Bakgrund: Varje år drabbas 55 000 personer i Sverige av cancer och behandlas oftast med kombinerade behandlingar. Den vanligaste biverkningen och det mest påfrestande symtomet vid cancer är fatigue. Fatigue betyder extrem trötthet/utmattninig och är en subjektiv upplevelse. Fatigue är inte en trötthet som går över efter sömn och vila. Syfte: Syftet med denna litteraturstudie är att beskriva hur det är att leva med fatigue vid cancer och cancerbehandling. Metod: En systematisk litteraturstudie som bygger på 15 vetenskapliga artiklar. Artiklarna är både kvalitativa och kvantitativa och har kvalitetsgranskats utifrån Fribergs kriterier för analys av vetenskapliga studier. Litteraturstudien utgår från det teoretiska begreppet livskvalitet. Resultat: Resultatet utmynnade i tre teman; Aspekter som påverkar graden av fatigue, Fatigues negativa påverkan på livskvalitet samt Sätt att hantera fatigue. I det första temat framkom det att fatigue är föränderligt beroende på vilken cancerdiagnos samt cancerbehandling personer genomgår. Det framkom hur fatigue är ett multidimensionellt begrepp där flera andra symtom är relaterade till fatigue. Andra temat innefattar hur avsaknad av energi och social isolation påverkar personers livskvalitet negativt. Det tredje temat innefattar hur personer hittar individuella strategier för att hantera sin fatigue och att fysisk aktivitet är den strategi som visats sig ha mest positiv inverkan på att minska graden av fatigue. Diskussion: I resultatdiskussionen diskuteras begreppet livskvalitet som är den teoretiska utgångspunkten i examensarbetet. Livskvalitet berör både sjukdomsspecifika aspekter samt biverkningar av behandlingen som bidrar till ohälsa. Detta är tillämpbart eftersom fatigue upplevs som psykiskt, fysisk och socialt påfrestande. Livskvalitet är något föränderligt och förändras då personer får en svår sjukdomsdiagnos. Även sjuksköterskans arbete är viktigt i mötet med personer med fatigue då sjuksköterkan kan komma med förslag på strategier som kan göra fatigue mindre påfrestande. / Background: Each year, 55 000people in Sweden affected by cancer and is usually treated with combined treatments. The most common side effect and the most distressing symptom of cancer is fatigue. Fatigue means extreme tiredness/exhaustion and it’s a subjective experience. Fatigue is not tiredness that goes over after sleep or rest. Aim: The aim of this study is to describe what it's like to live with fatigue in cancer and cancer treatment. Methods: A systematic literature review based on 15 scientific articles. The articles are both qualitative and quantitative and quality reviewed for Friberg's criteria for analyzing scientific studies. The literature review is based on the theoretical concept of quality of life. Results: The analysis resulted in three themes: Aspects that affect the level of fatigue, Fatigues negative impact on quality of life and method for managing fatigue. In the first place it was found that fatigue is constantly changing depending on the diagnosis of cancer and cancer treatment that people receiving. It also reached the conclusion how fatigue is a multidimensional concept where several other symptoms are related to fatigue. The Second theme includes the lack of energy and social isolation affects people's quality of life negatively. The third theme involves how people find individual strategies to deal with their fatigue and physical activity is the strategy that proved to have the most positive impact on reducing the severity of fatigue. Discussions: The results discussed the concept of quality of life, the theoretical concept in the literature review. Quality of life concerns both disease-specific aspects and treatment side effects that contribute to ill health. This is applicable because fatigue is experienced as mental, physical and social discomfort. Quality of life is something changing and change as people get a severe disease diagnosis. Even the nurse's work is important when meeting people with fatigue when nurses can make suggestions on strategies that can make fatigue less strenuous.

Thesis (M.Sc.Eng.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Nanoparticle-based drug delivery has been explored to circumvent the often-toxic chemotherapy treatments used today by providing a more efficient and specific delivery to diseased tissues. Recently we have developed polymeric pH-responsive expansile nanoparticles (eNPs) for intracellular delivery of paclitaxel (Pax) as an improvement upon the traditional methods of delivery of Pax with using Cremophor/ethanol. As eNPs are internalized by the cell, the hydrophobic protecting groups found on side chains along the polymer backbone are hydrolyzed, leaving behind hydrophilic moieties that cause the eNPs to slowly swell with water. In this manner, the encapsulation and controlled release of a hydrophobic drug can be achieved. By altering the surface characteristics of the eNPs, one can change the behavior of the delivery vehicle as well as the biological response. To explore this approach, two surfactant strategies were employed. Specifically, the original sodium dodecyl sulfate (SDS) surfactant has been substituted with PEGylated surfactants (either lipids or poloxamer) to improve circulation and in vivo stability. In addition, these surfactants were functionalized to target the folate receptor (FR), which is overexpressed in several cancers, in order to increase cancer cell-specific localization and uptake. The resulting eNPs retained their swelling characteristics while demonstrating improved cellular uptake in folate receptor-expressing KB and MDA-MB-231 carcinoma cells with no change in uptake in A549 cells, which do not express the folate receptor. / 2031-01-01

