requires both measurement of their cardiac dose and dose-response relationships, which depend on cardiac dosimetry of past regimens, in conjunction with long-term follow-up data. Methods: Virtual simulation and computed tomography 3-dimensional treatment planning on a representative patient were used to estimate mean heart and coronary artery doses for women irradiated since 1950 in 71 randomised trials in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview. Patient-to-patient variability in cardiac dose was assessed. Heart and coronary artery doses were also calculated for breast cancer radiotherapy regimens used since the 1950s in Sweden. Cardiac doses from contemporary (year 2006) radiotherapy were assessed for 55 patients who received tangential breast cancer irradiation at a large UK radiotherapy centre. The maximum heart distance (i.e. the maximum distance between the anterior cardiac contour and the posterior tangential field edges) was measured for the left-sided patients, and its value as a predictor of cardiac doses assessed. Results: Mean heart dose for women irradiated in the EBCTCG trials varied from <1 to 18 Gray, and mean coronary artery dose from <1 to 57 Gray. Patient-to-patient variability was moderate. Mean heart dose for women irradiated in Sweden since the 1950s varied from <1 to 24 Gray, and mean coronary artery dose from <1 to 46 Gray. Heart dose from tangential irradiation has reduced over the past four decades. However, mean heart dose for left-sided patients irradiated in 2006 was 2 Gray and around half of them still received >20 Gray to parts of the heart and left anterior descending coronary artery. For these patients, maximum heart distance was a reliable predictor of cardiac doses. For the other patients, mean heart dose varied little and was usually less than 2 Gray. Conclusions: Cardiac doses from breast cancer radiotherapy can be estimated reliably and are now available for use in deriving dose-response relationships in the EBCTCG data and in a Scandinavian case-control study. Cardiac dose has reduced over the past four decades. Therefore the cardiac risk is also likely to have reduced. Nevertheless, for some patients, parts of the heart still receive >20 Gray in the year 2006.
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Hall, Emma. "Benign breast disease as a risk factor for breast cancer." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322197.
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Huguet, Emmanuel L. "Wnt genes in human breast biology." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297228.
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Bird, Katherine. "Dysregulation of the polycystic kidney disease pathway in breast cancer." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708059.
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Qianren, Jin. "Search for susceptibility loci and candidate genes for breast cancer /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-030-3/.
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Wedrén, Sara. "Genetic susceptibility to breast and endometrial cancer /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-053-2/.
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Bundred, Nigel James. "The objective identification of apocrine change in benign and malignant breast disease." Thesis, University of Newcastle Upon Tyne, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241376.
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Erbas, Hakan. "Effect of breast cyst fluid and its constituents on oestrogen metabolism in breast cancer cell lines." Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265481.
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Søndergaard, Karen Lynn. "A study of hypoxia inducible factor and related genes in disease in man." Thesis, University of Plymouth, 2002. http://hdl.handle.net/10026.1/2496.
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In this study, the mRNA and protein levels of hypoxia inducible factor 1 (HIF-1α), and a number of genes regulated by hypoxia (VEGF, GLUT-1, p53), were determined in four breast carcinoma cell lines, peripheral blood mononuclear cells (PBMCs) of patients with breast cancer and Type 1 diabetes (TIDM), and in human breast and brain tumour tissue. Breast carcinoma cells and PMBCs from both patients and normal controls were exposed to hypoxia (≤1% 0 2) and/or high glucose. Both up-regulated and down-regulated HIF-1α, GLUT-1 and p53 mRNA expression was observed in the breast carcinoma cell lines exposed to hypoxia and/or high glucose, and in controls for osmolarity, confirming that hypoxic regulation of HIF-1α, p53 and possibly GLUT-1 occurs post-transcriptionally. Conversely, up-regulation of HIF- 1α and GLUT-1 mRNA was observed in patients with TIDM exposed to high glucose. The GLUT-1 mRNA up-regulation observed in patients without complications differed significantly from normal controls, where up to a 2 fold increase in expression was observed over that of patients with complications. This may indicate that the expression and function of glucose transporters differs in these patients, potentially leading to fewer complications. Investigation of breast and glial cell tumour tissue demonstrated that both HIF-1α and GLUT- 1 mRNA expression levels increase with disease progression, indicating that up-regulation of HIF-1α is partly at the transcriptional level (Søndergaard et al, 2002). Follow-up survival studies in all patients with glial cell tumours showed that HIF-1α protein expression is a significant prognostic factor in cumulative overall survival. An additional investigation of p53 or p73 polymorphisms in the development of carcinoma of the breast did not find that they were significant risk factors in the development of the disease in the British Caucasoid population. Further studies are required using larger sample populations investigating HIF-1α protein to determine the precise role of HIF-1 in the response to hypoxia and angiogenesis in disease in man.
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Hurrell, Karen Tracy. "Screening for serious disease : modelling the early detection of breast cancer." Thesis, University of Leicester, 1989. http://hdl.handle.net/2381/34546.
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Nilsson, Greger. "Cardiovascular Side Effects of Radiotherapy in Breast Cancer." Doctoral thesis, Uppsala universitet, Enheten för onkologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-179811.
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The aim of the thesis was to study cardiovascular side effects of radiotherapy (RT) in breast cancer (BC). In a study base of 25,171 women with BC diagnosed 1970-2000, we found a statistically significant 12% increase of stroke, compared to the stroke incidence in the background population. A case-control study of 282 cases with BC followed by a stroke and 1:1 matched controls with BC but not stroke was performed. In women irradiated to internal mammary chain (IMC) and supraclavicular lymph nodes (SCL) vs. a pooled group of women not irradiated or irradiated to targets other than IMC and SCL, a statistically significant increase of stroke with an odds ratio of 1.8 was observed. There were no associations between BC laterality, targets of RT, and hemisphere location of stroke. The radiation targets IMC and SCL, showed a statistically significant trend for an increased risk of stroke with daily fraction dose. A study of 199 patients with BC, examined by coronary angiography, detected a four- to seven-fold increase of high grade coronary artery stenosis in mid and distal left anterior descending artery (LAD), including distal diagonal branch, when comparing women with irradiated left-sided BC to those with right-sided. An increase of clinically significant coronary artery stenosis was found in pre-specified hotspot areas for radiation among women irradiated to the left breast/chest wall or to the IMC. Thus, the coronary arteries should be regarded as organs at risk in RT of BC. In a study of 15 BC patients treated with 3D conformal RT, a marked difference in dose distribution in mid and distal LAD between left- and right-sided BC was demonstrated. Irradiated right-sided BC mainly received low doses of scattered and transmitted radiation to the coronary arteries. On the contrary, tangential RT to the left breast without regional lymph node irradiation yielded coronary artery max doses of approximately 50 Gray to distal LAD, probably not safe concerning late radiation vascular effects. To conclude, we found cardiovascular side effects in women irradiated for BC, resulting in stroke and coronary artery disease, and showed an association between the targets for RT and the anatomical location of these vascular events.
