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1
Abate, Getahun. "Drug resistance in mycobacterium tuberculosis /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3833-4/.
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Marijani, Theresia. "Modelling drug resistance in malaria." Thesis, Stellenbosch : University of Stellenbosch, 2009. http://hdl.handle.net/10019.1/4063.
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Abrahem, Abrahem F. "Mechanisms of drug resistance in malaria." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0033/MQ50704.pdf.
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Scott, F. M. "Drug resistance mechanisms in multiple myeloma." Thesis, University of Edinburgh, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.661665.
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The aim of this thesis was to investigate expression of putative drug resistance markers in myeloma both by examining clinical material and through the development of a xenograft model. Pgp expression was examined in 57 samples from 37 patients with myeloma. Of 23 samples at presentation and 37 at relapse, 7 and 26 respectively were Pgp positive. A myeloma xenograft model was established to examine the acute effects of cytotoxic drugs on the expression of "classical" drug resistance markers and genes involved in regulation of apoptosis. The untreated xenografts were Pgp negative, expressed low levels of glutathione S-transferase-P (GSTP) and had readily detectable topo I and II. Little p62 myc or p53 were detected, whereas bcl-2 was strongly expressed. Treated xenografts contained only scattered apoptotic cells, but the majority demonstrated cell cycle arrest at the G2/M transition, and GSTP and topo IIα expression were increased. Pgp expression was also increased in animals treated on 3 consecutive days. C-myc was detected in dead or dying cells, but there was no mutational inactivation of p53, and bcl-2 expression was unaltered. The increased Pgp and GSTP expression following therapy, rather than inducing a resistant phenotype, may reflect activation of expression by drug administration. Cellular resistance occurred despite evidence of DNA damage suggesting that resistance arose from failure to engage apoptosis, possibly due to the strong bcl-2 expression. Bcl-2 expression was therefore evaluated in 40 samples from 31 individuals, with strong expression observed in over 80% of cases. This was not associated with rearrangement of the bcl-2 locus. The presence of abundant bcl-2 protein in the majority of cases has potentially important implications for drug resistance in this disease and suggests that future assessment of drug resistance in myeloma may be better directed downstream of immediate drug-target interactions to regulation of engagement of apoptosis.
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Wildridge, David. "Metabolism and drug resistance in Trypanosomatids." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3622/.
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The principle aim of this project is the investigation of metabolism and mechanisms of pentamidine resistance in trypanosomatids. An understanding of these mechanisms may allow the development of novel drugs to treat Leishmaniasis and human African trypanosomiasis (HAT), caused by the protozoan parasites Leishmania spp and Trypanosoma brucei. In this study a pentamidine resistance L. mexicana promastigote cell line was generated in vitro. This cell line was 20-fold resistant to pentamidine when compared to the parental wild type cells. Furthermore, these lines were cross resistant to other diamidine compounds. A proteomic analysis of these cell lines revealed numerous changes to the proteome, with the down regulation of several flagellar proteins. A hypothesis to investigate a role of the voltage dependent anion channel (VDAC) in pentamidine resistance was also explored. The metabolomic approach involved the investigation of transketolase and the pentose phosphate pawthway. A previous study involving a transketolase knockout T. brucei cell line indicated that an increased sensitivity to pentamidine and methylene blue. A transketolase deficient L. mexicana cell line was generated to test this hypothesis in Leishmania, however the differences were minimal. A metabolomic analysis of the L. mexicana tkt null cell line (lmtkt-/-) revealed an increase in ribose 5-phosphate, a key substrate of transketolase. Erythrose 4-phosphate also increased in the lmtkt-/- cells, indicating a source of this metabolite independent of TKT. It appears that the deletion of TKT prevents any flux through the oxidative branch of the PPP returning to the glycolytic pathway. Interestingly, the lmtkt-/- cells do not acidify the medium to the same extent as the wild type cells; however a glucose assay indicated that both cell lines used similar quantities of glucose. This would suggest that there is a change in the metabolites excreted by the lmtkt-/- cell line. Finally, a global metabolomics approach was investigated using high resolution mass spectrometry. Metabolomics is a rapidly developing field in systems biology, and whilst significant improvements have been made in mass spectrometry; the ability to analyse and interpret raw metabolomic datasets on a global scale has been largely neglected. Consequently, a database program to query these complex datasets was constructed.
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Pongtavornpinyo, Wirichada. "Mathematical modelling of antimalarial drug resistance." Thesis, University of Liverpool, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428249.
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Doherty, Catherine Jean. "Drug resistance mechanisms in multiple myeloma." Thesis, University of Edinburgh, 1997. http://hdl.handle.net/1842/22154.
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Galinytė, Daiva. "Antibiotikų vartojimo ir kai kurių mikroorganizmų rezistentiškumo pokyčių analizė." Master's thesis, Lithuanian Academic Libraries Network (LABT), 2008. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2008~D_20080616_100358-21547.
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Santrauka.
Didėjantis mikroorganizmų atsparumas antibiotikams yra aktuali visuomenės sveikatos problema. Vienas iš pagrindinių veiksnių, turinčių įtakos atsparumo plitimui, yra antibakterinių vaistų vartojimas.
Darbo tikslas. Nustatyti antibiotikų metinio vartojimo pokyčius bei jų galimas sąsajas su mikroorganizmų rezistentiškumo pokyčiais.
Metodas. Tretinio lygio ligoninėje atlikta mikroorganizmų atsparumo ir antibiotikų suvartojimo epidemiologinė analizė. Surinkti duomenys apie antibiotikų suvartojimą 2004- 2007 metais tretinio lygio ligoninėje. Vaistų suvartojimas išreikštas DDD skaičiumi, tenkančiu 100 lovadienių. Ištirtas antibiotikų suvartojimo kitimas 2004- 2007 metais. Panagrinėtas chirurginio profilio skyrių antibiotikų suvartojimas ir jo galimos sąsajos su atliekamų operacijų skaičiumi. Nustatytas kelių dažniausiai vartojamų panašaus veikimo spektro antibiotikų suvartojimas ir jo kitimas 2004–2007 metais tretinio lygio ligoninėje. Nustatytas dviejų svarbių mikroorganizmų (Escherichia coli ir Klebsiella pneumoniae) atsparumo kitimas 2004–2007 metais tretinio lygio ligoninėje bei sąsajos tarp panašaus spektro antibiotikų suvartojimo ir šių mikroorganizmų atsparumo kitimo. Duomenys apdoroti aprašomąja ir lyginamąja statistika (Mann–Whithey testas neparametriniams kriterijams bei Spirmano koreliacija).
Rezultatai. 2004 – 2007 metais tretinio lygio ligoninėje statistiškai patikimai didėjo šių antibiotikų suvartojimas: piperacilino–tazobaktamo (877,50 proc.)... [toliau žr. visą tekstą]Summary. Antimicrobial resistance is a serious public health problem worldwide. Irrational use of antibiotics is one of the reasons of increasing resistance to these preparations. The main goal of this study was to evaluate the variation of antibiotics consumption and relation between antibiotics consumption and microorganism resistance. Method. This analysis was performed in one of Lithuanian tertiary hospitals. The DDD analysis was performed to express consumption per every 100 OBD for single units in clinical departments. Average mean of DDD/100 OBD was estimated for 2004- 2007 years and mean values compared among all four years. The relation between the number of surgical operations and antibiotics consumption in surgery departments was analysed. E.coli and K.pneumoniae resistance for the four financial years (2004- 2007) was determined. Moreover the relation between microorganism resistance and variation of antibiotics consumption was determined. Data were analysed by descriptive and comparative statistics (by Mann–Whithey test for non-parametric criteria and Spirman correlation). Results. Comparing the DDD/100 OBD data year-on-year revealed the statistically significant increase of piperacillin and tazobactam (877.50%), metronidazole (114.00%), cefuroxime (77.31%), meroponem (47.55%), cefoperazone and sulbactam (173.11%) use. The increased usage of these antibiotics was determined in surgery department too. However the increased number of surgical operations can’t be... [to full text]
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Johnson, Rabia. "Understanding the mechanisms of drug resistance in enhancing rapid molecular detection of drug resistance in Mycobacterium tuberculosis." Thesis, Link to the online version, 2007. http://hdl.handle.net/10019.1/1265.
