Doxorubicin is one of the most effective anti-cancer agents; however its use is associated with adverse cardiac effects, including cardiomyopathy and progressive heart failure. Mitochondrial function and integrity are crucial for cellular processes in general and play an important role during diseased development. These characteristics of the mitochondria make them the prime target for treatments for majority of diseases and in particular of the cardiovascular system. The mitochondria are also considered to play an integral role in the manifestation of the cardiotoxic effects of compounds such as doxorubicin. The current project is designed to investigate the cardiotoxic effects of doxorubicin at tissue, cellular and protein level. In addition, it is investigated whether the inhibition of the mitochondrial permeability transition pore (mPTP) with cyclosporin A (CsA) or the inhibition of mitochondrial fission with the mitochondrial division inhibitor (mdivi-1) protects against the detrimental effects of doxorubicin on cardiac function. We also investigated whether co-treatment of doxorubicin with either CsA or mdivi-1 has any negative interaction with the cytotoxicity of doxorubicin against cancer cells. Langendorff results indicated that doxorubicin caused a time dependent reduction in the haemodynamic function of the heart as well as causing an increase in the infarct size to risk ratio in both naïve conditions and in conditions of ischaemia and reperfusion. Detrimental effects of doxorubicin on cardiac function were abrogated by co-treatment of doxorubicin with CsA or mdivi-1 in naïve conditions and in conditions of ischaemia and reperfusion. Cell viability data of isolated cardiac myocytes revealed that doxorubicin caused a concentration dependant decrease in the viability of neonatal cardiac myocytes as well as causing a reduction in the time taken to depolarisation and hypercontracture under sustained oxidative stress, all of which were prevented when co-treated with either CsA or mdivi-1. Doxorubicin significantly elevated the levels of p-Akt, p-Erk, p-Drp1 and p-p53. Co-treatment with CsA prevented the increase in the levels of p-Akt and p-Erk caused by doxorubicin in both naïve and IR condition whereas mdivi-1 prevented the increase in the levels of p-Erk, p-Drp1 and p-p53 and caused further increase in the levels of p-Akt. Using sinusoidal muscle length change during contraction and relaxation, it is demonstrated that doxorubicin caused a decrease in the power output, peak force and force during shorting. Detrimental effects of doxorubicin on work-loop contraction were abrogated when doxorubicin was co-administered with CsA. To conclude, results demonstrated that doxorubicin caused cardiotoxicity at tissue, cellular and protein level in both naïve conditions and in conditions of ischaemia and reperfusion injury. In addition, it is shown that the inhibition of mitochondrial permeability transition pore with CsA or the inhibition of the mitochondrial fission with mdivi-1 protect against doxorubicin-induced toxicity without affecting its anti-cancer properties.

Background: Prostate cancer is the most common type of cancer in Sweden. The three primary treatment types for prostate cancer are prostatectomy, radiotherapy and different types of endocrine therapy. With all treatments mentioned above comes adverse effects that may have big effects on the person treated. Aim: The aim of this study was to highlight men´s experiences of the adverse effects that comes with the treatment for prostate cancer. Method: The research method employed was a literature study based on eleven qualitative articles. The method of analysis was done according to Friberg five-step analysis of qualitative articles and through the analysis, six themes emerged. Results: The themes were A feeling of emotional imbalance, Not prepared enough, The experience of loosing control, Feeling of diminished masculinity, The experience of a feminized body and An altered identity. Conclusion: The result showed that men experience adverse effects of the prostate cancer treatment as difficult in many ways. The changes to the body and mental well-being tend to be difficult to deal with, and the men need relevant information prior to treatment to give them time to adjust to their new life.