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Einarsdóttir, Kristjana. "Genetic determinants of postmenopausal breast and endometrial cancer /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-037-4/.
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Vaittinen, Pauli. "Risk characterization of familial cancer using the Swedish Family-Cancer database with a special reference to breast cancer /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-723-1/.
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Padunchewit, Jularut. "THAI BREAST CANCER PATIENTS: EXPERIENCES AND VIEWS ABOUT PHOTOGRAPHS OF OTHER WOMEN WITH THE SAME DISEASE." Thesis, Connect to resource online, 2010. http://hdl.handle.net/1805/2103.
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Thesis (M.A.)--Indiana University, 2010.Title from screen (viewed on February 26, 2010). Department of Sociology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Lynn Blinn-Pike, Carrie E. Foote, Betsy Fife. Includes vitae. Includes bibliographical references (leaves 100-105).
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Mbuka-Ongona, Deogratias. "The knowledge and practice of patients suffering from cancer of the breast about their disease at Princess Marina Hospital (PMH) Gaborone, Botswana." Thesis, University of Limpopo (Medunsa Campus), 2009. http://hdl.handle.net/10386/205.
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Thesis (M Med. (Family Medicine))-- University of Limpopo, 2009.Introduction Inspired by the late presentation for care and consequently the diagnosis of breast cancer done at an advanced stage of the disease in majority of cases, this study aimed to explore the knowledge and practices related to breast cancer from patients presenting at Princess Marina Hospital (PMH) for care. Methodology The descriptive qualitative method using interviews (free attitude) was chosen to understand the trend of late presentation among participants, with following opening questions: 1. Can you please tell me all you know about the cancer of the breast? 2. How have you been treating your breast condition (growth/wound/pain) before you decided to come to PMH? Sampling was purposeful with a sample of twelve. Out of eleven interviews done with breast cancer patients fulfilling the criteria of inclusion, ten were used in the final analysis. Interviews were recorded (audiotape), transcribed verbatim and translated. Emerging themes were identified and coded into different categories Results This study noted a poor knowledge and understanding of patients about cancer of the breast. The knowledge and practice of the common well established screening methods like self breast examination (SBE) was equally poor. In majority, participants delayed going to the hospital as a result of the preceding( poor knowledge and understanding about Ca breast ), as well as the influence of lays beliefs and advices received from the surrounding. In some cases however advices from the surrounding resulted in timely medical consultation. Unexpectedly, Poor clinical practice of health worker in some cases and decision maker‟s inadequate involvement on issue of cancer awareness were other important themes which emerged during analysis of the results. Conclusions Cancer awareness together with consistent use of early detection measures by adhering to screening methods should be taken seriously and done throughout the country for the benefit of all potential victims, to address the poor knowledge, misconceptions and inappropriate health seeking behavior encountered in case of breast cancer.
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Luo, Liping. "A genetic study on familial breast cancer predisposing genes /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-628-5184-5.
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Smith, Brendan Michael. "The determination of minimal residual disease in patients with primary breast cancer." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408242.
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Profant, Judith. "Fatigue and sleep complaints in women treated for breast cancer /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2004. http://wwwlib.umi.com/cr/ucsd/fullcit?p3129934.
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Margolin, Sara. "Family history and breast cancer susceptibility : clinical and molecular studies /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-868-1/.
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Heatley, Mark Keith. "Intermediate filament protein expression as a diagnostic aid in disease of the breast and prostate." Thesis, Queen's University Belfast, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261884.
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Yang, Kaolee. "A Statistical Analysis of Medical Data for Breast Cancer and Chronic Kidney Disease." Bowling Green State University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1587052897029939.
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Cutter, David J. "Radiation-related cardiovascular disease following cancer therapy." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:3f02ca87-530d-4ee7-9382-4b457bec62b5.
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Introduction: Some cancer survivors are known to have an elevated risk of morbidity and mortality from cardiovascular disease. An important cause of this elevated risk is recognised to be irradiation of normal tissues during radiotherapy received as part of cancer therapy. There are substantial difficulties in studying radiation-related cardiovascular disease (RRCD). The reasons for this include the complexities of measuring radiation normal tissue doses retrospectively and the prolonged latencies of many of the cardiovascular endpoints. A variety of complimentary research methodologies can help provide additional knowledge to guide the appropriate management of patients treated in the past and of new patients in the future. Methods: 1) A cohort study of mortality from circulatory disease in the nationwide British Childhood Cancer Survivor Study (BCCSS). 2) A case-control study of valvular heart disease (VHD) in Dutch Hodgkin lymphoma (HL) survivors, including retrospective radiation dosimetry to estimate the radiation dose to heart valves. 3) A dosimetric study of cardiovascular radiation doses in patients entered into the UK NCRI Lymphoma Study Group RAPID trial, including predictions of 15-year cardiac mortality using innovative methods. 4) A modelling study to predict mean whole heart dose (MWHD) from involved field radiotherapy (IFRT) for HL using anatomical measures. 5) A prospective study using cardiovascular magnetic resonance (CMR) imaging to characterise the heart in women receiving radiotherapy for breast cancer. Results: 1) The risks of all types of circulatory mortality are elevated in survivors of childhood cancer. The absolute excess risks continue to increase 40+ years following diagnosis. The risk of death from cardiomyopathy and heart failure increased substantially with the introduction of anthracycline chemotherapy. There is no evidence of a reduction in risk of circulatory mortality in more recent eras of diagnosis. 2) There is a strong relationship between estimated radiation dose to the affected heart valve and the risk of subsequent VHD (p<0.001). This effect was modelled to allow prediction of the risk of VHD. 3) A proportion of patients treated with IFRT received a substantial cardiac radiation dose (MWHD = 8.8 Gy, SD = 5.6) but, on average, the predicted 15-year cardiac mortality following treatment is low (absolute risk 0.2%, range 0.0 to 2.7%). 4) It is possible to estimate the mean whole heart dose from IFRT prior to detailed radiotherapy planning based on pre-treatment diagnostic imaging to an accuracy of 5-6% of the prescribed dose. 5) Although women received low cardiac doses (MWHD = 1.5 Gy, SD = 0.8) and have a low predicted risk of cardiac radiation-related morbidity and mortality, there is some evidence of subclinical effects on strain and strain rate imaging of the anterior portions of the left ventricle that receive the highest radiation dose. Conclusions: Using a variety of methods these studies have all succeeded in adding to knowledge about the nature, magnitude and timing of RRCD. This knowledge can be used to help the future management of cancer patients. In addition, each of the studies has natural and planned extensions and will continue to contribute further knowledge into the future.