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Joseph, Renu. "Evolution of multiple antimicrobial drug resistance conservation of genes encoding streptomycin, sulfonamide and tetracycline resistance among Escherichia coli with increasing multi-drug resistance /." Online access for everyone, 2007. http://www.dissertations.wsu.edu/Thesis/Fall2007/R_Joseph_111707.pdf.
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Min, Junxia. "Sphingolipid metabolic enzymes modulate anticancer drug resistance." Diss., Columbia, Mo. : University of Missouri-Columbia, 2006. http://hdl.handle.net/10355/5899.
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Thesis (Ph. D.)--University of Missouri-Columbia, 2006.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file viewed on (March 5, 2007) Vita. Includes bibliographical references.
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Nutt, Catherine L. "Mechanisms of drug resistance in glial cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq28512.pdf.
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Zelcer, Noam. "MRP2-4, from drug resistance to physiology." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2003. http://dare.uva.nl/document/87138.
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Billington, Owen James. "Evolution of drug resistance in Mycobacterium tuberculosis." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1444546/.
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This thesis examines the contrasting roles of genetic drift and selection on the emergence of drug resistance in Mycobacterium tuberculosis . In clinical practice some alleles of rifampicin resistance are isolated more frequently than others. To identify if this variation is due to genetic drift or selection, the mutation rate to rifampicin resistance in M. tuberculosis (H37Rv) was determined. PCR-SSCP analysis revealed only three patterns from the rifampicin resistant isolates, each pattern arising at the same mutation rate (Mann-Whitney U test P>0.5). Fitness, defined as the ratio of generations of resistant and susceptible cells formed in mixed culture, of the differing rifampicin resistant alleles was determined relative to the parent fully susceptible strain. There was a significant correlation between fitness and the clinical isolation rate of each allele (regression analysis P=0.026). The fitness of two isolates, with identical IS6110 RFLP pattern isolated from 2 siblings, was determined. One isolate had developed multi drug resistance, the second isolate had remained fully drug susceptible. The fitness of the drug resistant isolate was significantly lower than the drug susceptible isolate (matched pair t test p=0.002). The decreased relative fitness of the resistant isolate implied a physiological cost for the development of drug resistance. Isolates of M. tuberculosis from three patients involved in a hospital outbreak of multi drug resistant tuberculosis were obtained. The fitness of these isolates was determined relative to H37Rv. Isolates obtained from the same patient did not vary in fitness (one way ANOVA p=0.34). However, the isolates from the three different patients had differing fitness values (one way ANOVA p=<0.001). This implied that there is adaptation of the isolates to the individual patient. In conclusion, selection has a major role in adaptation of drug resistance in M. tuberculosis. This adaptation includes adaptation to the infected host as well as drug resistance.
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Al-Dhaheri, Rawya. "Drug resistance and apoptosis in Candida biofilms." Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/1940/.
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Candida species are commonly part of the normal flora in humans; however, they are opportunistic fungal pathogens that are capable of causing a variety of infections in hospitalized and immunocompromised individuals. These infections range from superficial to systemic ones. Many Candida infections involve biofilm formation on the surfaces of implanted devices, such as catheters and prostheses, or host tissues. Candida biofilms are resistant to a range of antifungal agents in current clinical use but the basis of this drug resistance is not clear. The aim of this project was to investigate possible resistance mechanisms using two fungicidal agents, amphotericin B and caspofungin, a new drug reported to have anti-biofilm activity. The activity of amphotericin B and caspofungin at different development phases of Candida biofilms was investigated in vitro. Amphotericin B at two times the MIC (for planktonic culture) had the least effect on Candida biofilms, but at a higher concentration (five times the MIC) it showed relatively high activity against biofilms of C. parapsilosis and C. glabrata, especially at the late development phase. Biofilms of C. albicans were more resistant to amphotericin B throughout development (except for the earliest stage) than the other Candida species. Caspofungin, at two times the MIC, generally exhibited a greater effect on Candida biofilms than amphotericin B although this was not observed with C. parapsilosis biofilms in some development phases. Caspofungin, at five times the MIC, was slightly less effective than at the lower concentration against C. tropicalis in all development phases tested. The species most susceptible to caspofungin throughout biofilm development was C. glabrata. In no case were biofilm cells of any Candida species completely killed by either amphotericin B or caspofungin. The penetration of caspofungin through biofilms of different Candida species was evaluated using an in vitro filter disc bioassay. Caspofungin penetration through biofilms of C. albicans SC5314 was initially faster than C. albicans GDH2346; however, after 6 h drug diffusion was greater with biofilms of strain GDH2346 (70.8% of the control value). Among other Candida species tested, the highest drug penetration was observed with C. glabrata and C. parapsilosis (81.2% and 73.3% of the control value, respectively), while the lowest was seen with biofilms of C. krusei. Biofilms of C. tropicalis also showed poor penetration. Exposure of biofilms of any Candida species to caspofungin (or amphotericin B) in this assay failed to result in complete killing of biofilm cells. However, evaluation of caspofungin activity against biofilms was complicated by the paradoxical phenomenon (reduced activity of the drug at high concentrations, above the minimum inhibitory concentration). Scanning electron microscopy revealed that caspofungin caused more structural damage to biofilm cells and matrix than did amphotericin B; the highest degree of damage due to caspofungin was observed in biofilms of C. glabrata and C. krusei. The presence of a small number of drug-tolerant or persister cells is one possible mechanism of biofilm drug resistance. Biofilms and planktonic cells of five Candida species were surveyed for the presence of persister cell populations after exposure to amphotericin B. None of the planktonic cultures (exponential or stationary phase) contained persister cells. However, persisters were found in biofilms of one of two strains of C. albicans tested and in biofilms of C. krusei and C. parapsilosis, but not in biofilms of C. glabrata or C. tropicalis. Live-dead staining with fluorescein diacetate confirmed these results which do, however, suggest that persister cells cannot solely account for drug resistance in Candida biofilms. If microorganisms exposed to antimicrobial agents undergo a type of programmed cell death or apoptosis, persisters could be variant in which this process has been disabled. Here, specific staining methods were used to investigate the existence of apoptosis in Candida biofilms subjected to different concentrations of amphotericin B. Caspase activity, indicative of apoptosis, was detected with SR-FLICA and D2R fluorochrome-based staining reagents in all of these biofilms. The general inhibitor of mammalian caspases, Z-VAD-FMK, when used at a low concentration (2.5 μM), increased the viability of drug-treated biofilms up to 11.5-fold (P<0.001%). Seven specific caspase inhibitors had different effects on C. albicans biofilm viability, but inhibitors of caspases-1, -9, -5, -3, and -2 all significantly increased cell survival (40-fold, 8-fold, 3.5-fold, 1.9-fold and 1.7-fold, respectively). On the other hand, histone deacetylase (HDA) inhibitors enhanced the activity of amphotericin B against biofilms of all three Candida species. Sodium butyrate and sodium valproate, for example, when added concurrently with amphotericin B, completely eliminated biofilm populations of C. albicans. Overall, these results demonstrate an apoptotic process in amphotericin-treated biofilms of three Candida species. They also indicate that HDA inhibitors can enhance the action of the drug and in some cases even eradicate persister subpopulations, suggesting that histone acetylation might activate apoptosis in these cells.
