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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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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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Tam, Stanton Sui Yin. "Anticancer Drug Combinations to Overcome Drug Resistance in Breast Cancer". Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/27733.
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For triple negative breast cancer (TNBC) patients, taxanes are the mainstays of chemotherapy but remain susceptible to resistance. Combination therapy of paclitaxel/docetaxel and tyrosine kinase inhibitors (TKIs) improves overall response rates in TNBC patients. Ixabepilone, mechanistically similar to taxanes, shows efficacy in TNBCs refractory to paclitaxel/docetaxel. Yet, there is a lack of studies on ixabepilone-TKI combinations. The first aim was to investigate the efficacy of these combinations in docetaxel-resistant MDA-MB-231 (TXT) cells and parental non-resistant MDA-MB-231 (231C) cells.
In preliminary studies, ixabepilone, vandetanib and gefitinib monotherapy inhibited proliferative activity in both cell lines. Vandetanib and ixabepilone showed drug synergism and increased inhibition of cell proliferation. Gefitinib and ixabepilone demonstrated drug antagonism and reduced cell proliferation. Annexin V-FITC/7AAD staining demonstrated increased cell killing after vandetanib-ixabepilone treatment and ascertained apoptosis as the mechanism of cell death in both cell lines. It revealed that vandetanib increases apoptosis when in combination compared to ixabepilone alone. This was supported by Western blotting which yielded altered protein expression of apoptotic players, cleaved-caspase-3 and Bcl-2.
The second aim was to determine how the vandetanib-ixabepilone combination induces apoptosis and overcomes resistance in both cell lines. Using Western blotting, it was determined that vandetanib does not contribute to increased cell death via microtubule stabilisation – the principal apoptotic mechanism of ixabepilone. Instead, in 231C and TXT cells, vandetanib increased proapoptotic NOXA and PUMA respectively.
This thesis reveals a novel combination with antiproliferative/apoptotic activity in docetaxel-resistant and non-resistant TNBC cell lines and lays the foundation for more combinations to overcome resistance and provide novel therapies for TNBC patients.
5
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.
7
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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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.
9
Doherty, Catherine Jean. "Drug resistance mechanisms in multiple myeloma". Thesis, University of Edinburgh, 1997. http://hdl.handle.net/1842/22154.
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ROMANO, GABRIELE. "Molecular mechanisms of cancer drug resistance". Doctoral thesis, Università degli Studi di Milano-Bicocca, 2015. http://hdl.handle.net/10281/93577.
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Colorectal cancer (CRC) is one of the most prevalent and incident cancers worldwide and it has become soon an important public health issue. Although surgery represents the principal curative treatment, chemotherapy is one of the most important tools currently available for the treatment of CRC. 5-fluorouracil (5FU) is the chemotherapeutic agent of election for CRC treatment. Two main problems affect the outcome of cancer chemotherapy: the use of poorly specific drugs and, in a high percentage of patients, the lack of response due to drug resistance, seen as a major obstacle to improve the overall response and survival of cancer patients, limiting the effectiveness of chemotherapy.
GSK-3β and TGF-β are known to be master regulators of a plethora of signalling pathways in various mechanisms involved in cancer development, resistance and dissemination.
In this thesis is shown that inhibition of GSK-3β (mediated by shRNA or Lithium) is able to revert chemoresistance to 5-FU in HCT116 P53-/- cells (a colon cancer cell line resistant to chemotherapy because of P53 deletion), both in vitro and in vivo through a heterotopic xenograft model. We started from this model of restoration of chemosensitivity to analyze some major features of the TGF-β pathway. Microvasculature analysis on xenografted tumor sections, revealed a dramatic increase of tumor vascularization in consequence of 5FU administration whereas Lithium and 5FU combination was able to significantly decrease the vasculature density, restoring the basal value. Moreover, 5FU is able to stimulate nuclear translocation of SMAD3 and the transcription of specific genes such as ACVRL1,FN1 and TGFB1. Contrarily, the specific inhibition of TGF-βRI, not only is able to inhibit the 5FU-induced genes transcription, but also restores the sensitivity of chemoresistant cells to the action of chemotherapeutic, causing the repression of BCL2L1 and ID1 genes. Chemoresistant cells behavior was consistent to a sort of autocrine protective loop acted by TGFB1 in consequence of 5FU administration.