Thesis (MSc)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Breast Cancer remains one of the world’s leading causes of cancer related deaths amongst women. Its treatment has evolved from invasive, highly toxic therapies to treatments that possess a higher specificity and a lower toxicity. Despite improvements in overall survival, many patients do not benefit from these agents because of acquired and/or inherent tumour resistance, which could hinder treatment efficacy. Novel treatment strategies are, therefore, warranted to address these challenges and to significantly improve patient responses. Inhibiting components of the HER-2 signalling pathway can significantly sensitise breast cancer cells to low doses of ionising radiation. The objective of this study was to inhibit key molecular targets of the human epidermal growth factor receptor 2 (HER-2) signalling pathway and expose breast cancer cell lines to doses of radiation, so as to establish potential therapeutic targets that may be amenable to combined modality therapy, and formulate a cocktail of inhibitors to evaluate its radiosensitising capability. This study found that pre-treatment of two breast cancer cell lines (MDA-MB-231 and MCF-7) with a HER-2 inhibitor (TAK-165) had little or no effect on radiosensitivity. However, a radiation enhancement was observed when these cells were pre-treated either with BEZ235, a dual inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target for rapamycin (mTOR), or a cocktail of TAK-165 and BEZ235. These findings suggest that concurrent inhibition of HER-2, PI3K and mTOR during radiotherapy might improve treatment response of breast cancer patients. / AFRIKAANSE OPSOMMING: Borskanker bly steeds een van die leidende oorsake van sterftes aan kanker in vrouens. Behandeling het vanaf ‘n ingrypende, hoogs toksiese terapie verander na ‘n regimen wat hoogs spesifiek met ‘n laer toksisiteit is. Nogtans trek baie pasiënte geen voordeel uit hierdie nuwe benadering nie, omdat inherente en/of verworwe tumorweerstand daarteen suksesvolle uitkomste verhoed. Nuwe behandelingstrategieë is dus nodig om hierdie uitdagings te bekamp en om resultate in pasiënte aansienlik te verbeter. Inhibisie van komponente van die HER-2-seinoordragkaskade kan borskankerselle gevoelig maak vir lae dosisse van geïoniseerde bestraling. Die doelwit van hierdie studie was om sleutelteikens in die HER-2- seinoordragkaskade te inhibeer en om borskankerselle daarna aan bestralings dosisse bloot te stel. Sodoende word potensiële terapeutiese teikens wat vatbaar is vir gekombineerde modaliteitsterapie geïdentifiseer, waarna ‘n kombinasie van inhibitore geformuleer en geëvalueer kan word ten opsigte van hulle kapasiteit om gevoeligheid vir bestraling te verhoog. Die studie bevind dat voorbehandeling met ‘n HER-2-inhibitor (TAK-165) van borskankersellyne (MDA-MB-231 en MCF-7) min of geen invloed gehad het op stralingsensitiwiteit nie. ‘n Stralingsversterking is egter geïdentifiseer toe die selle vooraf behandel is met óf BEZ-235, ‘n tweevoudige inhibitor van fosforinositied 3-kinase (PI3K) en soogdierteiken vir rapamisien (mTOR), óf ‘n mengsel van TAK-165 en BEZ-235. Hierdie bevindinge suggereer dat gelyktydige inhibisie van die HER-2- seinoordragkaskade, PI3K en mTOR gedurende stralingsterapie moontlik die uitkoms in borskankerpasiënte kan verbeter.