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Leyland-Jones, Brian. "A molecular cytogenetic approach to drug resistance." Thesis, Institute of Cancer Research (University Of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.414825.
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Javanbakht, Marjan. "Antiretroviral drug resistance and adherence to HAART." Diss., Restricted to subscribing institutions, 2005. http://proquest.umi.com/pqdweb?did=1155567301&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Silal, Sheetal Prakash. "A simulation model of antimalarial drug resistance." Master's thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/9003.
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Includes bibliographical references (leaves 132-137).Malaria ranks among the world's most important tropical parasitic diseases with world prevalence figures between 350 and 550 million clinical cases per annum. [WHO, 2008a] 'Treatment and prevention of malaria places a considerable burden on struggling economies where the disease is rampant. Research in malaria does not stop as the change in response to antimalarial drug treatment requires the development of new drugs and innovation in the use of old drugs. This thesis focused on building a model of the spread of resistance to Sulfadoxine/Pyrimethamine (SP) in a setting where both SP and SP in artemisinin-based combination therapy (ACT) are the first line therapies for malaria. The model itself is suitable to any low transmission setting where antimalarial drug resistance exists but the country of choice in this modeling exercise was Mozambique. The model was calibrated using parameters specific to the malaria situation in Mozambique. This model was intended to be used to aid decision making in countries where antimalarial drug resistance exists to help prevent resistance spreading to such an extent that drugs lose their usefulness in curing malaria. The modeling technique of choice was differential equation modeling; a simulation technique that falls under the System Dynamics banner in the Operations Research armamentarium. It is a technique that allowed the modeling of stocks and flows that represent different stages or groupings in the disease process and the rate of movement between these stages respectively. The base model that was built allowed infected individuals to become infectious, to be treated with SP or ACT and to be sensitive to or fail treatment. Individuals were allowed a period of temporary immunity where they would not be reinfected until the residual SP had been eliminated from their bloodstream. The base model was then further developed to include the pharmacokinetic properties of SP where individuals were allowed to be reinfected with certain strains of infection given the level of residual drug in their bloodstream after their current infection had been cleared. The models used in this thesis were built with idea of expanding on previous models and using available data to improve parameter estimates. The model at its core is similar to the resistance model used in Koella and Antia [2003] where differential equation modeling was used to monitor a population as it became infected with a sensitive or resistant infection and then University of Cape Town recovered. The inclusion in the model of the PK component was derived from Prudhomme-O'Meara et al. [2006] where individuals could be reinfected depending on the residual drug in their bloodstream. Rather than modeling simply sensitive and resistant infections, mutations categories were used as was the case in Watkins et al. [2005] population genetics model. The use of mutation categories allowed one to use parameters specific to these categories rather than the sensitive/resistant stratification and this is particularly relevant in Mozambique where all mutation categories still exhibit some degree of sensitivity to treatment i.e. total resistance has not yet developed for any particular mutation category. The last adaptation of the model was to use gametocyte information directly to determine human infectiousness rather than through using a gametocyte switching rate (constant multiplier used to convert parasite density to gametocyte density) as was done in Pongtavompinyo [2006]. The models developed in this thesis found that the existing vector control and drug policy in Mozambique had the major effect of decreasing total prevalence of malaria by approximately 70% in the 11 year period. The distribution of Res3 (presence of DHFR triple) and Res5 (presence of DHFR triple and DHPS double) infections changed over the 11 year period with Res3 infections initially increasing and then decreasing while Res5 infections started low and increased to overtake Res3 infections. The timing of the change in this composition of infection corresponds with the introduction of ACT and thus it appears that the use of ACT prompted the increased prevalence of quintuple parasites over DHFR triple and sensitive parasites. The total number of failures decreased substantially after the introduction of ACT to 17% of its previous level. The results of the base model corresponded with the observed data from the SEACAT study in terms of the magnitude and the trends of the impact of the change to ACT policy, but underestimated the impact of the vector control strategies compared to rapid effect noted in Sharp et al. [2007]. The Scenario testing of the base model showed that vector control is an effective strategy to reduce prevalence and that it is sensitive to the time at which the control is started as it decreased prevalence very gradually. The Scenario testing of the base model also showed that the introduction of ACT in Mozambique had a greater impact on reducing prevalence and that the start time of the ACT strategy did not decrease the effect on prevalence though earlier start times decreased the total number of resistance cases. The ratio of Res5 to Res3 infections increased faster when ACT was the treatment policy than when SP was the policy. Thus higher values of this ratio are associated with ACT being the treatment strategy in place. Thus differential equation modeling is an effective modeling tool to capture the spread of disease and to test the effects of policy interventions as it allows one to assess these effects on populations and averages out individual-level intricacies to better inform policy decisions.
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Lewis, Alexander David. "Glutathione-dependent enzyme expression in drug resistance." Thesis, University of Edinburgh, 1988. http://hdl.handle.net/1842/19050.
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Glutathione and glutathione-dependent enzymes play a central role in the protection of cells from cytotoxic chemicals. In particular, reduced glutathione (GSH) and glutathione S- transferases (GST's) have been studied in relation to intrinsic and acquired resistance of tumours to cytotoxic drugs. There are however, other glutathione-dependent enzymes which may also be involved in drug resistance: these include glutathione perox-idase (GPX) and the enzymes, fglutamyltranspeptides (fGT), fglutamyl cysteinyl synthetase ('yGCS) and glutathione reductase (GRD). The latter enzymes are involved in the maintenance of reduced GSH levels within cells. GSH and the above glutathione-dependent enzymes have been studied in a series of drug resistance models, a) drug resistant tumour cell lines generated in vitro and in vivo; b) chemotherapeutic agent induced resistance in normal bone marrow cells; c) in oxygen resistant lung cells and d) in preneoplastic foci, in order to evaluate whether GSH and associated glutathione-dependent enzymes form part of an adaptive response involved in protection against the environment. Several models of drug resistance involving cell lines in culture were taken for study. A CHO cell line resistant to chlorambucil, an ovarian cell line generated in vivo, resistant to cis-Platinum and chlorambucil, and a sarcoma cell line resistant to adriamycin. In all these cell lines GST, GSH and 7GT were significantly elevated. In the latter two cell lines selenium dependent GPX was also induced. In the CHO line the elevated GST activity was explained by a 40 fold induction of the alpha class Yc GST subunit and a 2 fold elevation in the Ya subunit. In mouse bone marrow cells following the administration in vivo of a low 'primary dose' of cyclophosphamide, transient increase in alpha Ya and particularly mu Yb GST subunits were found. These increases have been associated with a subsequent protection against a higher lethal dose of the same agent. The changes observed in GST isozyme composition were confined to the granulocyte population. Differences in selenium-dependent GPX, GSH and fGT were also found in cells resistant to high oxygen, with only marginal changes in GST sub-unit profiles. In preneoplastic foci, significant elevations in pi class Yf GST and also alpha Ya and mu Yb were detected. Selenium- dependent GPX was decreased and TfGCS and GRD elevated in this model. These studies indicate therefore: 1) GST levels in certain cells appear to be directly related to resistance to cytotoxic chemicals; 2) Changes in GST expression associated with preneoplasia and in acquired drug resistance are not confined to one sub group of GST enzymes; 3) Changes in GST expression are often paralleled by changes in GSH and other glutathione- dependent enzymes; 4) The most consistent phenotypic changes observed in the drug resistant models studied were in GSH and fGT levels; 5) There seemed to be an inverse relationship in the regulation of selenium and non-selenium-dependent GPX activity in different drug resistant models. GSH and glutathione-dependent enzyme changes in acquired drug resistance, appear to be due to an adaptive response which may be of central importance in the resistance of tumours to chemotherapeutic agents.