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Dimock, Susan Halebsky. "Demanding disease dollars : how activism and institutions shape medical research funding for breast and prostate cancer /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC IP addresses, 2003. http://wwwlib.umi.com/cr/ucsd/fullcit?p3077795.
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Hartman, Mikael. "Risk and prognosis of breast cancer among women at high risk of the disease /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-303-0/.
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Couto, Elisabeth. "Investigation of the relationship between breast cancer and a family history of the disease." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439151.
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Ding, Hongliu. "Bone Health and Coronary Heart Disease in Postmenopausal Women with Breast Cancer Treated with Tamoxifen: A Dissertation." eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/404.
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Breast cancer, osteoporosis, and coronary heart disease (CHD) are three major threats to women’s health. Postmenopausal women with breast cancer are also at high risk for osteoporosis and CHD. Adjuvant tamoxifen therapy is not only an effective treatment for breast cancer, but has been shown to have a beneficial effect on bone and the cardiovascular system. Although tamoxifen has been convincingly demonstrated to be able to preserve bone mineral density (BMD), an unexpected increase of risk of fractures in patients treated with tamoxifen has been reported. The findings of the association of tamoxifen and CHD from previous studies were either borderline or inconsistent. To clarify the discrepancy between BMD and fractures and test the potential beneficial effect of tamoxifen on CHD, I conducted a series of retrospective studies in postmenopausal women with breast cancer who participated in the Cancer Surveillance in HMO Administrative Data (IMPACT study) or the Study of Osteoporotic Fractures (SOF).
In patients who participated in the IMPACT study, I demonstrated that the association of tamoxifen and fracture incidence varied at different skeletal sites. Although the association of tamoxifen and fractures in the spine (HR=0.40, 95% CI: 0.09-1.85), wrist (HR=2.49, 95% CI: 0.88-7.06), and total body (HR=0.87, 95% CI: 0.49-1.55) was inconclusive, tamoxifen was associated with an apparent reduction of the risk of hip fracture (HR=0.41, 95% CI: 0.17-1.03, p=0.0565). Importantly, the pattern of observed association of tamoxifen with the risks of fractures among postmenopausal women with breast cancer is consistent with its widely reported preserving effect on bone mineral density.
Using SOF data, I found that the association between BMD and fractures in women with breast cancer varied at different skeletal sites, and type of BMD measured. Non-specific BMD was not associated with hip fracture (HR=1.12; 95% CI: 0.78, 1.59). Site-specific BMD was more likely linked with hip fracture (HR=1.43, 95% CI: 0.99, 2.08) while change in BMD did not predict hip fracture (HR=1.05; 95% CI: 0.63, 1.72). The association of spine morphometric fracture with either non-specific or spine-specific BMD was similar (OR=1.40; 95% CI: 1.04, 1.90; OR=1.35, 95% CI: 0.99, 1.85, respectively). Overall, the association of BMD and fracture in elderly women with breast cancer is weak. Only site-specific BMD appears to have a consistently modest association with fractures in the corresponding skeletal sites.
In the IMPACT study population, compared to patients without tamoxifen, the overall incidence of CHD in tamoxifen-treated patients was lower (adjusted HR=0.60, 95% CI: 0.40-0.88). For each year of tamoxifen use, there was a statistically significant decrease in the risk of CHD (HR=0.90, 95% CI: 0.82-0.98). Further analyses categorized by length of tamoxifen use showed that an apparent association with a decreased CHD risk was found in patients who received tamoxifen for two to five years (HR=0.54, 95% CI: 0.33-0.86). No association was detected after the discontinuation of tamoxifen therapy.
In summary, I detected a possible benefit associated with tamoxifen on fractures in the hip, the most common fracture site. I also found that BMD did not predict osteoporotic fractures well in postmenopausal women with breast cancer. In addition, I demonstrated that tamoxifen was associated with a reduced risk of CHD in postmenopausal women with breast cancer in a dose-dependent manner. An apparent benefit was found in those patients who received tamoxifen therapy for at least two years.
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Boocock, David J. "A metabolic rationale for the carcinogenicity of tamoxifen : an inter-species comparison." Thesis, University of Liverpool, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343858.
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Gyenes, Gábor. "Cardiac side-effects of adjuvant radiotherapy for early breast cancer /." [Budapest] ; Stockholm, 1997. http://diss.kib.ki.se/1997/963-9106-04-6.
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Minton, Ollie. "An investigation into the biological pathogenesis and clinical correlates of cancer-related fatigue in disease-free breast cancer patients." Thesis, St George's, University of London, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.568717.
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Background: 30-40% of women successfully treated for breast cancer experience chronic fatigue for up to five years after the end of therapy. They experience a number of associated problems including reduced quality of life, lower mood and concentration difficulties. The causes of these problems and the underlying biological pathogenesis of these symptoms are unclear. The primary objective of this research was to identify whether there were differences in objective activity, cognitive function and inflammatory cytokines between fatigued and non-fatigued women post-treatment. Methods: This was a cross-sectional observational study. Women were recruited from a nurse-led follow-up clinic at St George's hospital over a two-and-a-half-year period. These women were categorised on the basis of a semi-structured interview as to whether they met the criteria to be a case of cancer-related fatigue syndrome (CRFS) or acted as a control. All participants completed a set of questionnaires, activity recording, cognitive testing and had blood taken for analysis. Samples were sent to a commercial company for analyte panel testing (88 markers) and were also analysed using proteomic techniques (including mass spectrometry) to identify any differences in plasma proteins between groups. Results: 114 women were recruited; 45 cases and 69 controls. A between group analysis demonstrated statistically significant differences in sleep quality (p=0.02) and daytime activity (p=0.03) on activity recording, and slower processing speed (p=0.009) and impaired verbal memory (p=0.03) on cognitive testing. Blood analysis demonstrated statistically significant differences (p<0.03) with raised inflammatory cytokines on commercial testing (interleukin 18, vascular endothelial growth factor and macrophage inflammatory protein 1) and increased non-specific inflammatory markers on an exploratory proteomic analysis (serum amyloid A and collectin). Conclusions: Statistically significant differences in subjective symptoms, e.g. difficulty concentrating, and linked objective data, e.g. reduced cognitive processing speed, were identified. These differences were associated with evidence of an underlying prolonged inflammatory response (indicated by raised cytokine levels) in the CRFS group. Future work should examine these observed differences prospectively before, during and after treatment.