Moreover, in this work is presented a bioinformatics study on colorectal cancer patients. Patients enrolled in the study underwent preoperative chemoradiotherapy, followed by surgical excision. By determining gene expression profiles, responders and non-responders showed significantly different expression levels for 19 genes (P < 0.001). We fitted a logistic model selected with a stepwise procedure optimizing the Akaike Information Criterion (AIC) and then validated by means of leave one out cross validation (LOOCV, accuracy D 95%). Four genes were retained in the achieved model: ZNF160, XRCC3, HFM1 and ASXL2. Real time PCR confirmed that XRCC3 is overexpressed in responders group. In vitro test on colon cancer resistant/susceptible to chemoradioterapy cells, finally prove that XRCC3 deregulation is extensively involved in the chemoresistance mechanisms. Protein-protein interactions (PPI) analysis involving the predictive classifier revealed a network of 45 interacting nodes (proteins) with TRAF6 gene playing a keystone role in the network.
In this thesis is also presented a work on Glioblastoma multiforme (GBM) drug resistance. GBM is one of the most fatal and least successfully treated solid tumors: current therapies provide a median survival of 12-15 months after diagnosis, due to the high recurrence rate. Glioma Stem Cells (GSCs) are believed to be the real driving force of tumor initiation, progression and relapse. Therefore, better therapeutic strategies GSC-targeted are needed. Resveratrol (RSV) is a polyphenolic phytoalexin found in fruits and vegetables displaying pleiotropic health benefits. Results showed that response to RSV exposure was highly heterogeneous among GSC lines, but generally it was able to inhibit cell proliferation, increasing cell mortality, and strongly decrease cell motility, modulating the Wnt signaling pathway.
11
Stordal, Britta Kristina. "Regrowth resistance in platinum-drug resistant small cell lung cancer cells". Bill Walsh Cancer Research Laboratories, Royal North Shore Hospital and The University of Sydney, 2007. http://hdl.handle.net/2123/2467.
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Doctor of Philosophy (PhD)The H69CIS200 cisplatin-resistant and H69OX400 oxaliplatin-resistant cell lines developed as part of this study, are novel models of low-level platinum resistance. These resistant cell lines do not have common mechanisms of platinum resistance such as increased expression of glutathione or decreased platinum accumulation. Rather, these cell lines have alterations in their cell cycle allowing them to proliferate rapidly post drug treatment in a process known as ‘regrowth resistance’. This alteration in cell cycle control has come at the expense of DNA repair capacity. The resistant cell lines show a decrease in nucleotide excision repair and homologous recombination repair, the reverse of what is normally associated with platinum resistance. The alterations in these DNA repair pathways help signal the G1/S checkpoint to allow the cell cycle to progress despite the presence of DNA damage. The decrease in DNA repair capacity has also contributed to the development of chromosomal alterations in the resistant cell lines. Similarities in chromosomal change between the two platinum resistant cell lines have been attributed to inherent vulnerabilities in the parental H69 cells rather than part of the mechanism of resistance. The H69CIS200 and H69OX400 resistant cells are cross-resistant to both cisplatin and oxaliplatin. This demonstrates that oxaliplatin does not have increased activity in low-level cisplatin-resistant cancer. Oxaliplatin resistance also developed more rapidly than cisplatin resistance suggesting that oxaliplatin may be less effective than cisplatin in the treatment of SCLC. The resistant cell lines have also become hypersensitive to taxol but show no alterations in the expression, polymerisation or morphology of tubulin. Rather, the PI3K/Akt/mTOR pathway is involved in both platinum resistance and taxol sensitivity as both are reversed with rapamycin treatment. mTOR is also phosphorylated in the resistant cell lines indicating that platinum resistance is associated with an increase in activity of this pathway. The mechanism of regrowth resistance in the platinum-resistant H69CIS200 and H69OX400 cells is a combination of activation of PI3K/Akt/mTOR signalling and alterations in control of the G1/S cell cycle checkpoint. However, more work remains to determine which factors in these pathways are governing this novel mechanism of platinum resistance.