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Millour, Julie. "FOXM1 in breast cancer and drug resistance." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/17849.
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Endocrine agents have become the primary adjuvant treatment for breast cancer. In addition to endocrine therapy, cytotoxic chemotherapeutic agents have also been frequently used in the neoadjuvant and adjuvant settings, to reduce tumour size prior to surgery or to reduce the chance of relapse or metastasis. However, patients can be resistant to endocrine and chemotherapeutic agents, or become resistant after long term treatment. In this study, I investigated the role and the regulation of FOXM1 in the sensitivity and resistance to the endocrine agent, tamoxifen, and the cytotoxic chemotherapeutic agent, epirubicin. Firstly, I demonstrated that tamoxifen repressed FOXM1 expression in sensitive but not in tamoxifen resistant breast cancer cell lines. In MCF-7 cells, FOXM1 protein and mRNA expression levels were regulated by ER-ligands, and depletion of ERα by RNA interference down-regulated FOXM1 expression. Importantly, ectopic expression of FOXM1 abrogated the cell cycle arrest mediated by the anti-oestrogen tamoxifen, and conferred tamoxifen resistance to MCF-7 cells. In contrast, silencing of FOXM1 in tamoxifen resistant cells abolished oestrogen-induced MCF-7 cell proliferation and overcame acquired tamoxifen resistance. Secondly, FOXM1 expression analysis in epirubicin resistant MCF-7 cells showed a higher level compared with MCF-7 cells. In addition, epirubicin treatment down-regulated FOXM1 expression in MCF-7, but FOXM1 protein level remained constant in epirubicin resistant MCF-7 cells. I established that p53 repressed FOXM1 expression in MCF-7 cells, while this protein is lost in the MCF-7 epirubicin resistant cells. I also found that ataxia-telangiectasia mutated (ATM) was overexpressed at protein and mRNA levels in epirubicin resistant MCF-7 compared with MCF-7 cells, and that ATM depletion strongly decreased FOXM1 expression. Epirubicin treatment increased DNA damage levels in MCF-7 cells while this remained constant in similarly treated epirubicin resistant MCF-7 cells, suggesting a higher level of DNA repair in these cells. Taken together, these results indicate that deregulation of FOXM1 may contribute to resistance to endocrine and cytotoxic agents through its involvement in cell proliferation and DNA repair.
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Oliveira, Pisco Angela. "Drug resistance mechanisms in cancer heterogeneous populations." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/drug-resistance-mechanisms-in-cancer-heterogeneous-populations(a5f2d318-3fd2-4491-84a5-fd2d69ac1b40).html.
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The development of drug resistance during treatment is possibly the most important factor hampering the success of cancer therapy. In order to survive in the presence of chemotherapeutic drugs cells must quickly adapt to their altered environment. This may involve a collective stress response of interacting cells, whose mechanism is not yet clear. In the course of this work we interrogated the conceptual framework used to describe cancer and examined different aspects of drug resistance. While the main focus was on the role of ABC transporters in the rapid acquisition of drug resistance following a short period of drug treatment, the long-term adaptation to continuous drug treatment was also studied. As a tangent to this subject, the possible role of endocytosis in the process of adaptation to continuous presence of drug and subsequent resistance was also assessed. Cancer cell populations inexorably develop resistance to therapeutic treatment. In addition to selection of genetic variants, resistance may arise through two possible non-genetic mechanisms, (1) Darwinian selection of cells occupying (non-genetic) resistant microstates, or (2) Lamarckian instruction, in which cells adopt a resistant (treatment) induced phenotype. To examine the relative contribution of these two mechanisms we studied the population dynamics of leukemic cells (HL60 cell line) following treatment with the mitotic inhibitor vincristine. Single-cell analysis and mathematical modelling of state transition kinetics demonstrated that the appearance of multi-drug resistance phenotype within 24h was overwhelmingly the result of instruction. Transcriptome dynamics pointed towards a genome-wide state transition into a stress response state. Resistance induction correlated with Wnt pathway upregulation and was suppressed by beta-catenin knockdown, revealing a new opportunity for early therapeutic intervention against the development of drug resistance. By addressing the adaptation of the cell culture to prolonged drug treatment we observed that the survivor cells mounted a cellular response that neutralised the cytotoxic stress. That response involved the stabilisation of a transcriptome state that confers drug resistance. Our results suggested that the positive correlation between Wnt signalling and ABC transporters expression is important not only for the short-term survival but also for the enduring MDR phenotype. As we explored population heterogeneity we realised that the dead cells might also help the rest of the population to survive. Thus, our results support the need for examining the role of each population fraction, and ultimately each individual cell, in the overall story of cancer adaptation towards multidrug resistance. Subsequently we examined the differential endocytic behaviour between drug-sensitive and drug-resistant cells. By combining confocal time-lapse microscopy with flow cytometry we demonstrated that fluid-phase endocytosis was reduced in the resistant cells. The differences in the endocytic pathway only became noticeable after MDR1 expression has become constitutive, suggesting another protective role of the ABC transporters. All the results obtained support the idea that acquired drug resistance is not simply the passive selection of pre-existing mutants but can be accelerated by active adaptation. Cancer treatment is a double-edge sword: while the weakest cells die, the survivors cope cell-autonomously with the therapeutic perturbation.
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Ndifor, Anthony Mbisah. "Drug metabolism in malaria parasites and its possible role in drug resistance." Thesis, University of Liverpool, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317180.
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Laxminarayan, Ramanan. "Economics of antibiotic resistance /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/7412.
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Lin, Kuan-Hung. "Viral Proteases as Drug Targets and the Mechanisms of Drug Resistance: A Dissertation." eScholarship@UMMS, 2009. http://escholarship.umassmed.edu/gsbs_diss/841.
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Viral proteases have been shown to be effective targets of anti-viral therapies for human immunodeficiency virus (HIV) and hepatitis C virus (HCV). However, under the pressure of therapy including protease inhibitors, the virus evolves to select drug resistance mutations both in the protease and substrates. In my thesis study, I aimed to understand the mechanisms of how this protease−substrate co-evolution contributes to drug resistance. Currently, there are no approved drugs against dengue virus (DENV); I investigated substrate recognition by DENV protease and designed cyclic peptides as inhibitors targeting the prime site of dengue protease.
First, I used X-ray crystallography and subsequent structural analysis to investigate the molecular basis of HIV-1 protease and p1-p6 substrate coevolution. I found that co-evolved p1-p6 substrates rescue the HIV-1 I50V protease’s binding activity by forming more van der Waals contacts and hydrogen bonds, and that co-evolution restores the dynamics at the active site for all three mutant substrates.
Next, I used aprotinin as a platform to investigate DENV protease–substrate recognizing pattern, which revealed that the prime side residues significantly modulate substrate affinity to protease and the optimal interactions at each residue position. Based on these results, I designed cyclic peptide inhibitors that target the prime site pocket of DENV protease. Through optimizing the length and sequence, the best inhibitor achieved a 2.9 micromolar Ki value against DENV3 protease. Since dengue protease does not share substrate sequence with human serine proteases, these cyclic peptides can be used as scaffolds for inhibitor design with higher specificity.