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Bondy-Chorney, Emma. "Characterization of Novel Post-Transcriptional Events Misregulated In Disease: Implications for the Development of Future Therapies." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/36034.
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The misregulation of post-transcriptional mechanisms has been linked to the development and progression of numerous human diseases, in particular neurological disorders and cancer. Investigating these misregulated RNA pathways is essential to fully understand the disease mechanisms, identify novel biomarkers, and to develop effective therapies. In this thesis, I present three manuscripts that investigate the mechanisms behind the post-transcriptional misregulation of RNA in human disease, with a focus on pre-mRNA splicing. In the first manuscript (Bondy-Chorney et al., 2016a), we investigated the role of Staufen1 (Stau1) in splicing regulation in the neuromuscular disorder Myotonic Dystrophy Type 1 (DM1). Here we report the first insights into the mechanism that Stau1 uses to regulate the alternative splicing of INSR exon 11 through an interaction with Alu elements located in intron 10. Moreover, using a high-throughput RT-PCR screen, we uncovered a number of additional Stau1-regulated alternative splicing events in both wild-type and DM1 myoblast cell lines. As Stau1 is known to be aberrantly upregulated in DM1 skeletal muscle, our findings suggest that Stau1 acts as a disease modifier in this disorder. The second manuscript (Sanchez, Bondy-Chorney et al., 2015), describes a novel role of the protein methyltransferase Coactivator-Associated Methyltransferase-1 (CARM1), a protein found to be overexpressed in Spinal Muscular Atrophy (SMA). We found that CARM1 can act as a mediator in the nonsense-mediated decay pathway (NMD) and associated UPF1 to promoted its occupancy on PTC-containing transcripts. We identified a subset of natural non-PTC containing NMD targets that were dependent on CARM1, a number of which were misregulated in SMA. This work uncovered a novel role for CARM1 in the NMD pathway and revealed that defective targeting of PTC-containing mRNAs should be included in the complex array of molecular defects associated with SMA. Finally, the third manuscript (Bondy-Chorney et al., – in prep) examines the alternative
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splicing regulation of the Protein Arginine Methyltransferase PRMT1 exon 2, an event shown to alter the growth, survival, and invasion of breast cancer cells. Here, we used an RNA interference (RNAi) RT-PCR screen to uncover several splicing proteins that regulate the inclusion of exon 2, several of which we found to be misregulated in a panel of breast cancer cell lines and patient tumours. These findings confirmed that the inclusion of PRMT1 exon 2 was regulated by alternative splicing via splicing factors that are altered in breast cancer. Moreover, depletion of one of these splicing factors, RALY, resulted in a decrease in the motility and invasive potential of an aggressive breast cancer cell line. These three manuscripts represent a collection of work focused on elucidating the mechanisms involved in post-transcriptional misregulation of RNA in three diverse human diseases. Taken together, the data presented here highlight the broad impact that proteins, such as Stau1 and CARM1, can have in neuromuscular disorders. Moreover, we also uncovered novel misregulation of splicing proteins that alter alternative splicing patterns in breast cancer. Elucidating these mechanisms is of the highest importance in order to identify potential new and effective treatment avenues.
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Lundquist, Debra. "The Experience of Young Women Living with Advanced Breast Cancer: A Hermeneutic Phenomenological Study." Thesis, Boston College, 2018. http://hdl.handle.net/2345/bc-ir:107902.
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Thesis advisor: Pamela J. GracePurpose/Specific Aims: Van Manen’s hermeneutic phenomenological method was used to design this study aimed at better understanding the meaning of day-to-day living with advanced breast cancer in young women. Rationale/Significance of Study: There is a gap in knowledge about the particular needs and daily life experiences of this cohort. Very little data specifically addresses this population. The limited literature that exists suggests that, due to the particular stage of life, their needs differ from those at other life stages as well as those coping with earlier stages of breast cancer. These women have described themselves as being invisible and having to live with the knowledge that their future is uncertain. Thus, this qualitative study is an important initial step in expanding our understanding of what daily life is like for this population. Sample and Recruitment: Women aged 25–39 with Stage III or IV breast cancer were purposively recruited via private FacebookTM groups specifically for women with breast cancer. The final sample consisted of 12 participants from across the U.S. Incidentally, all were parents. Data Analysis: Data were collected through two or more semistructured interviews and written journals. Analysis followed van Manen’s method of immersion, reading, and rereading, and using manual coding and NVivo software to develop themes to capture the participants’ lifeworlds. Findings: The meaning of their experiences is captured by the overarching theme: Wearing the mask of wellness in the presence of life-threatening illness. Five major themes were identified: Wanting to be known as the person I am, I’m still Mom, Living is more than surviving, Getting through it, and Being connected to others. Conclusions: Findings highlight that these young women are managing multiple roles and responsibilities despite the ongoing challenges of treatment and symptom management. They feel that their needs and struggles are not well understood because to outsiders they do not look ill. This study provides a base for further research and eventually interventions
Thesis (PhD) — Boston College, 2018
Submitted to: Boston College. Connell School of Nursing
Discipline: Nursing
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Maguire, Paula. "Investigation of the genetic basis of familial non-BRCA1/2 breast cancer /." Stockholm, 2005. http://diss.kib.ki.se/2006/91-7140-602-6/.
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Wekwete, Chessman Tavarwisa. "Genetics and critical illness insurance underwriting : models for breast cancer and ovarian cancer and for coronary heart disease and stroke." Thesis, Heriot-Watt University, 2002. http://hdl.handle.net/10399/1157.
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Lindgren, Monica Elissa. "Persistent fatigue in disease-free breast cancer survivors: Evaluating long-term effects of pretreatment depression and cancer-specific avoidance coping." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1468288760.