University of Macau / Institute of Chinese Medical Sciences

A series of structurally related BODIPY dyes were synthesised and characterised. Their photophysical properties were studied in order to determine whether they would be suitable candidates for use as photosensitisers in the photodynamic therapy (PDT) treatment of cancer. The synthesis of two highly fluorescent BODIPY cores was achieved via the acid-catalysed condensation of a pyrrole and a functionalised aldehyde. In order to promote intersystem crossing, and hence improve the singlet oxygen generation of these dyes, bromine atoms were added at the 2,6-positions of the BODIPY core. These dibrominated analogues showed good singlet oxygen quantum yields, and excellent photostability in ethanol. In order to red-shift the main spectral bands of the BODIPY dyes towards the therapeutic window, vinyl/ styryl groups were introduced at the 3-, 5-, and 7-positions via a modified Knoevengal condensation reaction. The addition of vinyl/ styryl groups to the BODIPY core caused an increase in fluorescence quantum yield as well as a decrease in singlet oxygen quantum yield with respect to the dibrominated analogues. However, two of the red-shifted BODIPY dyes still showed moderate singlet oxygen quantum yields. The use of BODIPY dyes in nonlinear optics (NLO) was explored. The nonlinear optical characterisations and optical limiting properties of a series of 3,5-dithienylenevinylene BODIPY dyes were studied, both in dimethylformamide (DMF) solution and when embedded in poly(bisphenol A carbonate) (PBC) as thin films. The 3,5-dithienylenevinylene BODIPY dyes showed typical nonlinear absorption behaviour, with reverse saturable absorption (RSA) profiles, indicating that they have potential as optical limiters. The second-order hyperpolarizability (Y), and third-order nonlinear susceptibility (/m[/(3)]) values are also reported for these dyes. The optical limiting values of one of the BODIPY dyes in solution, and two of the BODIPY-embedded PBC films, were below the maximum threshold of 0.95 J-cm-2. The effect of addition of substituents on the electronic structure of the BODIPY dyes was investigated using TD-DFT calculations. The calculated trends closely followed those determined experimentally.

M.Sc. / The ideal cancer treatment modality should not only cause tumour regression and eradication but also induce a systemic antitumour response, which is essential for the control of metastatic tumours and long-term tumour resistance. Photodynamic Therapy (PDT) is a current approach in the treatment of various cancers. It involves the administration of a tumour-localizing photoreactive compound, which is activated at a specific wavelength of light. This therapy results in a sequence of photochemical and photobiological processes that cause irreversible photodamage to tumour tissues. Eradication is achieved by anti-tumour effects induced in the parenchyma and tumour vascular network. PDT can lead to a rapid cell death response in malignant cells, which has provided insight into the mechanisms behind photokilling. Oesophageal cancer is the seventh leading cause of cancer death worldwide, and in South Africa remains a problem of epidemic proportions affecting predominantly black males. The appearance of a number of new photosensitizers being developed will not only extend the number of choices for treating specific cancers, but also aid in the effective destruction of various tumour tissues. PDT has been an experimental clinical modality for the past two xii decades and has been shown to be successful for the treatment of advanced oesophageal cancer where other options have failed. The full potential of PDT as a treatment modality has not been clearly evaluated, which is one of the objectives of this study. Overall, PDT has the potential of being a promising therapeutic option in the effective treatment of oesophageal cancer, and through this study and the elucidation of the mechanisms of PDT action, it will provide a better future for those suffering from oesophageal cancer. A new photosensitizer known as Zinc Sulphophthalo-cyanine (ZnPcSmix) was studied on an oesophageal SNO cancer cell line in order to determine treatment-induced cell viability, cytotoxicity and the pathway followed to cell death. The major observations of this study revealed that PDT using ZnPcSmix resulted in a decrease in cell viability and proliferation, resulting in a cytotoxic response experienced by the cell. The outcome of this study revealed that the SNO cells experience a necrotic mode of cell death after using ZnPcSmix to induce photodamage. This was examined by light microscopy and confirmed by the lack of DNA fragmentation and decreased caspase-3 and caspase-7 expression levels. Hsp70 levels decreased resulting in lowered cytokine TNF-α release from necrotic cells. Hoechst nuclear staining revealed a disorganized nuclear pattern characteristic of necrotic release of cellular contents. The major findings of this study revealed the efficacy of ZnPcSmix as a new photosensitizing drug used during PDT to treat oesophageal cancer resulting in a decrease in cell viability and proliferation. Necrosis was the primary mechanism by which cells pursued death, which was dependent on the photosensitizer dose, cell type and irradiation fluence. ZnPcSmix–induced photodamage seen during PDT offers a new treatment option for patients suffering from oesophageal cancer and shows great promise in effectively treating early-stage oesophageal cancer.

