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Master of Science / Department of Kinesiology / Carl Ade / Adjuvant systemic chemotherapy for the treatment of certain cancers, particularly breast and lymphoma, adversely impacts cardiovascular health. However, the extent to which it impairs endothelial function is not well understood. Therefore, the purpose of this study was to determine if microvascular and macrovascular endothelial-dependent vasoreactivity is attenuated in breast cancer and lymphoma patients currently being treated with chemotherapy compared to healthy counterparts. With laser Doppler imaging, cutaneous microvascular function was evaluated via changes in cutaneous vascular conductance (CVC) in response to iontophoresis of acetylcholine (ACh). Endothelium-dependent flow-mediated dilation (FMD) was evaluated in the brachial artery via ultrasonography. CVC responses to iontophoresis of ACh in the cutaneous microcirculation was significantly lower in cancer patients than in control subjects (cancer (n=7): 959.9 ± 187.3%; control (n=7): 1556.8 ± 222.2%; P = 0.03). Furthermore, FMD was significantly lower in cancer patients than in control subjects (cancer: 2.2 ± 0.6%; control: 6.6 ± 1.4%; P = 0.006). These data provide evidence of microvascular and macrovascular dysfunction in breast cancer and lymphoma patients currently undergoing adjuvant chemotherapy, which may contribute to the increased long-term risk of cardiovascular disease morbidity and mortality in those treated for cancer.

Made available in DSpace on 2014-06-11T19:23:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-16Bitstream added on 2014-06-13T20:29:33Z : No. of bitstreams: 1 rodrigues_ds_me_botib.pdf: 1326653 bytes, checksum: bc4be95f50663af52404583b788193ea (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Câncer é essencialmente caracterizado pelo crescimento desordenado de células que invadem órgãos e tecidos, sendo considerado atualmente um sério problema de saúde pública mundial. A despeito do atual e bem sucedido combate à doença, ainda permanecem em aberto questões relativas ao bom desempenho de suas modalidades de tratamento. Em particular, a quimioterapia anti-neoplásica carece de maior entendimento quantitativo e analítico. Assim sendo, propomos aqui um modelo matemático de equações diferenciais ordinárias, com o intuito de analisar as estratégias de administração de agentes quimioterápicos. Focamos nossa investigação nos protocolos antiangiogênicos e, a fim de aproximar-se da prática clínica, utilizamos dados experimentais, quando disponíveis, para simulações numéricas. Frente às implicações do tratamento oncológico, nossos resultados indicam que a administração de baixas doses e longos intervalos de tempo entre as dosagens estão relacionados ao fracasso terapêutico. Além disso, segundo o modelo proposto, a quimioterapia metronômica, se comparada ao regime convencional de tratamento, confere ao paciente um aumento de sobrevida. Por assim dizer, os protocolos antiangiogênicos podem ser uma alternativa aos pacientes oncológicos sem perspectiva de cura do câncer / Cancer is essentially characterized by the uncontrolled growth of cells that invade organs and tissues and it is now considered a serious public health problem worldwide. Despite the current and successful fight against the disease, there are some important questions concerning the efficient performance of its treatment modalities. In particular, the anti-cancer chemotherapy requires further quantitative and analytical understanding. So, we described here a mathematical model of ordinary differential equations, in arder to analyze the chemotherapeutic schedules. We focus our research on antiangiogenic schedule and, in order to get closer to clinical practice, we use some experimental data for numerical simulations. At the implications for cancer therapy, our results indicate that administration of low doses and longer intervals between doses are related to therapeutic failure. Moreover, according to the model, metronomic chemotherapy, compared to the conventional treatment, gives the patient an increased survival. Thus, the antiangiogenic scheduling can be an alternative to cancer patients with no prospect of curing cancer

One of the complications of cancer chemotherapy is an increased risk of secondary treatment-related malignancy. It is believed that secondary cancers arise as a result of mutagenic and genotoxic effects of chemotherapeutic agents. The mechanisms by which these agents induce secondary cancer are not known. This study was designed to investigate the potential genotoxic effects of two agents, etoposide and melphalan, in cancer patients receiving single drug chemotherapy. Both drugs are potent mutagens; and have been implicated as causative agents of secondary acute myeloid leukemia (sAML). Two groups of patients were studied: small cell lung cancer (SCLC) patients who received etoposide and multiple myeloma (MM) patients treated with melphalan. The induction of mutation at the hypoxanthine phosphoribosyl transferase (hprt) gene was investigated in patients' lymphocytes by using the hprt T-cell clonal assay. The results showed that the mean hprt mutant frequency (MF) did not increase after treatment with neither agent, however, a significant elevation of MF was detected in a patient who received the highest melphalan dose. The sequence analysis of mutants