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Baxter, Nancy. "The Body Image after Breast Cancer questionnaire, the design and testing of a disease-specific measure." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0025/NQ35108.pdf.
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Atkinson, C. "The effects of isoflavones on some risk factors for breast cancer, osteoporosis, and ischaemic heart disease." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596214.
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To investigate whether phytoestrogens had an antioestrogenic effect, a large double blind, randomised, placebo controlled trial was conducted for approximately one year. Mammographic breast density, hormone levels, menopausal symptoms, cardiovascular risk factors, bone density, and body composition were assessed. When compared with the effects of placebo, 40mg daily dose of isoflavones did not significantly alter mammographic breast density when assessed by several different methods. Mean change in estimated percent density determined from the mammogram comparison data was - 1.35% (SD 5.16) in the isoflavone group, and -1.79% (SD 7.41) in the placebo group. There was also no significant effect on levels of oestradiol, FSH, or LH. Menopausal symptoms, and hot flushes specifically, were not significantly altered by clover isoflavones. Cardiovascular risk factors (blood pressure, blood lipids, and blood clotting factors) were also not significantly altered. However, the isoflavones did affect bone density. Spine bone mineral density (BMD) decreased to a significantly lower extent in the isoflavone group compared with that seen in the placebo group (p<0.01). The effect on BMD was mainly seen in the pre- and peri-menopausal women, and isoflavones also had a significant effect on BMC in this group. Levels of the bone resorption marker, deoxypyridinoline (Dpd) increased in both the isoflavone and placebo pre- and peri-menopausal groups. However, the increase was significantly lower in the isoflavone group compared with placebo (p=0.03), supporting the finding of a beneficial effect of isoflavones on bone as judged by BMD and BMC. Similar trends (not significant) regarding BMC and BMD were seen in the hip in pre-and peri-menopausal women, and there was a significant increase in body fat with the isoflavone supplement in this group (p<0.01).
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Makhtar, Aesha. "Investigating the potential of metformin as an anti-cancer therapeutic in a model of breast disease." Thesis, University of Sheffield, 2018. http://etheses.whiterose.ac.uk/20903/.
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Metformin has been one of the most widely prescribed oral medications for type II diabetes for over six decades. It has recently received considerable attention because there is now evidence to show that metformin has a potential role in reducing the risk of cancer development and progression. However, the mechanisms behind the growth-inhibitory effect of metformin on breast cancer cells are not fully understood with little consensus on which tumour subtypes and/or patient populations will benefit from metformin treatment. Furthermore, it should be noted that much of the in vitro work published to date has used drug concentrations greatly exceeding the recommended clinical dose and most preclinical studies have given little attention to the cellular pharmacology of metformin uptake including the expression of metformin transporter molecules and intratumoral accumulation. As a result these studies may not translate directly into clinical practice. This project therefore tests the hypothesis that the anti-tumour effect of clinically relevant doses (0.03-0.3 mM) of metformin depends on breast cancer subtype and the presence of metformin transporters on breast cancer cells. Using immunohistochemistry on patient-derived tissues and various in vitro cell-based assays in a panel of increasingly transformed breast cell lines representing an in vitro model of breast disease progression, the expression of metformin transporters and the potential anti-proliferative effects of the clinical (0.03-0.3 mM) and potential tissue accumulation (1-5 mM) doses of metformin were evaluated. In parallel, global proteomic profiling was performed on three metastatic breast cancer cell lines to identify new potential molecular targets for metformin treatment. The data in this thesis show that metformin transporters are present on breast epithelial cells, pre-neoplastic, pre-invasive, invasive and metastatic breast cancer cells and that metformin has a cytostatic effect on the proliferation of these cells, causing cell cycle arrest, but not apoptosis at clinically relevant doses. The proteomic data suggest that metformin inhibits the expression of proteins within key cellular pathways in both triple negative breast cancer and the bone and lung-homed variants, with the lung-homed cells showing a greater response to metformin treatment. Taken together these data provide important novel insight into the useful role of metformin in breast cancer treatment, but further research is certainly required to identify biomarkers of response and mechanisms of action in breast cancer before metformin can be recommended in clinical practice.
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Erdem, Munire Tugba. "Modeling Diseases With Multiple Disease Characteristics: Comparison Of Models And Estimation Methods." Master's thesis, METU, 2011. http://etd.lib.metu.edu.tr/upload/12613531/index.pdf.
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Epidemiological data with disease characteristic information can be modelled in several ways. One way is taking each disease characteristic as a response and constructing binary or polytomous logistic regression model. Second way is using a new response which consists of disease subtypes created by cross-classification of disease characteristic levels, and then constructing polytomous logistic regression model. The former may be disadvantageous since any possible covariation between disease characteristics is neglected, whereas the latter can capture that covariation behaviour. However, cross-classifying the characteristic levels increases the number of categories of response, so that dimensionality problem in parameter space may occur in classical polytomous logistic regression model. A two staged polytomous logistic regression model overcomes that dimensionality problem. In this thesis, study is progressen in two main directions: simulation study and data analysis parts. In simulation study, models that capture the covariation behaviour are compared in terms of the response model parameter estimators. That is, performances of the maximum likelihood estimation (MLE) approach to classical polytomous logistic regression, Bayesian estimation approach to classical polytomous logistic regression and pseudo-conditional likelihood (PCL) estimation approach to two stage polytomous logistic regression are compared in terms of bias and variation of estimators. Results of the simulation study revealed that for small sized sample and small number of disease subtypes, PCL outperforms in terms of bias and variance. For medium scaled size of total disease subtypes situation when sample size is small, PCL performs better than MLE, however when the sample size gets larger MLE has better performance in terms of standard errors of estimates. In addition, sampling variance of PCL estimators of two stage model converges to asymptotic variance faster than the ML estimators of classical polytomous logistic regression model. In data analysis, etiologic heterogeneity in breast cancer subtypes of Turkish female cancer patients is investigated, and the superiority of the two stage polytomous logistic regression model over the classical polytomous logistic model with disease subtypes is represented in terms of the interpretation of parameters and convenience in hypothesis testing.
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Mandrell, Belinda Neal. "Molecular profile of women with and without secondary breast cancer the treatment of pediatric hodgkin lymphoma." View the abstract Download the full-text PDF version, 2008. http://etd.utmem.edu/ABSTRACTS/2008-010-Mandrell-index.html.