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Lin, Kuan-Hung. "Viral Proteases as Drug Targets and the Mechanisms of Drug Resistance: A Dissertation." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/841.
Full textAbstract:
Viral proteases have been shown to be effective targets of anti-viral therapies for human immunodeficiency virus (HIV) and hepatitis C virus (HCV). However, under the pressure of therapy including protease inhibitors, the virus evolves to select drug resistance mutations both in the protease and substrates. In my thesis study, I aimed to understand the mechanisms of how this protease−substrate co-evolution contributes to drug resistance. Currently, there are no approved drugs against dengue virus (DENV); I investigated substrate recognition by DENV protease and designed cyclic peptides as inhibitors targeting the prime site of dengue protease.
First, I used X-ray crystallography and subsequent structural analysis to investigate the molecular basis of HIV-1 protease and p1-p6 substrate coevolution. I found that co-evolved p1-p6 substrates rescue the HIV-1 I50V protease’s binding activity by forming more van der Waals contacts and hydrogen bonds, and that co-evolution restores the dynamics at the active site for all three mutant substrates.
Next, I used aprotinin as a platform to investigate DENV protease–substrate recognizing pattern, which revealed that the prime side residues significantly modulate substrate affinity to protease and the optimal interactions at each residue position. Based on these results, I designed cyclic peptide inhibitors that target the prime site pocket of DENV protease. Through optimizing the length and sequence, the best inhibitor achieved a 2.9 micromolar Ki value against DENV3 protease. Since dengue protease does not share substrate sequence with human serine proteases, these cyclic peptides can be used as scaffolds for inhibitor design with higher specificity.
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Lo, Maisie K. Y. "Role of transporters in pancreatic cancer drug resistance." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/361.
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Pancreatic cancer (PC) is known to be highly resistant to chemotherapy. Transporters, which regulate the influx and efflux of substrates across the plasma membrane, may play a role in PC drug resistance. ABC transporters are a large family of transmembrane proteins with diverse physiological functions, several of which play major roles in cancer drug resistance. Given that 90% of PC express a mutant K-ras oncogene and that PC are highly hypoxic, I postulated that constitutive K-ras activation and/or hypoxia may correlate with ABC transporter expression, which in turn may promote drug resistance in PC. Using normal and PC cell lines either overexpressing mutant K-ras or subjected to hypoxic treatment, mRNA expression was profiled for 48 ABC transporters. My findings indicate that expression of mutant K-ras and hypoxic treatment, as well as long-term exposure to chemotherapy, may contribute to the development of drug resistance in PC cells in part by inducing the expression of ABC transporters.
Similar to ABC transporters, I investigated whether amino acid transporters would mediate drug resistance in PC. The xc" amino acid transporter (xc") mediates cellular uptake of cystine for the biosynthesis of glutathione, a major detoxifying agent. Because the xc" has been regulates the growth of various cancer cell types, and x," is expressed in the pancreas, I postulated that the xc" may be involved in growth and drug resistance in PC. The xc" transporter is differentially expressed in normal pancreatic tissues and is overexpressed in PC in vivo. UsingPC cell lines, I found that cystine uptake via the N.: was required for growth and survival in response to oxidative stress, and that expression of the xc" correlated with gemcitabine resistance. Accordingly, inhibition of xc" expression via siRNA reduced PC cell proliferation and restored sensitivity to gemcitabine. I also identified the anti-inflammatory drug sulfasalazine as a mixed inhibitor of the x,-, which acts to inhibit cell proliferation via reducing xc" activity and not by reducing NFKB activity. My findings thus indicate that the xc" plays a role in PC growth in part by contributing to glutathione synthesis to promote PC cell proliferation, survival, and drug resistance.
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Zhou, Rong. "Topoisomerase II and drug resistance in leukemic cells /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4738-4/.
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Certain, Laura K. "Genetic profiling of drug resistance in Plasmodium falciparum /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/10252.
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Doorn, Hindrik Rogier van. "Rapid diagnosis and drug resistance of Mycobacterium tuberculosis." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2005. http://dare.uva.nl/document/88988.
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Mohammedali, Hani. "Computational studies of protein dynamics and drug resistance." Thesis, University of Essex, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.654529.
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Berezovsky et al.'s closed loop folding hypothesis suggests that the locks of closed loops (i.e. the ends of the interacting loop) of length ~25-35 residues interact through hydrophobic interactions and that this is a vital event in protein folding. Here we investigate a possible link between the lock residues and drug resistance. The hypothesis is that drug resistance can be limited if the drug binds to the high connectivity regions such as the lock regions. To follow this perspective, the work has moved on to develop an additional method for determining closed loops by using the X-ray crystallographic B-factors as a measure of flexibility. From previous kinetics studies, by using the correlation of folding rate with contact metrics evaluated over the locks of closed loops and their neighbours, we observed that the conservation, particularly maximum proportion is possibly the best method for determining closed loops; we also found that the closed loop hypothesis requires modification to include the neighbours of the lock residues. Berezovsky et al.'s hypothesis has been evaluated using literature results from time-resolved dynamic non-radiative excitation energy transfer measurements for bovine pancreatic ribonuclease A protein (RNase A), as studied by Haas' group. An analysis of the experimental data and molecular dynamics (MD) data in the light of Berezovsky et al.'s hypothesis shows that the MD results are consistent with the experiment results. To investigate the lock residues to look for any additional properties that may help in drug design, we investigated the lock residues of HIV reverse transcriptase and protease by analysing the positions of lock residues vis a vis positions of drug resistant mutations in both enzymes, focussing on the closed loops in accordance to the Berezovsky et al.'s hypothesis. Our results indicate that if these lock residues were to be targeted by drugs, they may be less likely to generate resistance mutations.
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Cocker, Hilary Anne. "Drug resistance in paediatric rhabdomyosarcoma : pathways and circumvention." Thesis, Institute of Cancer Research (University Of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250655.
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Dawes, Matthew. "Drug-induced vasodilation in human forearm resistance vasculature." Thesis, King's College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342326.
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Taylor, LaShan Denise. "Antibiotic Resistance: Multi-Drug Profiles and Genetic Determinants." [Johnson City, Tenn. : East Tennessee State University], 2001. http://etd-submit.etsu.edu/etd/theses/available/etd-1210101-134219/unrestricted/taylorl121101a.pdf.
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Taylor, Sonya Dorothy Anne. "Genetic analysis of drug resistance in Trypanosoma brucei." Thesis, University of Glasgow, 2004. http://theses.gla.ac.uk/30898/.
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Genetic mapping, positional cloning and reverse genetics provide an alternative to the biochemical and molecular approaches used to date, to determine the basis of arsenical resistance in Trypanosoma brucei. Genetic mapping of loci determining phenotypes of relevance to diseases has proved to be a powerful approach in a number of organisms including humans and Plasmodium falciparum, particularly when coupled with a full genome sequence. In this thesis, this approach has been established in T. brucei by determining the genetic basis of naturally occurring arsenical resistance and undertaking linkage analysis using our recently developed genetic map. I adapted a simple, verified screening assay for assessing drug sensitivity based on the use of AlamarBlue. Three stocks used as parents in genetic crosses differed in drug sensitivity; STIB 247-Sensitive, STIB 386-Resistant and TREU 927-Resistant. Genetic linkage analysis using 101 polymorphic markers Identified from the extensive sequence available from the genome project was then used to examine inheritance of the drug resistance phenotype in T. brucei. From this, the co-segregation (into F1 progeny) of markers and the resistance phenotype was determined using crosses, 247 x 386 and 247 x 927. Inheritance of resistance in both crosses was compatible with a simple single locus genetic model with one dominant allele determining resistance. Linkage analysis showed that the locus conferring resistance lay within an ~25 kilobase region on Chromosome II, which contains 6 open reading frames (ORFs). A reverse genetic approach was then used to disrupt alleles for each of the six ORFs in turn. An allele of one gene, Tb927.2.2380, was shown to determine resistance and this was confirmed by transfecting the resistance allele into a drug sensitive stock to generate an arsenical resistant line. This gene also determines cross-resistance to the major veterinary trypanocide, diminazene aceturate and has been named the arsenical and diamidine (ard) resistance gene.