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Stordal, Britta. "Regrowth resistance in platinum-drug resistant small cell lung cancer cells". Connect to full text, 2006. http://hdl.handle.net/2123/2467.
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Thesis (Ph. D.)--University of Sydney, 2007.Title from title screen (viewed 10 June 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Discipline of Medicine, Faculty of Medicine. Degree awarded 2007; thesis submitted 2006. Includes bibliographical references. Also available in print form.
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Hayes, Cindy. "Prevalence and resistance gene mutations of multi-drug resistant and extensively drug resistant mycobacterium tuberculosis in the Eastern Cape". Thesis, Nelson Mandela Metropolitan University, 2014. http://hdl.handle.net/10948/d1020374.
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The emergence and spread of multi-drug resistant (MDR-TB) and extensively drugresistant tuberculosis (XDR-TB) are a major medical and public problem threatening the global health. The objectives of this study were to (i) determine the prevalence of MDR-TB and XDR-TB in the Eastern Cape; (ii) analyze patterns of gene mutations in MDR-TB and (iii) identify gene mutations associated with resistance to second line injectable drugs in XDR-TB isolates. A total of 1520 routine sputum specimens sequentially received within a period of 12 months i.e. February 2012 to February 2013 from all MDR-TB and XDR-TB patients treated by Hospitals and clinics in the Eastern Cape were included in this study, of which 1004 had interpretable results. Samples were analyzed with the Genotype MTBDRplus VER 2.0 assay kit (Hain Lifescience) for detection of resistance to Rifampicin and Isoniazid while solid and liquid culture drug susceptibility tests were used for ethambutol, streptomycin, ethionamide, ofloxacin, capreomycin and amikacin. PCR and sequence analysis of short regions of target genes gyrA, (encode subunit of DNA topoisomerase gyrase), rrs (16S rRNA) and tlyA (encodes a 2’-O-methyltransferase) were performed on 20 XDR-TB isolates. MTBDRplus kit results and drug susceptibility tests identified 462 MDR-TB, 284 pre-XDR and 258 XDR-TB isolates from 267 clinics and 25 hospitals in the Eastern Cape. There was a high frequency of resistance to streptomycin, ethionamide, amikacin, ofloxacin and capreomycin. Mutation patterns indicated differences between the health districts as well as differences between the facilities within the health districts. The most common mutation patterns observed were: (i) ΔWT3, ΔWT4, MUT1 [D516V+del515] (rpoB), ΔWT, MUT1 [S315T1] (katG), ΔWT1 [C15T] (inhA) [39 MDR, 204 XDR-TB and 214 pre XDR-TB isolates], (ii) ΔWT8, MUT3 [L533P+S531L] (rpoB), ΔWT, MUT1 [S315T1] [145 MDR, 18 pre-XDR and 3 XDR-TB solates] and (iii) ΔWT3, WT4 [D516Y+del515] (rpoB), ΔWT, MUT1 [S315T1] (katG) [75 MDR, 1 pre-XDR and 7 XDR-TB isolates]. Mutations in inhA promoter regions were strongly associated with XDR-TB isolates. Two thirds (66.6 percent (669/1004) of the isolates had inhA mutations present with 25.4 percent (170/669) found among the MDR isolates, 39.2 percent (262/669) among the pre-XDR isolates and 35.4 percent (237/669) among the XDR-TB isolates, which implies that these resistant isolates are being spread by transmission within the community and circulating in the province. There was good correlation between XDR-TB drug susceptibility test results and sequence analyses of the gyrA and rrs genes. The majority of XDR-TB isolates contained mutations at positions C269T (6/20) and 1401G (18/20) in gyrA and rrs genes respectively. Sequence analysis of short regions of gyrA and rrs genes may be useful for detection of fluoroquinolone and amikacin/ kanamycin resistance in XDR-TB isolates but the tlyA gene is not a sensitive genetic marker for capreomycin resistance. This study highlighted the urgent need for the development of rapid diagnostics for XDR-TB and raised serious concerns regarding ineffective patientmanagement resulting in ongoing transmission of extremely resistant strains of XDRTB in the Eastern Cape suggesting that the Eastern Cape could be fast becoming the epicenter for the development of Totally Drug-resistant Tuberculosis (TDR-TB) in South Africa.