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Thesis (Ph.D.)--University of Tennessee Health Science Center, 2008.Title from title page screen (viewed on July 20, 2008). Research advisor: Ann K. Cashion, PhD. Document formatted into pages (xi, 118 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 96-102).
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Solyom, S. (Szilvia). "BRCA/Fanconi anemia pathway genes in hereditary predisposition to breast cancer." Doctoral thesis, Oulun yliopisto, 2011. http://urn.fi/urn:isbn:9789514294099.
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Abstract Two major genes are involved in hereditary predisposition to breast and ovarian cancer – BRCA1 and BRCA2. However, germline mutations in these tumor suppressors account for a maximum 20% of the familial breast cancer cases. A significant portion of the genes predisposing to this disease is unknown and therefore needs to be discovered. The aim of this study was to identify novel breast cancer susceptibility genes from the interweaving BRCA/Fanconi anemia (FA) pathway. Five candidate genes – MERIT40, ABRAXAS, BRIP1, CHK1, and FANCA – were screened for mutations by utilizing conformation-sensitive gel electrophoresis and sequencing, or with multiplex ligation-dependent probe amplification in blood DNA samples of Finnish familial breast cancer patients. Investigation of the MERIT40 gene revealed novel nucleotide changes, being the first report on mutation screening of this gene. None of the observed alterations, however, appeared to be disease related, suggesting that germline mutations in MERIT40 are rare or absent in breast cancer patients. A missense alteration (c.1082G>A, leading to Arg361Gln) was identified in ABRAXAS in 3 out of 125 Northern Finnish breast cancer families (2.4%), but not in any of the 867 healthy controls. The prevalence of the mutation between familial and control cases was statistically significantly different (p=0.002). ABRAXAS c.1082G>A appears to have pathological significance based on its exclusive occurrence in cancer cases, evolutionary conservation, disruption of a putative nuclear localization signal, reduced nuclear localization of the protein, and defective accumulation at DNA damage sites. The BRIP1 (FANCJ) and CHK1 genes were screened for large genomic rearrangements, but no abnormalities were detected, ruling out a significant contribution to breast cancer susceptibility in the Northern Finnish population. A novel large heterozygous deletion was identified in the FANCA gene in one out of 100 breast cancer families, removing the promoter and the first 12 exons. The deletion allele was not present in the tested controls, suggesting that it might contribute to breast cancer susceptibility. This is the first report on the association of a large-size germline deletion in a gene acting in the upstream part of the FA signaling pathway with familial breast cancerTiivistelmä BRCA1 ja BRCA2 ovat kaksi tärkeintä perinnöllisen rinta- ja munasarjasyövän alttiusgeeniä. Niissä esiintyvät ituradan muutokset selittävät kuitenkin vain noin 20 % familiaalisista rintasyöpätapauksista. Suurin osa alttiusgeeneistä on edelleen tunnistamatta ja näitä tekijöitä etsitään aktiivisesti. Tämän tutkimuksen tarkoituksena on ollut tunnistaa uusia alttiustekijöitä toisiinsa läheisesti liittyviltä BRCA/Fanconin anemia (FA) signaalinsiirtoreiteiltä. Viisi kandidaattigeeniä - MERIT40, ABRAXAS, BRIP1, CHK1 ja FANCA – kartoitettiin mutaatioiden suhteen suomalaisissa rintasyöpäperheissä käyttämällä konformaatiosensitiivistä geelielektroforeesia ja sekvensointia, tai multiplex ligation-dependent probe amplification- menetelmää. MERIT40-geenissä havaittiin useita aikaisemmin raportoimattomia nukleotidimuutoksia, mutta yhdenkään niistä ei havaittu liittyvän rintasyöpäalttiuteen. MERIT40-geenimuutosten mahdollista yhteyttä rintasyöpäalttiuteen ei ole tutkittu aikaisemmin. ABRAXAS-geenissä havaittiin missense-mutaatio (c.1082G>A, joka johtaa Arg361Gln aminohappokorvautumiseen) kolmessa pohjoissuomalaisessa rintasyöpäperheessä (3/125, 2.4 %). Muutosta ei havaittu terveissä kontrolleissa (N=867), ja ero mutaation esiintyvyydessä familiaalisten rintasyöpätapausten ja terveiden kontrollien välillä oli tilastollisesti merkitsevä (p=0.002). ABRAXAS c.1082G>A-muutos on todennäköisesti patogeeninen, sillä kyseinen aminohappopaikka on evolutiivisesti konservoitunut ja sijaitsee todennäköisellä tumaanohjaussignaalialueella. Funktionaaliset kokeet osoittivat, että mutatoitunut proteiinituote lokalisoitui villityypin proteiinia heikommin tumaan ja sen ohjautuminen DNA-vaurioalueille oli puutteellista. BRIP1- (FANCJ) ja CHK1-geeneistä etsittiin laajoja genomisia uudelleenjärjestelyjä, mutta niitä ei havaittu. Näin ollen kyseisillä muutoksilla ei ole merkittävää roolia perinnöllisessä rintasyöpäalttiudessa suomalaisessa väestössä. FANCA-geenissä havaittiin laaja heterotsygoottinen deleetio yhdessä tutkitusta 100 rintasyöpäperheestä. Deleetio poistaa geenin promoottorialueen lisäksi sen 12 ensimmäistä eksonia. Deleetioalleelia ei havaittu terveissä kontrolleissa, joten se mahdollisesti liittyy perinnölliseen rintasyöpäalttiuteen. Tutkimus on ensimmäinen, jossa raportoidaan laaja genominen deleetio FA-signaalinsiirtoreitin ylävirran geenissä familiaalisessa rintasyövässä
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Rosell, Johan. "Long-term effects of adjuvant tamoxifen treatment on cardiovascular disease and cancer." Doctoral thesis, Linköpings universitet, Avdelningen för kliniska vetenskaper, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-112085.