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Barbosa, Mónica Rodrigues. "Evolution of antifungal drug resistance in Candida albicans." Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/15332.
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Mestrado em Biologia Molecular e CelularThe human pathogen Candida albicans is characterized by the presence of a hybrid tRNA (tRNACAGSer) that can be aminoacylated by both LeuRS and SerRS. This tRNA is responsible for the ambiguity of the CUG codon that can be decoded as serine (97%) and Leucine (3%). Previous studies showed that the level of ambiguity is variable depending on the growth condition of the fungus. These studies also revealed that strains mistranslating at a higher level grew better in the presence of azoles, particularly in the presence of fluconazole. To analyse the effect of translation errors on the acquisition of drug resistance, three strains of C. albicans were used (T0, T1 and T2). These strains have increasing levels of Leu misincorporation and were constructed by inserting a copy (T1) or two copies (T2) of a tDNACAG Leu gene. These strains were evolved experimentally in the presence and absence of the antifungal agent according to the approved EUCAST protocol. The level of ambiguity of all strains was measured along the evolution experiment, using a reporter system based on the green fluorescent protein (GFP). Finally, the type of acquired resistance was also evaluated (genetic or phenotypic resistance). Experimental data suggest that the acquisition of resistance is dependent on the drug and the percentage of mistranslation. Strains with increased mistranslation (T2) acquired more resistance (256 μg/ml) and faster than the control T0. Mutations in ERG11 gene might be responsible for this resistance. Also, T2 strain showed a decrease in the mistranslation level during both evolution experiments (with and without drug) as a consequence of the deletion of one of the two copies of the mutant tDNACAG Leu gene. This result further highlights the genetic instability of strain T2.
O fungo patogénico Candida albicans tem a particularidade de possuir um tRNA (tRNACAGSer) híbrido que é aminoacilado pelas sintetases SerRS e LeuRS. Esta característica é responsável pela ambiguidade do codão CUG que é decodificado como Ser (97%) e como Leu (3%). Estudos anteriores demonstraram que o nível de ambiguidade é variável dependendo da condição de crescimento do fungo e revelaram que estipes com maior erro de tradução crescem melhor na presença de azoís, particularmente em meio com fluconazol. Para analisar os efeitos dos erros de tradução na aquisição de resistência a drogas, construímos três estirpes de C. albicans (T0, T1 e T2) com níveis crescentes de incorporação de Leucina, inserindo uma cópia (T1) ou duas cópias (T2) do gene tDNACAG Leu. Estas estirpes foram evoluídas experimentalmente na presença e na ausência de fluconazol de acordo com o protocolo da EUCAST. O nível de ambiguidade destas estirpes foi avaliado durante o período da evolução usando um sistema reporter baseado na proteína fluorescente GFP. Finalmente foi também avaliada o tipo de resistência adquirida pelas estirpes ambíguas (resistência genética ou fenotípica). Os dados experimentais sugerem que a aquisição de resistência depende da droga e da percentagem do erro de tradução. As estirpes com maior erro de tradução (T2) adquirem mais resistência (256 μg/ml) e mais rapidamente sendo que mutações no gene ERG11 poderão ser responsáveis por essa resistência. Esta estirpe apresentou também um decréscimo da taxa de erro de tradução em ambas as evoluções (com e sem droga), resultado da deleção de uma das duas cópias do gene tDNACAG Leu. Este resultado reforça a instabilidade genética da estirpe T2.
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Araújo, Ana Rita Dias. "Antifungal drug resistance driven by mistranslation in yeast." Master's thesis, Universidade de Aveiro, 2011. http://hdl.handle.net/10773/7942.
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Mestrado em Biotecnologia MolecularAntifungal drug resistance has become a severe clinical problem and new targets for the development of new antifungal drugs need to be discovered. Ongoing work in our laboratory indicates that codon mistranslation due to codon ambiguity accelerates antifungal drug resistance in the human pathogen Candida albicans. The present work aimed to elucidate if non pathogenic yeasts behave similarly. Therefore, mistranslation was artificially induced in Saccharomyces cerevisiae strains by the expression of chimeric tRNAs. Each of the constructed strains carried a low-copy number plasmid, containing a C. albicans tRNAUGA Ser gene, whose anticodon was changed by site-directed mutagenesis, in order to replace it by several other anticodons. As the identity elements of the tRNA remained unchanged it was still acylated with serine. These mutant tRNAs are expected to compete with the native ones and have an impact on the proteome. To verify if mistranslation leads to an advantageous phenotype regarding antifungal drug resistance, cells were exposed to different antifungals. Additionally, microarray analyses were performed on non-exposed mutant strains in order to detect a possible predisposition to resist antifungal exposure.
A resistência a antifúngicos é, hoje em dia, um problema sério a nível clínico, pelo que há necessidade de descobrir novos alvos que possibilitem o desenvolvimento de novos antifúngicos. Investigação a decorrer no nosso laboratório indica que a ambiguidade no reconhecimento de codões em Candida albicans, um patogénio humano, acelera a resistência a antifúngicos. O presente trabalho teve como objectivo elucidar se a ambiguidade em leveduras não patogénicas aumenta a resistência a antifúngicos. Para tal foi induzida artificialmente ambiguidade no reconhecimento de diferentes codões em Saccharomyces cerevisiae. As estirpes resultantes possuem um plasmídeo de replicação reduzida contendo um tRNAUGA Ser de C. albicans sujeito a mutagénese dirigida, de modo a mutar o anticodão. Os novos anticodões reconhecem codões de diferentes aminoácidos mas o tRNA mantém os elementos de reconhecimento, sendo acilado com serina. Os tRNAs mutantes vão competir com os nativos, formando-se um proteoma estatístico. Para verificar se estas estirpes apresentam um fenótipo mais vantajoso em resposta a variados antifúngicos, foram expostas a diferentes classes dos mesmos. Adicionalmente, foram analisados microarrays de estirpes não expostas a qualquer stress adicional, de modo a perceber se as mesmas apresentam já tendência para responderem de modo diferente perante os diferentes antifúngicos.
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Lalonde, Matthew Scott. "HIV Drug Resistance Polymorphism Analysis Using Ligase Discrimination." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1244059520.
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Shahi, Thakuri Pradip. "MODELING ANTI-CANCER DRUG RESISTANCE USING TUMOR SPHEROIDS." University of Akron / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=akron1574725861735168.
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Hayward, Ian Philip. "Experimental studies on drug resistance in ovarian cancer." Thesis, University of Edinburgh, 1986. http://hdl.handle.net/1842/18951.
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Matthews, Amanda. "A Mathematical Model for Anti-Malarial Drug Resistance." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1721.