Thesis (MSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Introduction: Breast cancer is a major contributor to mortality in women worldwide. Although, anthracyclines, such as doxorubicin, are among the most valuable treatments for breast cancer, their clinical use is limited due to detrimental side-effects such as cardiotoxicity. Additionally, evidence suggests that cancer cells are becoming increasingly resistant to chemotherapeutic agents. The consequence of poor vascularisation within tumours subsequently leads to a nutrient deprived microenvironment which cancer cells are known to adapt to via metabolic remodelling and increasing autophagy. Autophagy is an intracellular degradation system, which is induced as a survival mechanism in response to starvation and other environmental stressors. Recent studies have shown that starvation protects non-tumourigenic cells against chemotherapy-induced cell death. Furthermore, patients who starved prior to chemotherapy reported reduced side-effects. However, these studies investigated the effects of long-term starvation, which maybe clinically challenging. Therefore, this concept, under shorter and more tolerable periods of starvation still needs to be investigated. We hypothesis, that short-term starvation will sensitize breast cancer cells to doxorubicin-induced cell death. In order to test this hypothesis this study was approached by the following aims: (i) to establish a time point at which MCF12A breast epithelial cells are protected against starvation; (ii) to determine the effect of short-term starvation on doxorubicin induced cell death; (iii) to assess autophagy and; (iv) to assess these above mentioned aims using an in vivo model. Methods: MDAMB231 cells and MCF12A cells were starved for 0, 3, 6, 12, 24 and 48 hours using Hanks Balanced Salt Solution. Cell viability was assessed using the trypan blue, MTT and Caspase-Glo assays. MDAMB231 cells and MCF12A cells were subjected to the following conditions: (1) control; (2) 5 μM doxorubicin; (3) starvation of 3 hours and (4) a combination of starvation and doxorubicin. Following treatment an MTT assay to assess cell viability was performed. MDAMB231 cells were further examined using Live-Cell Imaging and western blot analysis. C57BL6 tumour bearing mice were treated with doxorubicin (5 mg/kg) or in combination with starvation of 24 hours. Upon termination of the protocol, tumour tissue was assessed using western blot analysis. In both in vitro and in vivo analyses cleaved-caspase 3 and cleaved-PARP were used as markers for apoptosis, LC3 and p62 as autophagic markers and p-AMPK and p-mTOR as markers of oxygen and energy sensing, respectively. Results and discussion: Three hours of starvation was chosen for in vitro experiments since no significant reduction in cell viability or increases in apoptosis occurred at this time-point in the normal MCF12A breast epithelial cells. As expected, doxorubicin induced a significant decrease in cell viability in the cancerous MDAMB231 cells. Short-term starvation in combination with doxorubicin treatment caused a further significant decrease in cell viability in MDAMB231 cells compared to the doxorubicin group alone. Interestingly, starved MCF12A cells were protected against doxorubicin-induced cytotoxicity as cell viability significantly increased. A significant decrease in autophagy was further observed with the combined treatment of doxorubicin and starvation which corresponded with a significant increase in cell death. In contrast, although the in vivo study also demonstrated a significant elevation in cell death and autophagy in response to doxorubicin treatment, the combined treatment (starvation and doxorubicin) did not have an additive effect when compared to the doxorubicin group alone. Conclusion: Our in vitro results clearly demonstrate that short-term starvation sensitizes breast cancer cells to doxorubicin-induced cell death. Additionally, decreased levels of autophagy appear to contribute to this phenomenon of sensitization. Although doxorubicin treatment resulted in increased apoptosis in vivo, 24 hours