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Ellis, Lucy C. J. "Human and rat multidrug resistance-associated proteins (MRP/Mrp)". Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=128325.
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The multidrug resistance associated proteins (MRP(human)Mrp (rat) are ATP-dependent transporters responsible for the efflux of a wide range of substrates, including endogenous compounds e.g. bilirubin, drug metabolites e.g. paracetamol glucuronide and fluorescent dyes e.g. 5 (and 6)-carboxy-2’,7’-dichlorofluorescein (CDF). Mrp1-6 (abccl-6) are expressed in rat liver, with Mrp2 being expressed at the highest level. Isolation of hepatocytes by in situ collagenase perfusion causes bile canalicular disruption and internalisation of Mrp2. Cells cultured in a sandwich configuration of Matrigel or collagen (Type 1) showed bile canalicular reformation at different days in cell culture, depending on the extracellular matrix and time of overlay. We have developed a method for quantifying Mrp-mediated efflux in hepatocytes cultured in a sandwich configuration of collagen (Type 1). This method is unique in its ability to distinguish between sinusoidal efflux, canalicular efflux and diffusion in intact hepatocytes. Alternative in vitro models of Mrp2-mediated efflux include the vesicular (direct and indirect methods) and the ATPase assays. We have used these assays to identify atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin as substrates of human and rat MRP2/Mrp2. A close correlation was seen between the kinetic parameters of transport of the Mrp2 substrate; CDF determined in sandwich cultured rat hepatocytes using the method above (Km = 3.5 – 9.9 μM), vesicle preparations (Km = 37.9 μM) and membrane preparations (Km = 18.7 μM). We also present data to implicate the nuclear receptors, PXR, CAR and FXR in the regulation of abcc2 and abcc3 and PXR and CAR in abcc1 gene regulation. Abcc2 and abcc5 are also up-regulated in response to a toxic insult to the cell, probably via Nrf2 activation, suggesting a role in cell defence.
15
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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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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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.
22
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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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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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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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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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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Baker, Nicola Louise. "Screening for new natural drugs and drug resistance determinants in African trypanosomiasis". Thesis, London School of Hygiene and Tropical Medicine (University of London), 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590629.
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Sostelly, Alexandre. "Mechanistic model-based drug development in the management of anticancer drugs resistance". Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10203.
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La résistance aux chimiothérapies anticancéreuses constitue un problème majeur dans la prise en charge du cancer. Les transporteurs d'efflux contribuent à ce phénomène de résistance en altérant l'accumulation intracellulaire des cytotoxiques. Dans le passé, l'inhibition du transporteur d'efflux P-gp n'a pas permis de surmonter ce phénomène notamment à cause du manque de méthodes adéquates pour identifier et quantifier la pharmacologie des inhibiteurs d'efflux. Récemment de nouveaux inhibiteurs de BCRP, l'un des derniers transporteurs d'efflux découverts, ont été synthétisés permettant de retester l'intérêt de l'inhibition de ces transporteurs dans la prise en charge de la résistance aux anticancéreux. Néanmoins, afin d'éviter les mêmes écueils que lors du développement des inhibiteurs de P-gp, il est nécessaire d'utiliser d'autres approches telles que la modélisation mathématique dès le début du développement préclinique de ces inhibiteurs. Cette thèse a pour but de montrer les bénéfices de la modélisation et de la simulation dans le développement préclinique des inhibiteurs de transporteurs d'efflux et plus largement dans le développement des molécules anticancéreuses. L'exemple utilisé au travers de ce travail concerne l'étude de l'interaction entre l'irinotecan, un cytotoxique largement utilisé dans le traitement du cancer colorectal, et le MBLI87, un nouvel inhibiteur de BCRP. Deux principaux axes ont été abordés dans ce travail : - Le développement de modèles (semi-) mécanistiques à effets mixtes pour identifier et quantifier les facteurs impactant l'efficacité de la combinaison irinotecan-MBLI87 - Le développement de modèles d'inhibition de la croissance tumorale à effets mixtes pour évaluer précocement ce type d'interaction de traitements et pour optimiser la réponse tumorale. Les résultats obtenus avec l'approche de modélisation ont permis d'identifier certains des mécanismes tumoraux impactant l'efficacité des inhibiteurs de transporteur d'efflux. De plus cette approche s'est révélée supérieure aux approches classiques dans l'évaluation de ces molécules et dans l'optimisation de la réponse tumorale démontrant la puissance de la modélisation et de la simulation comme outil de développement des molécules anticancéreusesAnticancer drug resistance is a major issue in the management of cancer disease. Efflux transporters contribute to the multidrug resistance by altering the intracellular disposition of cytotoxic drugs. In the past, the inhibition of P-gp efflux transporter essentially failed because of the lack of adequate methods to identify their mechanisms of action. Recently, new inhibitors of BCRP, one of the latest efflux transporter that have been discovered, have been developed that allow re-testing the multidrug resistance inhibition through efflux inhibition. Nevertheless, to avoid the same issues of development as for P-gp inhibitors, new methods have to be used. This PhD work aims to demonstrate the benefits of mechanistic models to support the development of efflux transporter inhibitors and more generally of oncology compounds through two axes: - The development of mechanistic models of the interaction between cytotoxic and efflux transporter inhibitors - The development of quantitative tumour growth inhibition models to early evaluate oncology compounds and optimize patients’ response The results obtained with this approach allow the identification of key mechanisms of efflux transporter inhibitors and demonstrate the power of modelling and simulation to support oncology drug development
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Fleeman, Renee. "Discovering Antibacterial and Anti-Resistance Agents Targeting Multi-Drug Resistant ESKAPE Pathogens". Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6839.
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Antibiotic resistance has been a developing problem for mankind in recent decades and multi-drug resistant bacteria are now encountered that are resistant to all treatment options available. In 2014, the World Health Organization announced that this problem is driving us towards a “post-antibiotic era” that will change the face of modern medicine as we know it. If lack of novel antibiotic development and FDA approval continues, by the year 2050, 10 million people will die each year to an antimicrobial resistant bacterial infection. With lack of pharmaceutical industry involvement in developing novel antibiotics, the responsibility now lies within the academic institutions to identify potential novel therapeutics to fuel the antibiotic drug discovery pipeline. Combinatorial chemistry is one technique used to expedite the discovery process by assessing a large chemical space in a relatively short time when compared to traditional screening approaches. Combinatorial libraries can be screened using multiple approaches and has shown successful application towards many disease states. We initially discovered broad spectrum antibacterial bis-cyclic guanidines using combinatorial libraries and expanded on the knowledge of the physiochemical attributes necessary to inhibit Gram negative bacterial pathogens. Following this success, we continued to assess the combinatorial libraries for adjunctive therapeutics that potentiate the activity of obsolete clinical antibiotics. The polyamine efflux pump inhibitors discovered in this subsequent study prove the benefits of using the large chemical space provided in the combinatorial libraries to identify a variety of therapeutics. Our studies always begin with identifying an active compound and active compounds undergo hit-to-lead optimization. This optimization studies are of utmost importance in developing a novel antibacterial agent for therapeutic applications. Our medicinal chemistry work described here is proof of the success of careful structure activity analyses to optimize a hit scaffold to create a more effective antibacterial agent. Overall, our work described here reveals the potential role of academic institutions in fending off the impending “post-antibiotic era”.
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Stenhouse, Lindsay Joanne. "Characterisation of anthelmintic resistance in a multiple drug resistant Teladorsagia circumcinta isolate". Thesis, University of Glasgow, 2007. http://theses.gla.ac.uk/4251/.