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Despite the array of medical advances of our modern day society, infectious diseases still plague millions of people worldwide. Malaria, in particular, causes substantial suffering and death throughout both developed and developing countries. Aside from the socioeconomic challenges presented by the disease's prevalence in impoverished nations, one of the major difficulties scientists have encountered while attempting to eradicate the disease is the parasite's ability to become resistant to new drugs and methods of treatment. In an effort to better understand the dynamics of malaria, we analyze a mathematical model that accounts for both the treatment aspect as well as the drug resistance that accompanies it. Simulations demonstrating the effects of treatment rates and the level of resistance are studied and discussed in hopes of shedding additional light on the characteristics of this devastating epidemic.
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Screen, Michael P. "MicroRNA control of drug-resistance in haematological malignancies." Thesis, University of Leicester, 2015. http://hdl.handle.net/2381/32535.
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miRNAs have been shown to play a role in fundamental cellular processes. They are also involved in drug-resistance mechanisms, which hamper the treatment of many types of cancer, including haematological malignancies. This study sought to uncover mechanisms of miRNA-induced drug-resistance in two haematological malignancies: diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). To this end, profiling of DLBCL and MM-derived cell lines was carried out to identify miRNAs whose levels were altered relative to their respective controls. The expression levels of these miRNAs were then modulated in the cell lines to examine the effect upon cell survival. The miRNA profiling data of the DLBCL cell lines compared to their control “normal” B-cell lines, was then combined with the results of previously performed “translational profiling” in which levels of mRNA translation are compared. Translational profiling identified upregulation of certain DNA damage repair (including BRCA2) and anti-apoptotic (including Bcl-2) proteins in the DLBCL cell lines. Importantly, the miRNA profiling data identified downregulation of miR-34a and miR-146 in the DLBCL cell lines, which are reported to target Bcl-2 and BRCA2, respectively. In GCB-DLBCL patient samples low miR-34a expression correlated with poor prognosis. In MM, the miRNA profile of an acquired multidrug-resistant cell line (8226/R5) was compared with the profile of its parental sensitive cell line and the miR-200 family was identified as upregulated in the resistant line. Overexpression of miR-200b, miR-200c or miR-429 in the parental cell line increased resistance to the proteasome inhibitor bortezomib. The increased resistance was due to direct targeting of the pro-apoptotic protein, Noxa, by the miR-200bc/429 family. Acquired bortezomib-resistant cell lines, which were only resistant to proteasome inhibitors, were then generated. miR-200b was again upregulated in these new cell lines, suggesting that increased expression of the miR-200bc/429 family is a possible mechanism for acquired bortezomib-resistance in MM.
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Richardson, Julie. "Ovarian cancer stem-like cells and drug resistance." Thesis, University of Leeds, 2014. http://etheses.whiterose.ac.uk/8009/.
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Ovarian cancer is characterised by late diagnosis, relatively poor survival and high recurrence due to the development of multidrug resistance (MDR – resistance to various types of drug). Cancer stem-like cells (CSCs) are thought to contribute to drug resistance due to the over-expression of ABC transporters which efflux chemotherapeutic drugs. Frequently overexpressed ABC transporters include Multidrug resistance protein 1 (MRP1), P-glycoprotein (Pgp) and Breast cancer resistance protein (BCRP). No definitive stem cell marker panel has been determined for ovarian CSC detection; investigation of multiple putative stem cell markers (CD133, CD24, CD44 and Aldehyde dehydrogenase (ALDH)) may prove beneficial to the identification of these cells. All three ABC transporters are heterogeneously expressed in the ovarian cancer cell lines studied. Functional MRP1 and Pgp activity was identified utilising the Calcein-AM assay. Stem cell markers CD133 and ALDH were undetectable by western blot (WB). However small populations of ALDH expressing cells were detected using the ALDEFLUOR™ assay. Low-level CD44 was observed by WB, and confirmed by IF. RT-qPCR and microarray analysis confirmed the gene expression of all three ABC transporters and stem cell markers. A potential CSC population of high Hoechst effluxing cells, called a side population (SP) was identified. However, the viability of the SP was greatly reduced. Chemotherapeutic resistance to carboplatin, paclitaxel and doxorubicin was determined in ovarian cancer cell lines. The ovarian cancer cell line 1847 supports CSC and MDR theories, showing greater colony and spheroid formation and is most resistant to chemotherapeutics. Heterogeneous ABC transporter and stem cell marker expression was confirmed in primary samples. IHC analysis confirmed marker expression was not correlated with patient survival. Correlations were observed between MRP1 and CD44 and ALDH, CD44 and Pgp, BCRP and ALDH expression. Cells derived from patient ascites were also capable of forming colonies and spheroids, indicative of CSC properties.
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Blake, Lynn Dong. "Antimalarial Exoerythrocytic Stage Drug Discovery and Resistance Studies." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6182.
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Malaria is a devastating global health issue that affects approximately 200 million people yearly and over half a million deaths are caused by this parasitic protozoan disease. Most commercially available drugs only target the blood stage form of the parasite, but the only way to ensure proper elimination is to treat the exoerythrocytic stages of the parasite development cycle. There is a demand for the discovery of new liver stage antimalarial compounds as there are only two current FDA approved drugs for the treatment of liver stage parasites, one of which fails to eliminate dormant forms and the other inducing hemolytic anemia in patients with G6PD deficiency. In efforts to address the dire need for liver stage drugs, we developed a high-throughput liver stage drug-screening assay to identify liver stage active compounds from a wide variety of chemical libraries with known blood stage activity. The liver stage screen led us to further investigate an old, abandoned compound known as menoctone. Menoctone was developed as a liver stage active antimalarial, however, the development of more potent compounds led to the abandonment of further menoctone research. Our research demonstrated that resistant parasites can transmit mutations through mosquitoes, which was previously believed to not be possible. Furthermore, we studied a novel genetic marker that may indicate potential resistance against malaria parasite infection and the cytotoxic effects associated with the disease. Future experiments aim to identify and advance our methods for the elimination of Plasmodium exoerythrocytic parasites.
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Othman, Ramadhan T. "ABCB1 and MGMT mediated drug resistance in medulloblastoma." Thesis, University of Nottingham, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.718995.
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Background: Medulloblastoma (MB) is the most common malignant paediatric brain tumour. Recurrence and progression of disease occurs in a substantial number of patients with current multimodal treatment. Drug resistance is a major obstacle to successful chemotherapy treatment of MB. Chemotherapeutic drugs must remain in the tumour cell long enough to damage DNA and this damage must not be accurately repaired. The expression of multidrug efflux transporter ABCB1 and DNA repair protein 06-methylguanine-DNA-methyltransferase (MGMT) might be involved in chemotherapeutic drug resistance. In this study, I investigated the correlation of ABCB1 expression with clinicopathological features in MB patients. Additionally, I evaluated expression and function of ABCB1 and MGMT as putative drug resistance mechanisms in a panel of MB cell lines. Material and Methods: Immunohistochemistry analysis of patient tissue microarrays was used to assess ABCB1 expression in paediatric MB. Expression of ABCB1 and MGMT was assessed by quantitative reverse transcription polymerase chain reaction, western blotting and flow cytometry in MB cell lines. Clonogenic- assays were used to assess cell survival in response to chemotherapeutics. Wound healing-assay was used to assess MB cell migration in vitro. Results: ABCB1 expression was expressed in 43 % (112/260) of tumours, showed significant association with high-risk (P= 0.035) patients and metastatic disease (P= 0.04). In cell line analysis, inhibition of ABCB1 using vardenafil or verapamil resulted in a significant increase in sensitivity to etoposide (ABCB1 substrate) in ABCB1-expressing MB cell lines (P< 0.0001). In the presence of verapamil or vardenafil. the capacity of MED1 cells (high ABCB1-expressing cell line) to migrate in vitro was significantly inhibited (P< 0.01). Sensitivity to temozolomide (TMZ) was MGMT-dependent, but two novel imidazotetrazine derivatives (N-3 sulfoxide and N-3 propargyl) demonstrated a significantly higher cytotoxicity compared to TMZ that was independent of MGMT and base excision repair. Conclusion: Data from this study indicate that ABCB1 is clinically associated with high-risk MB and MB cell invasion/metastasis. Thus, inhibition of ABCB1 by vardenafil may represent a valid approach in high-risk MB patients. In addition imidazotetrazine analogues of TMZ are promising clinical approaches to overcome resistance to alkylating drugs in MB tumours expressing MGMT.