starvation in combination with doxorubicin did not sensitize the tumours to doxorubicin treatment. Thus, for future in vivo studies more time points should be considered in order to translate the beneficial effects of short-term starvation observed in our in vitro study to an animal model. / AFRIKAANSE OPSOMMING: Inleiding: Borskanker is ‘n belangrike faktor wat bydrae tot sterftes in vrouens wêreldwyd. Alhoewel antrasikliene soos doxorubicin, waardevol is vir die behandeling van borskanker, word die kliniese gebruik daarvan beperk deur newe-effekte soos kardiotoksisiteit. Verder, word daar al hoe meer bewys dat kankerselle toenemend weeerstandbiedend word teen chemoterapeutiese middels. Swak vaskularisasie van tumore lei tot ‘n mikro-omgewing met beperkte voedingstowwe waaby kankerselle kan aanpas deur middel van metaboliese hermodelering en ‘n toename in autofagie. Autofagie is ‘n intrasellulêre degraderingsisteem wat as ‘n oorlewingsmeganisme aangewend word tydens verhongering en ander omgewingstressors. Onlangse studies het getoon dat verhongering nie-tumourigeniese (normale) selle teen chemoterapie-geïnduseerde seldood beskerm. Verder is daar ook geraporteer dat pasiënte wat gevas het voor chemoterapie, verminderde newe-effekte getoon het. Hierdie studies het egter gefokus op ‘n relatief lang-termyn vas, wat klinies nogal uitdagend kan wees. Daarom moet hierdie konsep nog op korter, meer hanteerbare tye getoets word. Ons hipotese is dus dat kort-termyn vas borskankerselle kan sensitiseer tot doxorubicin-geïnduseerde seldood. Om hierdie hipotese te toets, is die volgende doelwitte gestel: (i) om ‘n tydspunt te bepaal waar MCF12A borsepiteelselle beskerm is teen verhongering; (ii) om die effek van kort-termyn verhongering op doxorubicin-geïnduseerde seldood te toets; (iii) om autofagie te karakteriseer in ons model en; (iv) om hierdie doelwitte ook in ‘n in vivo model te toets. Metodes: MDAMB231 en MCF12A selle is verhonger vir 0, 3, 6, 12, 24 and 48 ure deur van Hanks se gebalanseerde soutoplossing gebruik te maak. Sellewensvatbaarheid is bepaal deur middel van trypan blou, MTT en die Caspase-Glo tegnieke. MDAMB231 en MCF12A selle is onderwerp aan die volgende omstandighede: (1) kontrole; (2) 5 μM doxorubicin; (3) verhongering van 3 ure en (4) ‘n kombinasie van verhongering en doxorubicin. Na behandeling is die sellewensvatbaarheid deur middel van die MTT tegniek bepaal. MDAMB231 selle is verder ondersoek deur middel van “Live-Cell Imaging” en die westelike klad tegniek. C57BL6 tumor-draende muise is behandel met doxorubicin (5 mg/kg) of met ‘n kombinasie van verhongering van 24 ure en doxorubicin. Aan die einde van die protokol, is die kankerweefsel geanaliseer deur die westelike klad tegniek. In beide in vitro en in vivo analises, is gekliefde- caspase 3 en -PARP as merkers vir apoptose, LC3 and p62 as merkers vir autofagie en p-AMPK en p-mTOR as suurstof- en energie sensors respektiewelik gemeet. Resultate en bespreking: Vir die in vitro eksperimente, is ‘n tydspunt van 3 ure gekies as gevolg van die feit dat geen afname in sellewensvatbaarheid en ‘n toename in apoptose in hierdie tydsgleuf tydens verhongering in die normale MCF12A borsepiteelselle plaasgevind het nie. Soos verwag, het doxorubicin behandeling ‘n insiggewende afname in sellewensvatbaarheid in die kankeragtige MDAMB231 selle veroorsaak. Die kombinasie-terapie van verhongering en doxorubicin het ‘n verdere verhoging in seldood teweeg gebring in die MDAMB231 selle, maar het die normale MCF12A borsepiteelselle teen doxorubicin-geïnduseerde toksisiteit beskerm. Die kombinasie-behandeling is ook geassosieer met ‘n afname in autofagie. Alhoewel, die in vivo studie ook getoon het dat doxorubicin alleen insiggewende hoeveelheid seldood teweeggebring het, het die kombinasie-behandeling nie die additiewe effek, soos in die in vitro studie, teweeg gebring nie. Gevolgtrekking: Die in vitro resultate het duidelik getoon dat kort-termyn verhongering borskankerselle kan sensitiseer vir doxorubicin terapie. Verder het dit geblyk dat ‘n afname in autofagie tot die fenomeen van sensitisering bygedrae het. Alhoewel doxorubicin behandeling in vivo tot ‘n toename in apoptose in die tumor gelei het, het die kombinasie behandeling nie die kankerweefsel ten op sigte van doxorubicin gesensitiseer nie. Daar sal dus vir toekomstige in vivo studies meer tydsgleuwe van behandeling ondersoek moet word om die optimum verhongeringsperiode te vind sodat die in vitro resultate ook in vivo van toepassing kan wees. / NRF and CANSA for financial support