revealed a significant enhancement of AT > TA transversions in post-etoposide spectra compared to the control spectra, however, no mechanistic explanation for the induction of such mutation by etoposide can be proposed. Etoposide, a topoisomerase II inhibitor and an inducer of DNA strand breaks, is expected to produce large genomic deletions and rearrangements. No enhancement of large deletions or rearrangements was seen in post-etoposide spectra. The elimination of mutated cells by apoptosis is proposed to explain the negative result. In post-melphalan spectra, a significant enhancement of GC > TA transversions was detected compared to the control spectra. GC > TA transversion is an expected melphalan-induced mutation since alkylating agent melphalan preferentially causes guanine adducts and crosslinks. The results suggest that while single drug chemotherapy does not induce mutation in the majority of patients, exposure to high doses of chemotherapy agents may be associated with the induction of mutation. This correlates with the dose-dependent increase in the risk of secondary malignancy after chemotherapy. The significance of drug-specific changes in the mutational spectra seen in patients' lymphocytes can be evaluated after mutations in proto-oncogenes and/or tumor suppressor genes are identified in secondary cancer cases. Results also suggest that the hprt mutational spectrum might be a more sensitive biomarker of the genotoxic exposure than the hprt MF. To investigate the clastogenic effect of etoposide chemotherapy, blood cells from SCLC patients were screened for the appearance of multiple lineage leukemia (MLL) gene rearrangements using fluorescent in situ hybridization (FISH). MLL gene is rearranged in more than 50% of sAML cases in patients previously treated with etoposide or related compounds. Analysis of the results revealed that FISH is not sensitive enough method for the detection of rare rearrangements. The use of RT-PCR technique is proposed as a more realistic approach for monitoring patients treated with etoposide chemotherapy for the appearance of the MLL gene rearrangements. / Graduate

Malignant melanoma results in 132,000 cases worldwide each year with an incidence rate that is increasing faster than for any other skin cancer. In the UK, cutaneous melanoma is the sixth most commonly diagnosed cancer and the second most common in young people aged 15-34 (excluding non-melanoma skin cancer). Furthermore, while less common than NMSC, malignant melanoma accounts for 4% of skin cancer cases and 74% of skin cancer-related deaths. Although early surgical removal of primary tumours is an effective treatment, patients that develop metastatic melanoma have a very poor prognosis (5 year survival rate is only 5%). Elevated expression of a number of DNA repair genes has been reported in primary melanomas that subsequently metastasised when compared to non-recurrent primary tumours. In addition, patients who do not respond to chemotherapy have elevated expression of DNA repair genes. One chemotherapeutic that is effective against a range of other cancers, but not melanoma is cisplatin. Elevated levels of the DNA repair protein ERCC1, which is needed to remove cisplatin-induced DNA damage, has been found to be an indicator of poor prognosis in ovarian and lung cancer. To test our hypothesis that elevated ERCC1 levels account for an increased resistance to cisplatin in melanoma, a xenograft experiment was performed. Our results show that ERCC1 proficient melanoma xenografts initially responded to cisplatin treatment however resistance soon followed. Tumours deficient in ERCC1 however could be cured after only two treatments of cisplatin, indicating a novel method to overcome chemoresistance in metastatic melanoma. The aim of the project was to identify novel compounds to improve therapy of melanoma. To achieve this, in collaboration with Dr Patton we performed a cell culture screen to identify compounds which display specificity against melanoma cell lines. In addition, we sought to identify compounds which would overcome cisplatin resistance. We identified a series of nitrofuran compounds which are potent against melanoma and neuroblastoma cell lines and enhanced the toxicity of cisplatin through an ERCC1 independent pathway. In addition, we showed that melanin pigmentation is protective against nitrofuran toxicity. We have proposed the structure specific endonuclease, ERCC1-XPF, as a drug target to overcome chemoresistance. We collaborated with Professor Walkinshaw to perform an in silico screen for protein-protein interaction inhibitors to disrupt the obligate dimerization between ERCC1 and XPF. In addition we directly inhibited the endonuclease activity by developing XPF endonuclease domain inhibitors and utilised a range of biochemical, molecular biology and cell culture assays to validate ERCC1-XPF inhibitors. Furthermore, we developed an in vitro endonuclease assay for ERCC1-XPF, FEN1 and DNase1 and utilised these to demonstrate compound specificity of our validated ERCC1-XPF inhibitors. In collaboration with MRC Technology we utilised the ERCC1-XPF endonuclease assay to perform a high throughput screen. We characterised hit compounds to demonstrate physical binding and in vitro specificity for ERCC1-XPF. In conclusion, we have discovered new compounds which may prove beneficial for the treatment of malignant melanoma.