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The aims of this thesis were to investigate the long-term effects of adjuvant tamoxifen treatment on breast cancer recurrence and mortality, cardiovascular disease, and the incidence of secondary cancer. Between 1982 and 1992, postmenopausal patients with early stage breast cancer were included in a randomized clinical study of 2 or 5 years of postoperative tamoxifen therapy. The trial was planned by the Swedish Breast Cancer Group, and it included 4610 patients. Follow-up on causes of death, hospitalizations and secondary cancers were obtained from national population-based registries. All-cause mortality, breast cancer-specific mortality and mortality from coronary heart disease were decreased in the 5-year group, but the incidence of endometrial cancer was increased (Paper I). The incidence and mortality of cerebrovascular diseases were increased during the active treatment phase, and reduced after the active treatment (Paper II). Similar results were seen for subgroups of cerebrovascular diseases such as stroke and ischemic stroke. In the 5-year group, the morbidity from coronary heart disease was reduced during treatment but not after treatment was stopped (Paper III). This was the case also for heart failure and for atrial fibrillation/flutter. For secondary cancers the lung cancer risk was reduced, as well as the lung cancer mortality (Paper IV). An increased risk was observed for endometrial cancer, but appeared to decrease over time. The risk of contralateral breast cancer was reduced, with most of the reduction after treatment was stopped. For distance recurrences the risk was reduced both during treatment and a few years after treatment was stopped. The breast cancer mortality was also reduced, especially during the post-treatment phase.
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Smith, Bryan Ronain. "Nanoparticulate platforms for molecular imaging of atherosclerosis and breast cancer." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1150309580.
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Alladin, Ashna [Verfasser], and Martin [Akademischer Betreuer] Jechlinger. "Studying the origins of primary tumours and residual disease in breast cancer / Ashna Alladin ; Betreuer: Martin Jechlinger." Heidelberg : Universitätsbibliothek Heidelberg, 2020. http://d-nb.info/1222032562/34.
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Wang, Elaine. "Warburg or reverse Warburg effect: Tumor microenvironment reprograms breast cancer metabolism to upregulate cell proliferation." Scholarship @ Claremont, 2018. http://scholarship.claremont.edu/cmc_theses/1966.
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Cancer cells are most clearly characterized by their abnormal and uncontrolled cell growth. One of the most notable theories that explains the vast proliferative capacity of tumorigenic cells is the Warburg effect, a significant shift in metabolism wherein cancer cells preferentially fuel cell division using aerobic glycolysis instead of aerobic respiration. This upregulation of glycolytic fermentation in aerobic environments is highly unusual - glycolysis is typically utilized in anaerobic conditions, but nonetheless dominates cancer metabolic activity in spite of the presence of oxygen. Since the discovery the Warburg effect in the 1920s, researchers have struggled to identify whether aerobic glycolysis is a cause or consequence of carcinogenesis. Interestingly, a new theory recently emerged that challenges this widely-accepted metabolic paradigm for cancer. Known as the reverse Warburg effect, this new mechanism shows that in carcinomas such as breast cancer, the Warburg effect occurs not in cancer cells, but rather in tumor-adjacent stromal fibroblasts. These cancer-associated fibroblasts (CAFs) in the greater tumor microenvironment produce lactate - a high-energy metabolite formed as a byproduct of aerobic glycolysis - to fuel aerobic respiration and rapid tumorigenesis in neighboring cancer cells. This emerging theory emphasizes the pivotal role of the tumor microenvironment in determining whether cancer cells undergo aerobic glycolysis or aerobic respiration. Central to this lactate-linked metabolic intersection are two critical enzymes that regulate a cell's metabolic commitment - lactate dehydrogenase (LDH) and pyruvate dehydrogenase complex (PDHc). In order to clarify the mechanisms through which CAFs induce tumorigenesis in breast cancer, we plan to carry out two specific aims: (1) evaluate the enzymatic activity of LDH and PDHc, and (2) compare LDH and PDHc enzyme content. Using co-culture techniques to study the breast cancer tumor microenvironment in vitro, we will compare the enzymatic activity and enzyme content of both MCF7 breast cancer cells and CAFs to identify whether the reverse Warburg effect occurs due to post-translational enzyme activation or increased enzyme synthesis.
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Pylkäs, K. (Katri). "ATM, ATR and Mre11 complex genes in hereditary susceptibility to breast cancer." Doctoral thesis, University of Oulu, 2007. http://urn.fi/urn:isbn:9789514283833.
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Mutations in BRCA1 and BRCA2 explain only about 20% of familial aggregation of breast cancer, suggesting involvement of additional susceptibility genes. In this study five DNA damage response genes, ATM, ATR, MRE11, NBS1 and RAD50, were considered as putative candidates to explain some of the remaining familial breast cancer risk, and were screened for germline mutations in families displaying genetic predisposition.
Analysis of ATM indicated that clearly pathogenic mutations seem to be restricted to those reported in ataxia-telangiectasia (A-T). However, a cancer risk modifying effect was suggested for a combination of two ATM polymorphisms, 5557G>A and IVS38-8T>C, as this allele seemed to associate with bilateral breast cancer (OR 10.2, 95% CI 3.1–33.8, p = 0.001).
The relevance of ATM mutations, originally identified in Finnish A-T patients, in breast cancer susceptibility was evaluated by a large case-control study. Two such alleles, 6903insA and 7570G>C, in addition to 8734A>G previously associated with breast cancer susceptibility, were observed. The overall mutation frequency in unselected cases (7/1124) was higher than in controls (1/1107), but a significantly elevated frequency was observed only in familial cases (6/541, p = 0.006, OR 12.4, 95% CI 1.5–103.3). These three mutations showed founder effects in their geographical occurrence, and had different functional consequences at protein level.
In ATR no disease-related mutations were observed, suggesting that it is not a breast cancer susceptibility gene.
The mutation screening of the Mre11 complex genes, MRE11, NBS1 and RAD50, revealed two novel potentially breast cancer associated alleles: NBS1 Leu150Phe and RAD50 687delT were observed in 2.0% (3/151) of the studied families. The subsequent study of newly diagnosed, unselected breast cancer cases indicated that RAD50 687delT is a relatively common low-penetrance susceptibility allele in Northern Finland (cases 8/317 vs. controls 6/1000, OR 4.3, 95% CI 1.5–12.5, p = 0.008). NBS1 Leu150Phe (2/317) together with a novel RAD50 IVS3-1G>A mutation (1/317) was also observed, both being absent from controls. Loss of the wild-type allele was not observed in the tumors of the studied mutation carriers, but they all showed an increase in chromosomal instability of peripheral T-lymphocytes. This suggests an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer.
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Gajeton, Jasmine Joy. "Hyperglycemia Induced-miR-467 in Regulation of Inflammation in Health and Disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1607684190604311.
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Erkko, H. (Hannele). "TOPBP1, CLSPN and PALB2 genes in familial breast cancer susceptibility." Doctoral thesis, University of Oulu, 2008. http://urn.fi/urn:isbn:9789514289682.