Thesis (PhD)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Phytoestrogen containing extracts of Cyclopia, an indigenous South African fynbos plant used to prepare honeybush tea, may serve as a source of new estrogen analogues. It would be of great benefit if these new analogues would not only prevent the development and progression of breast cancer which, globally, is responsible for the highest number of cancer associated deaths among females, but also have a reduced side-effect profile when compared to current treatments and, in addition, also alleviate menopause associated symptoms. In this study three extracts, P104, SM6Met, and cup-of-tea, from two species of Cyclopia, C. genistoides and C. subternata, were evaluated for their potential to modulate molecular targets involved in prevention and treatment of breast cancer. We show that the phytoestrogenic extracts of Cyclopia antagonise estrogen-induced cell proliferation both in vitro as well as in vivo. Furthermore, our study presents various molecular mechanisms whereby the Cyclopia extracts may be eliciting this effect. Importantly, we show, for the first time, that the Cyclopia extracts behave as ERα antagonists and ERβ agonists which, with respect to the known role of the ER subtypes in breast cancer, where the ERα subtype is associated with the stimulation of cell proliferation and the occurrence of breast cancer, while ERβ ameliorates the action of ERα in breast cancer and could act as an inhibitor of breast cancer development, may be beneficial for the prevention or treatment of breast cancer. In addition, we also show that the extracts of Cyclopia behave as selective estrogen receptor degraders by down-regulating ERα protein levels while stabilising ERβ protein levels, which not only provides a possible molecular explanation for the observed ERα antagonism and ERβ agonism, but, in addition, may be beneficial as higher ERα levels are associated with malignant breast cancer tumours, while higher ERβ levels are associated with benign tumours. Furthermore, we show that the Cyclopia extracts affect the nuclear localization and distribution of both ER subtypes in a manner that provides an additional molecular explanation for the observed ERα antagonism and ERβ agonism. Investigation of the molecular processes involved in the promotion and progression of breast cancer, such as the distribution of cells between the phases of the cell cycle, cancer cell invasion, and the regulation of genes governing these processes provides evidence that the Cyclopia extracts are not as proliferative as estrogen. In addition, Cyclopia extracts display anti-inflammatory properties, which may be beneficial as inflammation is an enabling characteristic in cancer development and progression. Furthermore, this study, for the first time, shows that the phytoestrogenic extracts of Cyclopia are absorbed, are not toxic, and display biological ERα antagonist activity in vivo by retarding uterine growth. Thus, we propose that the Cyclopia extracts act as selective estrogen receptor subtype modulators with potential to be developed as a nutraceutical for the treatment or prevention of breast cancer. / AFRIKAANSE OPSOMMING: Fitoëstrogeen-bevattende ekstrakte van Cyclopia, ‘n inheemse Suid Afrikaanse fynbosplant wat gebruik word vir die voorbereiding van heuningbostee, mag as ‘n bron van nuwe estrogeen-analoë dien. Dit sal baie voordelig wees indien hierdie nuwe analoë nie net die ontwikkeling en progressie van borskanker sal voorkom nie, aangesien borskanker wêreldwyd verantwoordelik is vir die grootste getal kankerverwante sterftes onder vroue, maar ook ‘n verminderde newe-effek profiel vertoon in