No description available.

Magister Artium - MA / Breast cancer is a common cause of death among women worldwide. It has long been recognized as a major public health burden in high-income countries, however, the majority of cases are said to occur in low and middle-income countries, such as in South Africa. A breast cancer diagnosis and treatment heralds a series of frightening events and can be a traumatic experience. The manner in which women perceive and cope with their illness is predictive of emotional and physical health outcomes. It is thus imperative to explore the experiences of South African women, whose voices may have been silenced in the past. The purpose of my study was to explore the subjective lived experiences of women with early stage breast cancer undergoing treatment. The objectives of the study were to; explore the emotional experiences of women with early stage breast cancer undergoing treatment and secondly to explore how women perceive their bodies through their experience of early stage breast cancer while undergoing treatment. Phenomenology was used as the theoretical position conceptualising the study as well as the research design. This research study adopted a qualitative approach utilising in-depth face to face semi-structures interviews for collecting data. The participants were selected through purposive sampling and comprised six women aged between 30 and 40 who are undergoing treatment for early stage breast cancer. The data was analysed using interpretative phenomenological analysis. Emotions experienced were characterised by the shock of the diagnosis due to factors such as lack of family history and age. Participants reported positive changes and viewpoints which they gained through their breast cancer journey. Emotions were heightened during treatment due to the physical change experienced and the effects this had on family members and the general public. Furthermore, results indicated that participants, even though they discovered a new found love for life and for their wellbeing, neglected their emotional needs in order to protect family members. An additional reason for this neglect centered on the lack of understanding other individuals may have regarding the experiences of participants. Recommendations involves the encouragement of accessing counselling services and that interventions tailored to the needs of each patient especially according to age. All ethical considerations as stipulated by the University of the Western Cape were adhered to.

Current dogma suggests that the Heat Shock Protein (Hsp) molecular chaperones and associated co-chaperones function primarily within the cell, although growing evidence suggests a role for these proteins on the plasma membrane of cancer cells. Hsp90 does not function independently in vivo, but instead functions with a variety of partner chaperones and co-chaperones, that include Hsp70 and Hsp90/Hsp70 organising protein (Hop), which are thought to regulate ATP hydrolysis and the binding of Hsp90 to its client proteins. Hsp90 on the plasma membrane appears to have distinct roles in pathways leading to cell motility, invasion and metastasis. We hypothesised that Hsp90 on the plasma membrane is present as part of a multi-chaperone complex that participates in the chaperone-assisted folding of client membrane proteins in a manner analogous to the intracellular chaperone complex. This study characterised the membrane expression of Hsp90, Hsp70 and Hop in different cell models of different adhesive and migratory capacity, namely MDA-MB-231 (metastatic adherent breast cancer cell line), MCF-7 (non-metastatic adherent breast cancer cell line), U937 and THP1 (monocytic leukemia suspension cell lines). Membrane expression of the Hsps was analysed using a combination of subcellular fractionation, biotin-streptavidin affinity purification and immunofluorescence. This study provided evidence to suggest that Hsp90, Hsp70 and Hop are membrane associated in MDA-MB-231 and MCF-7 breast cancer cells. Hsp90, Hsp70 and Hop associated with the plasma membrane such that at least part of the protein is located extracellularly. Immunofluorescence analysis showed that Hsp90, Hsp70 and Hop at the leading edge may localize to membrane ruffles in MDA-MB-231 cells, in accordance with the published role of Hsp90 in migration. An increase in this response was seen in cells stimulated to migrate with SDF-1. By immunoprecipitation, we isolated a putative extracellular membrane associated complex containing Hsp90, Hsp70 and Hop. Using soluble Hsp90 and antibodies against membrane associated Hsp90, we suggested roles for soluble extracellular Hsp90 in mediating migration by wound healing assays and inducing actin reorganisation and vinculin-based focal adhesion formation. The effects of extracellular Hsp90 are mediated by signalling through an ERK1/2 dependent pathway. An anti-Hsp90 antibody against an N-terminal epitope in Hsp90 appeared to be able to overcome the death inducing effects of a combination of SDF-1 and AMD3100, while soluble Hsp90 could not overcome this effect. We propose that this study provides preliminary evidence that extracellular Hsp90 functions as part of a multi-chaperone complex that includes Hsp70 and Hop. The extracellular Hsp90 chaperone complex may mediate cell processes such as migration by modulating the conformation of cell surface receptors, leading to downstream signalling.