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The purpose of this study was to undertake detailed molecular and phenotypic characterisation of a MDR isolate of T. circumcincta (MTci5) with particular focus upon the mechanisms underlying benzimidazole (BZ) resistance. MTci5 was isolated from a farm in Central Scotland, which employed a suppressive anthelmintic dosing regime and was closed in 2002 when control of the parasite population became unsustainable. Underpinning all of the experiments in this study was an anthelmintic selection process whereby the MTci5 isolate was pressured individually with three broad-spectrum anthelmintics (benzimidazole, ivermectin and levamisole). There are three main areas of investigation in this study, the first being an investigation of the population genetic structure or a MDR isolate. A central question was whether the MDR phenotype of MTci5 is conferred by the inheritance of genes present in a single interbreeding population or whether there is genetic sub-structuring, whereby discrete sub-populations of the isolate each show resistance to different anthelmintics. Microsatellite analysis was employed to investigate the population genetic structure of the MTci5 isolate. The results suggest that the MTci5 isolate is a single, freely interbreeding population with triple resistance, showing no evidence of genetic sub-structuring. The second area of investigation was the role of the F200Y isotype I ß-tubulin mutation in the determination of BZ resistance and the potential involvement of this mutation in resistance to ivermectin (IVM) and levamisole (LEV). There was no evidence of an effect of IVM or LEV selection upon the F200Y isotype I ß-tubulin mutation. The third area of investigation was the origin and diversity of BZ resistance alleles in the MTci5 isolate. Single strand conformation polymorphism (SSCP) analysis of small region extending through exons 1 and 2 and intron 1 of the isotype I ß-tubulin gene was used to assess the genetic diversity of this locus in the MTci5 isolate and of five other UK T. circumcincta populations. Results are consistent with the theory of multiple independent, spontaneous mutations at the P200 locus of the isotype I ß-tubulin gene.
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Liu, Fengling. "Kinetic and Crystallographic Studies of Drug-Resistant Mutants of HIV-1 Protease: Insights into the Drug Resistance Mechanisms". Digital Archive @ GSU, 2007. http://digitalarchive.gsu.edu/biology_diss/19.
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HIV-1 protease (PR) inhibitors (PIs) are important anti-HIV drugs for the treatment of AIDS and have shown great success in reducing mortality and prolonging the life of HIV-infected individuals. However, the rapid development of drug resistance is one of the major factors causing the reduced effectiveness of PIs. Consequently, various drug resistant mutants of HIV-1 PR have been extensively studied to gain insight into the mechanisms of drug resistance. In this study, the crystal structures, dimer stabilities, and kinetics data have been analyzed for wild type PR and over 10 resistant mutants including PRL24I, PRI32V, PRM46L, PRG48V, PRI50V, PRF53L, PRI54V, PRI54M, PRG73S and PRL90M. These mutations lie in varied structural regions of PR: adjacent to the active site, in the inhibitor binding site, the flap or at protein surface. The enzymatic activity and inhibition were altered in mutant PR to various degrees. Crystal structures of the mutants complexed with a substrate analog inhibitor or drugs indinavir, saquinavir and darunavir were determined at resolutions of 0.84 – 1.50 Å. Each mutant revealed distinct structural changes, which are usually located at the mutated residue, the flap and inhibitor binding sites. Moreover, darunavir was shown to bind to PR at a new site on the flap surface in PRI32V and PRM46L. The existence of this additional inhibitor binding site may explain the high effectiveness of darunavir on drug resistant mutants. Moreover, the unliganded structure PRF53L had a wider separation at the tips of the flaps than in unliganded wild type PR. The absence of flap interactions in PRF53L suggests a novel mechanism for drug resistance. Therefore, this study enhanced our understanding of the role of individual residues in the development of drug resistance and the structural basis of drug resistance mechanisms. Atomic resolution crystal structures are valuable for the design of more potent protease inhibitors to overcome the drug resistance problem.
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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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Huijben, Silvie. "Experimental studies on the ecology and evolution of drug-resistant malaria parasites". Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/3945.
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Drug resistance is a serious problem in health care in general, and in malaria treatment in particular, rendering many of our previously considered ‘wonder drugs’ useless. Recently, large sums of money have been allocated for the continuous development of new drugs to replace the failing ones. We seem to be one step behind the evolution of antimalarial resistance; is it possible to get one step ahead? Are interventions which slow down the evolution and spread of drug-resistant malaria parasites achievable? In this thesis, I address these issues with experimental data, using the well-established rodent malaria model Plasmodium chabaudi to understand the selective advantages and disadvantages drug-resistant parasites endure within a vertebrate host and the selective pressures various drug treatment regimes exert on these parasites. Competitive interactions between drug-resistant and drug-sensitive parasites were observed within the host, with resistant parasites having a competitive disadvantage in the absence of drug treatment. The frequency of resistant parasites at the start of the infection was an important determinant of the strength of selection: the lower their frequency, the stronger the competitive suppression in non-treated hosts and the greater their competitive release following drug treatment. Genetically similar genotypes, one resistant and one sensitive, showed similar dynamics following drug treatment. Multiplicity of infection did not have an effect on the within-host dynamics: a larger number of co-infecting susceptible genotypes did not lead to greater competitive suppression or release of resistant parasites. Lastly, various drug treatment regimes were compared. Conventional drug treatment resulted in the greatest selective advantage for drug-resistant parasites, while less aggressive treatments were equally as effective, or even better, at improving host health and reducing overall infectiousness. These studies demonstrate that altering the within-host ecology of drug-resistant parasites by administering drugs and hence removing the drug-sensitive competitors has a large influence on the transmission potential of drug-resistant parasites. Furthermore, this thesis provides proof of principle that other drug treatment regimes different from those currently in use could better control drug-resistant parasites, without compromising other treatment goals. In the case of malaria, less drugs may mean extending the useful lifespan of that drug.