vergelyking met huidige behandelings en ook, boonop, simptome wat met menopouse geassosieer word, sal verlig. In hierdie studie is drie ekstrakte, P104, SM6Met, en cup-of-tea, vanaf twee spesies van Cyclopia, C. genistoides en C. subternata, geëvalueer vir hul potensiaal om die molekulêre teikens betrokke by die voorkoming en behandeling van borskanker te moduleer. Ons wys dat die fitoëstrogeniese ekstrakte van Cyclopia antagoniseer estrogeen-geïnduseerde selproliferasie beide in vitro as ook in vivo. Verder bied ons studie ook verkskeie molekulêre meganismes aan oor hoe die Cyclopia ekstrakte hierdie effek mag ontlok. ‘n Belangrike bevinding is dat ons vir die eerste keer wys dat die Cyclopia ekstrakte hulself as ERα -antagoniste en ERβ-agoniste gedra wat, met betrekking tot die erkende rol van die ER-subtipes in borskanker, waar die ERα-subtipe geassosieer word met die stimulasie van selproliferasie en die gebeurtenis van borskanker, terwyl ERβ die aksie van ERα onderdruk en as ‘n inhibeerder van borskankerontwikkeling kan dien, voordelig mag wees vir die voorkoming of behandeling van borskanker. Ons wys boonop ook dat die ekstrakte van Cyclopia hulself soos selektiewe estrogeen- reseptor-degradeerders gedra deurdat hul ERα-proteïnvlakke verlaag terwyl hul ERβ-proteïnvlakke stabiliseer. Dit verksaf nie net ‘n moontlike molekulêre verduideliking vir die waargeneemde ERα-antagonisme en ERβ-agonisme nie, maar mag ook voordelig wees in borskanker aangesien hoër ERα-vlakke geasosieer word met kwaadaardige borskankertumors en hoër ERβ-vlakke met nie-kwaadaardige tumors. Verder wys ons dat die Cyclopia ekstrakte die lokalisering en verspreiding van beide ER-subtipes in die selkern op so ‘n wyse beïnvloed dat dit ‘n addisionele molekulêre verduideliking bied vir die ERα-antagonisme en ERβ-agonisme wat waargeneem is. Verdere ondersoek van die molekulêre prosesse betrokke by die promosie en progressie van borskanker, soos die verspreiding van selle tussen die fases van die selsiklus, die beweging van kankerselle na omliggende weefsels, en die regulering van gene wat hierdie prosesse beheer, verskaf bewyse dat die Cyclopia-ekstrakte nie so proliferatief is soos estrogeen nie. Die ekstrakte van Cyclopia vertoon boonop ook anti-inflamatoriese eienskappe, wat voordelig mag wees aangesien inflammasie ‘n bydraende eienskap in kankerontwikkeling en -progressie is. Verder wys hierdie studie vir die eerste keer dat die fitoëstrogeniese ekstrakte van Cyclopia geabsorbeer word, nie toksies is nie, en dat hulle biologiese ERα-antagonis aktiwiteit vertoon deurdat hulle uterus-groei vertraag in vivo. Dus stel ons voor dat die Cyclopia-ekstrakte optree soos selektiewe-estrogeen-reseptor-subtipe-moduleerders met die potensiaal om ontwikkel te word as ‘n nutraseutiese middel vir die behandeling of voorkoming van borskanker.

Thesis (DMed (Obstetrics and Gynaecology))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: Chapter 1 is a literature review investigating the incidence of cancer in children and young adults. It describes the most important treatment options including chemotherapy, radiotherapy and surgery and the effect of treatment on future endocrine development and fertility. Different primary cancer sites are discussed in more detail. Chapter 2 is a literature review on the effects of cancer surgery in women and the options for fertility sparing. Cervical cancer and pre-cancer are discussed in detail with options for more conservative surgery in selected patients. A summary of the available published cases of trachelectomy with pregnancy outcomes is included. Other gynaecological cancers requiring surgery are also discussed with reference to conservative options. Chapter 3 is a literature review about the medical (pharmacological) options for protection of ovarian function in patients undergoing oncotherapy. The role of gonadotrophin releasing hormone analogues and hormonal contraceptives in ovarian suppression is discussed in detail. Chapter 4 This chapter examines germ cell physiology with reference to cryopreservation. It includes two major parts. Part 1 is the