This thesis is divided into two parts and the rationale of the research conducted is based on the cytotoxicity of the prenylated quinones 1.24-1.29, isolated from the South African nudibranch Leminda millecra, against oesophageal cancer cells. The first part (Chapters 2 and 3) of the thesis initially documents the distribution of cytotoxic and antioxidant prenylated quinones and hydroquinones in the marine environment. We have been able to show, for the first time, that these compounds can be divided into eight structural classes closely related to their phyletic distribution. Secondly, we attempted to synthesize the two marine natural products 1.24 and 1.26 in an effort to contribute to an ongoing collaborative search with the Division of Medical Biochemistry at the University of Cape Town for new compounds with anti-oesophageal cancer activity. Accordingly, we followed the published synthetic procedure for 1.26 and, although we were unable to reproduce the reported results, we have generated five new prenylated quinone analogues 3.53-3.55, 3.63 and 3.71, which are a potentially viable addition to our ongoing structure-activity relationship (SAR) studies. Moreover, we embarked on a 7Li NMR mechanistic study for the synthesis of 3.2 from 3.1 which rewarded us with an improved and reproducible methodology for this crucial reaction that is detailed in Chapter 3. The second part of this thesis (Chapters 4 and 5) is concerned with a synthetic, structural, electrochemical and biological exploration of the 1,4-naphthoquinone nucleus as a primary pharmacophore in our search for new chemical entities which can induce apoptosis in oesophageal cancer cells, thus contributing to our overall ongoing SAR study in this class of compounds. Seven new naphthoquinone derivatves (4.19, 4.30, 4.31, 4.33 and 4.46-4.48) of the natural products 2-deoxylapachol (2.44), lapachol (4.1) and β-lapachone (5.2) were synthesized and 2-(1`-hydroxy-`-phenylmethyl)-1,4-naphthoquinone (4.29) was found to be the most cytotoxic (IC50 1.5 μM) against the oesophageal cancer cell line WHCO1, while 5.2, which is currently in phase II clinical trials as an anticancer drug, was found to be similarly active (IC50 1.6 μM). Electrochemical investigations of the redox properties of the benzylic alcohol derivatives 4.29-4.31 indicated a higher reduction potential compared to their oxidized counterparts 4.45-4.48, and this finding has been correlated to the increased activity of 4.29-4.31 against the WHCO1 cell line. Additionally, 4.29 is synthetically more accessible than either 1.26 or 5.2 and potentially a lead compound in our search for new and more effective chemotherapeutic agents against oesophageal cancer

To date, a significant portion of research has been devoted to understanding the biological role of the molecular chaperone, heat shock protein 90 (Hsp90), in cancer development and metastasis. Studies have alluded to over 300 clients for intracellular Hsp90, many of which are involved in oncogenic signaling pathways, making Hsp90 a bone fide drug target with several inhibitors already in clinical trials. In recent years, a limited number of extracellular Hsp90 clients have been elucidated with roles in cancer cell migration and invasion. Examples of such clients include matrix metalloproteinase-2 (MMP-2), LRP-1/CD91 and HER-2. Inhibition of extracellular Hsp90 using cellimpermeable inhibitors has been shown to reduce cancer cell migration and metastasis by a hitherto undefined mechanism. Using surface biotinylation and an enzyme linked immunosorbent assay, we provided evidence to support that Hsp90 was found extracellularly in cancers of different origin, cell type and malignancy. Next, we isolated extracellular Hsp90-containing complexes from MDA-MB-231 breast cancer cells using a cell impermeable crosslinker followed by immunoprecipitation and identified by mass spectrometry that the extracellular matrix protein, fibronectin, co-precipitated with Hsp90β. This interaction between Hsp90β and fibronectin was confirmed using pull down assays and surface plasmon resonance spectroscopy with the purified proteins. The ability of exogenous Hsp90β to increase the insoluble fibronectin matrix in Hs578T breast cancer cells indicated a role for Hsp90 in fibronectin matrix stability or fibrillogenesis. Hsp90 knockdown by RNA interference or inhibition with the small molecule inhibitor, novobiocin, resulted in a dose and time-dependent reduction of the extracellular fibronectin matrix. Furthermore, novobiocin was shown to cause the internalization of a fluorescently-labeled exogenous fibronectin matrix incorporated into the extracellular matrix by Hs578T cells. This suggested endocytosis as a possible mechanism for fibronectin turnover. This was supported by the colocalization of fibronectin with key vesicular trafficking markers (Rab-5 and LAMP-1) in small, intracellular vesicles. Furthermore, treatment with the vesicular trafficking inhibitor, methyl-β-cyclodextrin, resulted in a dose-dependent recovery in the extracellular fibronectin matrix following treatment with novobiocin. Taken together, these data provided the first evidence to suggest fibronectin as a new client of Hsp90 and that Hsp90 was involved in regulating extracellular fibronectin matrix dynamics.