In the last decades, there has been an escalating consumption of antibiotics with the number of antibiotic prescriptions increasing worldwide. Overuse or inappropriate use of antibiotics has resulted in a major increase in the development of multi-drug resistant pathogens. Antimicrobial resistance is one of the world’s most serious public health problems with great implication in terms of morbidity, mortality, and costs. To date, there has been no formal antibiotic use study conducted in the West Wollega zone of Ethiopia to assess antibiotic utilization. The objective of this study was to determine the pattern of antibiotic use in two hospitals in the West Wollega zone of Ethiopia, namely Gimbie Adventist Hospital and Nedjo Hospitals, using drug utilization metrics and the costs associated. In addition it was to assess the correlation between diagnosed infectious diseases and antibiotic prescriptions. This study was a cross-sectional, retrospective, descriptive review of antibiotic usage in the two hospitals in the year 2007. Prescriptions dispensed in the first month of each quarter of 2007 were reviewed. The number of prescriptions screened, antibiotic courses started, antibiotic days by specific agent and overall, the cost of individual and all antibiotics, the number and type of infectious diseases diagnosed were collected from which core drug use indicators were calculated. The correlation between infectious disease diagnosed and the antibiotic days prescribed were analyzed. A total of 18568 antibiotic and non-antibiotic prescriptions were reviewed retrospectively in the four months of the study period, 47 percent of which contained at least one antibiotic. The average number of antibiotics per prescription was 1.33 and 1.09 whilst the percentage of injectable antibiotics prescribed was 83.2 percent and 3.76 percent to outpatients and inpatients respectively. Antibiotics prescribed from the Essential Drug List (EDL) and List of Drugs for District Hospital (LDDH) were 63.0 percent, 74.8 percent, and 90.8 percent and 76.1 percent for outpatients and inpatients respectively. 98.6 percent of outpatient and 97.0 percent inpatient prescribed antibiotics were actually dispensed. Penicillins and quinolones were the most prescribed antibiotics in both inpatient and outpatient departments constituting 43.46 percent and 24.08 percent respectively. The antibiotic utilization ratio, incidence of outpatient antibiotic use, incidence of inpatient antibiotic use, the number of Defined Daily Doses (DDD)/1000inhabitants/year and DDD/100 Occupied Bed Days (OBD) for the zone was 0.16, 17.25, 23.56, 158.61, and 70 respectively. Antibiotic cost constituted 33.7 percent of all expenditure on drug, cost of antibiotic per patient care day and cost per antibiotic day was 3.84 Ethiopian Birr (ETB) ($0.40) and 6.29 ETB ($0.66) respectively. The correlation between infectious diseases diagnosed and antibiotic prescription shows significant variation. At outpatient departments alone an average number of antibiotic courses started was 2.7 at Gimbie Adventist Hospital and 7.6 for Nedjo Hospital. When overall antibiotic days prescribed and required was compared in both hospitals, there were 2.4 and 5 times more antibiotic days prescribed than were required for Gimbie and Nedjo Hospitals respectively. This suggests that the overuse of antibiotic is worse in the government hospital (Nedjo Hospital) than in the mission hospital (Gimbie Adventist Hospital). This study suggested that there was overuse of antibiotics in the West Wollega hospitals although further investigation is needed to identify its underlying causes and nature. It is recommended that the health personnel, the hospital management, the zonal and regional Health Bureau, the regulatory bodies and Non-Governmental Organizations (NGOs) work hand-in-hand to promote the rational use of antibiotics in this region so that the consequences and financial cost of antimicrobial resistance can be prevented.