description of germ cell- and follicle physiology, the principles of cryobiology followed by a review of oocyte cryopreservation and ovarian tissue preservation. Both slow freezing and vitrification techniques are described. The second part of chapter 4 is a report on a randomised controlled evaluation of two different slow freezing cryopreservation protocols. This experimental study compared ultrastructural changes in fresh and previously cryopreserved ovarian cortical tissue after equilibration and thawing using two different cryoprotectants. This is the first randomised investigation into DMSO and PROH as cryoprotectants. Chapter 5 is an investigation into cryopreservation of ovarian tissue as a strategy to protect hormonal function and fertility against gonadotoxic treatment. This chapter consists of two parts. The first part is a thorough literature review of all the published work about grafting of previously cryopreserved ovarian tissue. The largest case series found from a single institution was five patients. Another report of six patients included patients from various sites in Denmark. Part 2 is a description of a cohort of patients followed up after re-implantation of previously cryopreserved ovarian cortical tissue. Follow-up hormone levels of 13 individual cases are described in detail. This is the largest case series ever reported. The experimental study described in Chapter 4 and the clinical study described in Chapter 5 was approved by the ethical research committee of the Faculty of Health Sciences, Stellenbosch University, project number N05/10/182. Chapter 6 provides an integrated overview of the incidence and treatment of cancer in young women and how its negative effects may be prevented or mitigated. Aspects of chemotherapy, radiotherapy and surgery are evaluated where it may affect future reproductive health. The role of oocyte and ovarian tissue cryopreservation is discussed. Guidelines are provided for clinicians. / AFRIKAANSE OPSOMMING: Hoofstuk 1 Hierdie is ‘n literatuuroorsig wat die insidensie van kanker in kinders en jong volwassenes ondersoek. Dit sluit die mees belangrike behandelingsopsies in, naamlik chemoterapie, radioterapie en chirurgie en die effek wat behandeling mag hê op toekomstige endokriene ontwikkeling en fertiliteit. ‘n Verskeidenheid kanker tipes word in meer detail beskryf. Hoofstuk 2 Hoofstuk 2 is ‘n literatuuroorsig oor die effekte van kankerchirurgie in vroue en die geleenthede tot beskerming van fertiliteit. Servikale kanker en voorlopers van servikale kanker word bespreek en die opsies vir konserwatiewe chirurgie in uitgesoekte pasiënte word gegee. ‘n Opsomming van die inligting wat beskikbaar is oor tragelektomie en swangerskap uitkomste word ingesluit. Ander ginekologiese kankers wat chirurgie mag benodig, word ook bespreek met verwysing na konserwatiewe hantering. Hoofstuk 3 ‘n Literatuuroorsig oor die mediese (farmakologiese) opsies vir die beskerming van ovariële funksie in pasiënte wat behandeling ontvang vir kanker. Die rol van gonadotropien-vrystellingshormoon-analoë en hormonale kontrasepsie vir ovariële onderdrukking word in detail bespreek. Hoofstuk 4 Hierdie hoofstuk ondersoek kiemselfisiologie met verwysing na vriesbewaring. Dit is verdeel in twee dele. Deel 1 is ‘n beskrywing van kiemsel- en follikelfisiologie en die beginsels van vriesbiologie. Dit word gevolg deur ‘n oorsig van oösiet vriesbewaring en ovariële weefselbewaring. Stadige bevriesing en vitrifikasie- metodes word bespreek. Die tweede deel van hoofstuk 4 is ‘n verslag oor ‘n gerandomiseerde, gekontroleerde evaluasie van twee stadige bevriesingsmetodes. Hierdie eksperimentele studie het die ultrastrukturele veranderinge vergelyk in vars en voorheen bevrore ovariële kortikale weefsel na ekwilibrasie en ontdooiing met twee verskillende vriesbeskermers. Dit is die eerste gerandomiseerde studie oor DMSO en PROH as vriesbeskermers. Hoofstuk 5 Hierdie hoofstuk handel oor ‘n ondersoek na vriesbewaring van ovariële weefsel as ‘n benadering tot beskerming van hormonale funksie en fertiliteit teen gonadotoksiese behandeling. Die hoofstuk bestaan