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Zelnikar, Mojca. "Evolution of drug resistance in influenza A viruses." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/16203.
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Influenza A viruses are important pathogens of humans, other mammals and birds. Swine are considered to be the ‘mixing vessel’ for influenza viruses because of their susceptibility to infection with not only swine influenza viruses but also human and avian influenza viruses. After infection of pigs with different influenza viruses, reassortment events between genomic RNA segments and point mutations can take place which can result in novel influenza virus strains capable of causing human pandemics. To combat infections, vaccination is available in many countries for humans, but not typically used in pigs. However, anti-influenza drugs have been used to treat livestock, and mutations conferring drug resistance occur in circulating strains. The mechanisms responsible for the emergence and spread of drug resistant mutations against amantadine and oseltamivir have been studied previously but often gave conflicting results. Therefore, this PhD thesis focused on resolving the mechanisms responsible for this rapid drug resistance spread. In chapter one I examine the extent of reassortment events in swine influenza A viruses by analysing within subtype reassortment and extrapolating the results for the between subtype reassortment. Reassortment is one of the mechanisms that can be responsible for mutations, conferring resistance to drugs, to spread between strains, and thus spread in the host population. The findings of this chapter show that the genomic segments most prone to reassortment code for a polymerase (PB1) and both glycoproteins, within all three subtypes studied. Since particular mutations in the matrix protein (MP) segment cause resistance to amantadine, my study focused on MP compared to other segments and revealed moderate level of reassortment. MP reassorts well with polymerases, both within and between subtype, while nonstructural (NS) is least likely to reassort. Chapter two of this thesis aimed at resolving the origin and spread of the most common drug resistance conferring mutation in swine influenza viruses which causes amantadine resistance. I show first that this mutation occurred in swine influenza viruses and was therefore not transmitted from the recently ancestral avian influenza strains, and second that the prevalence of resistance in swine influenza viruses is due to functional linkage of mutations at other sites and not by direct drug pressure. In chapter three I examine the mechanisms responsible for the rapid rise and spread of oseltamivir resistance in human influenza H1N1 viruses which arose in the absence of drug use. The primary mutation lies in the neuraminidase glycoprotein but because of the close functional interaction I focus on changes in haemagglutinin that occurred in association with resistance. The results showed several mutations in haemagglutinin were associated with resistance suggesting selection acting on haemagglutinin in order to balance the activity of both glycoproteins. Overall these results show the importance of functional linkage between segments as a mechanism for the occurrence of drug resistance conferring mutations, and reassortment as a means of spreading these mutations into newly emerging strains.
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Mak, Chun-kit Gannon. "Antimicrobial resistance in Haemophilus species." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B36213664.
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Daoud, Roni N. "A study of MRP1-drug interactions : identification of the drug binding site(s)." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=36801.
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Over-expression of either P-gp1 and/or MRP1 in tumor cell lines confers resistance to structurally diverse anti-cancer drugs. Although the role of these two proteins in clinical drug resistance remains to be confirmed, the use of Pgp1-specific inhibitors in combination with standard anti-cancer drugs have demonstrated significant improvement in clinical response. However, evidence exists that reversal of P-gp1 alone is not sufficient. Therefore, while no drugs are currently available that can efficiently reverse MRP1 drug efflux in tumor cells, there is an urgent need to develop MRP1-specific blockers. In an effort to gain a better understanding of MRP1-drug interactions and to identify sequences within MRP1 that interact directly with drugs, we developed two structurally diverse photosensitive drug analogues, a quinoline-based compound (IACI) and a xanthone-derivative (IAARh123). Both compounds photolabeled MRP1 and showed a direct and specific interaction with the protein at physiologically relevant sites. Initial mapping of photolabeled sequences in MRP1 (Chapters 2 and 3), identified multiple IACI- or IAARh123-photolabeled peptides (∼4--7 kDa) derived from both the N-terminal (MSD0+MSD1+NBD 1) and C-terminal (MSD2+NBD2) domains of MRP1. A subsequent study (Chapter 4), using MRP1 variants with hemagglutinin (HA) epitopes inserted at eight different locations, led to a higher resolution mapping of the previously identified IACI- or IAARh123-labeled peptides. Specifically, two photolabeled peptides (∼6--7 kDa), derived from variants with insertions at positions 574 and 1222, were immunoprecipitated with anti-HA monoclonal antibody. Based on the location of the HA epitopes in the latter variants together with molecular masses of the two peptides, the photolabeled amino acid residues were localized to MRP1 sequences encoding transmembranes 10 and 11 of MSD1 and transmembranes 16 and 17 of MSD 2. Interestingly, the same sequences were photolabeled with both
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Nebel, Sibylle F. "The role of DNA mismatch repair in drug resistance /." [S.l.] : [s.n.], 1998. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=12553.
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Svedhem, Johansson Veronica. "Kinetics of HIV-1 drug resistance mutations in vivo /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-671-9/.
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Lin, Ti. "Mechanisms of drug resistance inv-src transformed rat fibroblasts." Diss., The University of Arizona, 1990. http://hdl.handle.net/10150/185090.
Full textAbstract:
The central question of my dissertation is does cellular transformation increase the occurrence of gene amplification. I used a model system in which cellular transformation could be controlled by shifting the temperature. Rat-1 was the parental cell line and was not transformed at any temperature. The LA24 cell line carries an avian sarcoma virus with a temperature sensitive mutation in the v-src gene. These cells are transformed at 35°C, but become nontransformed at 40°C. Measurements of cell transformation included (1) growth on plastic, (2) growth in soft agar and (3) v-src RNA and protein expression. My first experiments were to examine the frequency and mechanisms of MTX and colchicine resistant variants. The frequency in generating MTX resistant clones was the same in transformed and nontransformed LA24 cells. However, dihydrofolate reductase gene amplification was the preferred mechanism of MTX resistance in transformed LA24 clones. The frequency in generating colchicine resistant clones was no different in transformed and nontransformed LA24 cells. P-glycoprotein gene amplification was also the preferred mechanism of colchicine resistance in transformed LA24 clones. To directly study the mutation rate of colchicine resistant variants on transformed and nontransformed LA24 cells, Luria-Delbruck fluctuation analysis was performed. Colchicine resistant variants were derived from a single cell that were grown to a population size of 10⁵ cells; they were then selected with colchicine. The data showed no increase in the mutation rate of transformed LA24 cells compared to untransformed cells upon selection in colchicine. In summary, I have shown that v-src transformation in Rat-1 fibroblasts causes a high frequency of P-glycoprotein gene amplification when selected with colchicine, and a high frequency of dihydrofolate reductase gene amplification when selected with MTX. Even though gene amplification is enhanced by v-src transformation, the frequency of generating colchicine and MTX variants is not related to cellular transformation state.