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Kosmas, Petrus Ndiiluka. "Extensively drug-resistant tuberculosis in Africa: prevalence and factors associated: a systematic review and meta-analysis". Master's thesis, Faculty of Health Sciences, 2019. http://hdl.handle.net/11427/31604.
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Background: There is a dearth of information regarding prevalence of extensively drugresistant tuberculosis (XDR-TB) in Africa. Although countries in Africa conduct national tuberculosis surveys on a regular basis, this information has not been systematically reviewed to ascertain the overall prevalence of XDR-TB in Africa. Methods: The study aimed to perform a systematic review and meta-analysis of the prevalence and factors associated with prevalence of pulmonary XDR-TB among adults in Africa. Eligible studies, published between 2006 and 2018, were sourced from various electronic databases including PubMed, Scopus, and Web of Science. Meta-analysis was performed using STATA (version 14.2) statistical software. The protocol of this review was registered with PROSPERO, reg No CRD42018117037. Result: A total of 6242 records were retrieved. Forty-eight studies were screened for eligibility and seven, which varied in terms of country setting and study design, were included. The prevalence of XDR-TB is 4% (95%CI 2-7) among participants tested for second-line anti-TB drug resistance, and 3% (95%1-6) among participants with drug resistant TB. The prevalence of XDR-TB was 7% (95%CI 1-18) among participants with MDR-TB. A few studies reported on the factors associated with the prevalence of XDR-TB. Discussion: The reported prevalence of XDR-TB among participants tested for second-line anti-TB drug resistance is low compared to WHO estimates. The systematic review underscores a dearth of studies depicting the reality regarding the prevalence of XDR-TB in Africa. Policymakers and stakeholders interested in drug-resistant TB should apply prudence when considering XDR-TB prevalence reported for Africa.
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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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Heinrich, Anne-Kathrin [Verfasser]. "Overcoming drug resistance by stimulus-sensitive drug delivery systems : a preclinical characterization of polymer-drug conjugates for the treatment of multi-drug resistant cancer / Anne-Kathrin Heinrich". Halle, 2017. http://d-nb.info/1144955262/34.
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Cheng, Kim-wai. "Fluoroquinolone resistance mechanisms in ten clinical isolates of fluoroquinolone-resistant Streptococcus pneumoniae in Hong Kong". Click to view the E-thesis via HKUTO, 2000. http://sunzi.lib.hku.hk/hkuto/record/B42575199.
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Stegner, Andrew L. "Drug resistance in D. discoideum isolation of 4-nitroquinoline 1-oxide resistant mutants /". Diss., Columbia, Mo. : University of Missouri-Columbia, 2005. http://hdl.handle.net/10355/4236.
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Thesis (M.A.)--University of Missouri-Columbia, 2005.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 (July 14, 2006) Includes bibliographical references.
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Wood, Daniel J. T. "Reversal of subcellular drug resistance mechanisms in multidrug resistant human KB carinoma cells". Thesis, University of York, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297167.
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Marfurt, Jutta. "Drug resistant malaria in Papua New Guinea and molecular monitoring of parasite resistance /". Basel : [s.n.], 2006. http://edoc.unibas.ch/diss/DissB_8080.
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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.
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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, 2009. http://escholarship.umassmed.edu/gsbs_diss/841.
Texto completo da fonteResumo:
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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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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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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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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