uit twee dele. Die eerste deel is ‘n deeglike oorsig van die literatuur oor al die beskikbare werk wat handel oor terugplasing van voorheen bevrore ovariële weefsel. Die grootste pasiëntreeks van ‘n enkel instelling was slegs vyf pasiënte. ‘n Ander beskrywing van ses pasiënte het pasiënte van verskeie eenhede in Denemarke ingesluit. Deel 2 is ‘n beskrywing van ‘n groep pasiënte wat opgevolg is na oorplanting van voorheen bevrore ovariële kortikale weefsel. Opvolg hormoonvlakke van 13 gevalle word in detail bespreek. Hierdie is die grootste pasiëntreeks wat tot nog toe beskryf is. Die eksperimentele studie wat in hoofstuk 4 beskryf word en die kliniese studie wat in hoofstuk 5 beskryf word, is goedgekeur deur die etiese navorsingskomitee van die Fakulteit Gesondheidswetenskappe van die Universiteit Stellenbosch met die projeknommer N05/10/182 Hoofstuk 6 Hierdie is ‘n geïntegreerde oorsig van die voorkoms en behandeling van kanker in jong vroue en hoe die negatiewe effekte daarvan voorkom of verminder kan word. Aspekte van chemoterapie, radioterapie en chirurgie word geëvalueer ten opsigte van die effek op toekomstige reproduktiewe gesondheid. Die rol van oösiet- en ovariële weefselvriesbewaring word bespreek. Riglyne vir klinici word gegee.

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Surgery / Doctoral / Doctor of Philosophy

No description available.

Acute Myeloid Leukemia (AML), the most common form of acute leukemia in adults, is only curable in approximately 30% of all cases. Despite prognostic risk stratification using sub-typing and cytogenetic analysis to direct therapy, the mortality and relapse rate remains high. AML patients with normal karyotypes are defined as intermediate risk and are the most challenging to treat. Somatic mutations may be the key in refining prognostic stratification and providing useful therapeutic targets. The FMS-like tyrosine kinase 3 (FLT3) and Nucleophosmin (NPM1) genes have common mutated forms that are associated with overall survival and response to therapy. We assessed mutations in the FLT3 and NPM1 genes and their levels of expression in twenty eight AML patients in the presence and absence of HIV and their response to induction therapy. Furthermore, we used a novel technique, High Resolution Melting (HRM) Analysis to detect FLT3 Internal Tandem Duplications (ITD) and NPM1 exon 12 mutations. Five of the patients in this study were HIV positive, three of whom did not survive post-induction therapy. Of the AML patients, 17.9% were positive for the NPM1 mutation and 21% had mutated FLT3. Interestingly, the presence of the FLT3 and NPM1 mutations were coupled with an increase in expression levels of FLT3 and NPM1 from presentation to post-induction respectively and the loss of these mutations were coupled with a decrease in levels of expression from presentation to post-induction. However, an increase/decrease from presentation to post-induction did not necessarily denote the presence/absence of a mutation. Therefore, while mutational status of genes may generally confer mRNA levels, our results showed that there existed no definitive trend between mRNA levels of NPM1 and FLT3 expression and mutational status. We found that the HRM method was definitive for the simpler NPM1 mutation however detection of the FLT3-ITD mutation was challenging. There isn’t a clear distinction between mutated and non-mutated FLT3 due to the formation of hetero-duplexes during analysis, making detection highly subjective and error-prone. Sequencing allowed confirmation of mutated FLT3 and non-mutated FLT3 which were not in all instances in concordance with HRM analysis. The prognostic value in terms of overall survival of NPM1 and FLT3 mutations in this study is indefinite. Furthermore, the analysis of the HIV positive AML patients revealed no clear correlation between NPM1 and FLT3 levels of mRNA expression and mutational status. Also, the small number of HIV positive AML patients did not allow for conclusions to be made regarding HIV status and survival when affected with AML. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2012.