The purpose of this study was to investigate nurses’ roles within nurse-led chemotherapy clinics. There has been a rapid expansion and development of nursing roles and responsibilities in oncology, but little understanding of how roles are enacted and their impact on patient experiences and outcomes. This was a two stage approach comprising a survey of UK oncology specialist nurses followed by an ethnographic study of nurses’ roles in nurse led chemotherapy clinics. Ethics approval was obtained prior to each study; research and development approval was obtained from each hospital site prior to Study 2. Study 1 used a questionnaire survey to explore the scope of nurses’ roles. A purposive sample of oncology specialist nurses perceived to be undertaking nurse-led clinics was obtained using snowball methods. Data analysis included descriptive and inferential statistics. Study 2 used ethnographic methods to explore nurses’ roles in nurse-led chemotherapy clinics, which included clinical observations, interviews with nurse participants and studying documentation (protocols) for nurse-led chemotherapy clinics. Findings were coded and thematic analysis undertaken. In study 1, 103 completed questionnaires were received with a response rate of 64%, however analysis identified 79 (76.7%) nurses undertaking nurse-led clinics, therefore statistical analysis was limited to this sample of 79 nurses. An additional 12 (11.7%) nurses wanted to undertake nurse-led clinics, therefore findings from this group were analysed separately. There was little congruence between nurses’ titles and clinical roles, with significant differences in practice between different groups of nurses, in relation to history-taking (p=.036), assessing response to treatment (p=.033). Although there was no difference in the number of nurses undertaking clinical examinations (p=.065), there were differences in the nature of examinations undertaken, including respiratory (p= .002). There were also significant differences between groups of nurses in relation to nurse prescribing (p<.0001). Study 2 included observations (61 consultations by 13 nurses) and interviews (n=11). There was variability in patient numbers within nurse-led clinics, identifying implications for service delivery and sustainability. Disparities in nurses’ roles and responsibilities revealed four different levels of nurse-led chemotherapy clinics, from chemotherapy administration to totally nurse-led clinics. The identification of four levels of nurse-led chemotherapy is a new finding, and suggests a framework for nurse-led chemotherapy clinics that could link with nurse competencies and training. Five main themes were identified in study 2; a central theme of autonomy linked with themes of knowledge, skills, power and beliefs. A key finding was the reduced emphasis on compassionate care with greater medical (clinical) responsibilities within nurses’ roles, and poor communication skills by some nurses. Despite a great diversity in oncology specialist nurses’ roles, the lack of clarity in roles and responsibilities is creating confusion. Similarly the rapid increase in nurse-led chemotherapy clinics has been ad hoc with no formal evaluations. Although nurses in study 2 perceived they were providing holistic care there was no evidence of this in observations, and nurses appear to use a medical model care based on doctor-nurse substitution, which may have led to reduced emphasis on nursing skills and compassionate care.

Includes bibliographical references. / The diamino-diamide ligands have been investigated in an attempt to develop an antirheumatic drug. The ligands N,N'-di-(2-dimethylamino)ethyloxamide and N,N'di-(2-diethylamino)ethyloxamide, were synthesised and characterised using the physical techniques, NMR, mass- and infrared spectrometry. The stability constants of the complexes of Mg, Ca, Zn and several first transition metal-ions with the ligands were determined potentiometrically. The solution conformation of the CuII complexes were determined using visible spectrophotometry. Finally the physico-chemical studies were carried out. Firstly by studying the interaction of the copper complex with albumin at the physiological pH 7.4 using visible spectrophotometry. Secondly by determining the superoxide dismutase activity of the ligand by reduction of nitrobluetetrazolium using visible spectrophotometry. Lastly the ligands and the carr, CuII, MgII and ZnII metalions were monitored in vitro using the computer blood plasma model.