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The currently known susceptibility genes account for approximately 25% of familial breast cancer predisposition. Additional factors contributing to the pathogenesis of breast cancer are, therefore, likely to be discovered. Most of the known genes affecting breast cancer predisposition function in the DNA damage response pathway. In this study three genes, TOPBP1, CLSPN and PALB2, involved in this complex process were investigated to reveal potentially pathogenic mutations associated with breast cancer susceptibility.
In the analysis of the TOPBP1 gene, one novel putative pathogenic alteration was observed. The Arg309Cys variant was found at an elevated frequency among familial cases (19/125) vs. controls (49/697) (p = 0.002; OR 2.4; 95% CI 1.3–4.2). In addition, altogether 18 other germline alterations were observed in this gene, but they all appeared to be harmless polymorphisms.
Investigation of CLSPN alterations among familial breast cancer families revealed altogether seven different changes. No clearly pathogenic alterations were observed. However, a potential modifier effect was discovered for the 1195delGlu change. The obtained results suggest that CLSPN alterations are unlikely to be significant breast cancer susceptibility alleles.
In the PALB2 gene, a pathogenic mutation c.1592delT was identified at an elevated frequency among breast cancer patients (0.9%) compared to controls (0.2%) (p = 0.003, OR 3.94, 95% CI 1.5–12.1). Among familial cases the frequency of c.1592delT was even higher (2.7%). This mutation was also functionally deficient. It had a markedly decreased BRCA2-binding affinity and was unable to support homologous recombination or to restore cross link repair in PALB2 knock-down cells. Additionally, this mutation was discovered in a familial prostate cancer family and was found to segregate with the disease, suggesting some association also with prostate cancer.
The penetrance and hazard ratio associated with PALB2 c.1592delT were determined in unselected breast cancer families. A substantially increased risk of breast cancer (HR 6.1; 95% CI 2.2–17.2; p = 0.01) was discovered resulting in an estimated 40% (95% CI 17–77) breast cancer risk by age 70 years, comparable to that for carriers of BRCA2 mutations. This markedly increased cancer risk suggests that genetic counselling for carriers is needed and screening for this mutation should be considered.
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Bani, Baker Qanita. "Computational Modeling to Study Disease Development: Applications to Breast Cancer and an in vitro Model of Macular Degeneration." DigitalCommons@USU, 2015. https://digitalcommons.usu.edu/etd/4409.
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There have been several techniques developed in recent years to develop computer models of a variety of disease behaviors. Agent-based modeling is a discrete-based modeling approach used agents to represent individual cells that mechanically interact and secrete, consume or react to soluble products. It has become a powerful modeling approach, widely used by computational researchers. In this research, we utilized agent-based modeling to study and explore disease development, particularly in two applications, breast cancer and bioengineering experiments. We further proposed an error-minimization search approach and used it to estimate cellular parameters from multicellular in vitro data.
In this dissertation, in the first study, we developed a 2D agent-based model that attempted to emulate the in vivo structure of breast cancer. The model was applied to describe the progression from DCIS into DCI. This model confirms that the interaction between tumor cells and the surrounding stroma in the duct plays a critical role in tumor growth and metastasis. This interaction depends on many mechanical and chemical factors that work with each other to produce tumor invasion of the surrounding tissue. In the second study, an in silico model was developed and applied to understanding the underlying mechanism of vascular-endothelial growth factor (VEGF) auto-regulation in REP and emulate the in vitro experiments as part of bioengineering research. This model may provide a system with robust predictive modeling and visualization that could enable discovery of the molecular mechanisms involved in age-related macular degeneration (AMD) progression and provide routers to the development of effective treatments. In the third and final study, a searching approach was applied to estimate cellular parameters from spatiotemporal data produced from bioengineered multicellular in vitro experiments. We applied a search method to an integrated cellular and multicellular model of retinal pigment epithelial cells to estimate the auto-regulation parameters of VEGF.
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Korneluk, Yolanda G. "Psychological functioning of adolescent girls at risk for breast cancer: The role of disease, individual, and family variables." Thesis, University of Ottawa (Canada), 2001. http://hdl.handle.net/10393/9300.
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In the face of maternal illness, adolescent daughters are thought to be at risk for emotional problems (e.g., Compas et al., 1994; Compas et al., 1996). This may be due to a number of variables, including those related to the functional impact of the disease, perceptions of increased personal risk, or other individual and family influences. To date, however, adolescent daughters of ill mothers remain an understudied population and variables for predicting or explaining adjustment problems in this group have not been thoroughly investigated. The purpose of this study was to examine the disease, family, and individual psychological variables that are related to adolescent girls' adjustment following maternal breast cancer. It was expected that maternal distress and family functioning would moderate the relationship between disease variables and adolescent psychological functioning. The current study included 60 mother-daughter pairs in which the mother was at least 1 year post-treatment for non-metastatic breast cancer. The mean age of mothers in the current sample was 45.4 years, and the average age of daughters was 15.5. Predictor variables examined were: (1) maternal health-related quality of life (HQL, measured with the Short Form-36; Ware et al., 1993), and adolescent perceptions of (2) disease severity, (3) personal risk for cancer, and (4) breast cancer worries (Severity Perceptions, Risk Perceptions and Worries subscales on the Breast Cancer Survey [BCS], Cappelli et al., 1999). Proposed moderators examined were: (1) family functioning (Family Assessment Measure-III; Skinner et al., 1983), and (2) maternal psychological distress (Symptoms Checklist 90-Revised; Derogatis, 1983). Adolescent psychological adjustment was the outcome variable, and was measured in two ways: (1) adolescent reports on the Youth Self Report (YSR; Achenbach, 1991), and (2) maternal reports on the Child Behavior Checklist (CBCL; Achenbach, 1991). Some support was provided for the hypothesis that adolescent role functioning moderates the relationship between certain disease-related factors and adolescent psychological adjustment. Specifically, poorer maternal HQL in the presence of greater problems with adolescent functioning within the family was associated with adolescent reports of poorer social competence. When adolescents reported high family functioning, however, no such relationship was observed, suggesting that good family functioning can help to buffer the negative effects maternal illness on adolescent social functioning. Additional analyses suggested that maternal distress levels mediate the significant association between maternal reports of adolescent problems and maternal HQL. In contrast, the relationship between maternal HQL and adolescent self-reports of psychological problems was mediated by family functioning. Results are considered in light of existing research in this area and clinical implications are discussed.