You searched for subject:(Drug resistance).
Showing records 1 – 30 of
1115 total matches.
◁ [1] [2] [3] [4] [5] … [38] ▶
1.
Wong, Neelum.
Development of Improved Chemotherapeutics in Pancreatic and
Colorectal Cancer: Ceramide as a Potential Adjuvant with Sigma-2
Receptor Ligands.
Degree: Department of Molecular Pharmacology, Physiology and
Biotechnology, 2018, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:792844/ 
► Pancreatic and colorectal cancer are highly aggressive and challenging to treat. Both cancers have low survival rates and there is a need for more elaborate…
(more)
▼ Pancreatic and colorectal cancer are highly aggressive
and challenging to treat. Both cancers have low survival rates and
there is a need for more elaborate therapies as patients suffer
from
drug resistance to commonly used chemotherapeutics. The
difficulty in finding novel and effective treatments has led
researchers to explore the sigma-2 receptor and the sphingolipid
ceramide for their roles in inducing apoptosis in cancer cells.
Ceramide has recently been studied for its ability to potentiate
chemotherapeutics for pancreatic and colorectal cancer patients
with a mutation in the KRAS oncogene that contributes to
drug
resistance. The sigma-2 receptor is upregulated in cancer cells and
a cytotoxic response by the activation of the receptor in cancer
cells is a property that can be exploited in the attempt to
overcome
drug resistance and kill pancreatic and colorectal cancer
cells. Here, the cytotoxicity of C-6 ceramide on cell viability for
PANC-1, MIA PaCA-2, and L3.6 pancreatic cancer cell lines and
KRAS-wild-type SW48 and KRAS-mutated SW480 colorectal cell lines
was found using the MTT cell viability assay. Additionally, this
study revealed that a combination treatment of C-6 ceramide with
the sigma-2 receptor agonists, siramesine and SV119 had a
synergistic effect on cytotoxicity while C-6 ceramide with the
sigma-2 receptor agonist, MAM03055A had an additive effect on the
colorectal cancer cell lines. Interestingly, no difference in
cytotoxicity was observed in the combination therapy treatments
between the KRAS-wild-type and KRAS-mutated cell lines. Altogether,
this data suggests that a combination treatment of ceramide with
sigma-2 receptor agonists is promising for the development of
improved chemotherapeutics for pancreatic and colorectal
cancer.
Advisors/Committee Members: Mathiowitz, Edith (Reader), Morgan, Jeffrey (Reader), Bowen, Wayne (Advisor).
Subjects/Keywords: Drug resistance
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Wong, N. (2018). Development of Improved Chemotherapeutics in Pancreatic and
Colorectal Cancer: Ceramide as a Potential Adjuvant with Sigma-2
Receptor Ligands. (Thesis). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:792844/
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Wong, Neelum. “Development of Improved Chemotherapeutics in Pancreatic and
Colorectal Cancer: Ceramide as a Potential Adjuvant with Sigma-2
Receptor Ligands.” 2018. Thesis, Brown University. Accessed October 23, 2019.
https://repository.library.brown.edu/studio/item/bdr:792844/.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Wong, Neelum. “Development of Improved Chemotherapeutics in Pancreatic and
Colorectal Cancer: Ceramide as a Potential Adjuvant with Sigma-2
Receptor Ligands.” 2018. Web. 23 Oct 2019.
Vancouver:
Wong N. Development of Improved Chemotherapeutics in Pancreatic and
Colorectal Cancer: Ceramide as a Potential Adjuvant with Sigma-2
Receptor Ligands. [Internet] [Thesis]. Brown University; 2018. [cited 2019 Oct 23].
Available from: https://repository.library.brown.edu/studio/item/bdr:792844/.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Wong N. Development of Improved Chemotherapeutics in Pancreatic and
Colorectal Cancer: Ceramide as a Potential Adjuvant with Sigma-2
Receptor Ligands. [Thesis]. Brown University; 2018. Available from: https://repository.library.brown.edu/studio/item/bdr:792844/
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Zambia
2.
Shawa, Misheck.
Risk factors and Alleles of extended spectrum Beta-Lactamase(ESBL) producing Escherichia coli at the University Teaching Hospital, Zambia
.
Degree: 2015, University of Zambia
URL: http://dspace.unza.zm:8080/xmlui/handle/123456789/4464
► The limitation of antibacterial treatment options imposed by the emergence of bacterial resistant organisms calls for the correct identification of the genes involved in mediating…
(more)
▼ The limitation of antibacterial treatment options imposed by the emergence of bacterial resistant organisms calls for the correct identification of the genes involved in mediating resistance. In this study, antimicrobial resistance was determined in terms of the presence of extended-spectrum beta-lactamases (ESBL) among Escherichia coli isolates obtained from patients admitted at the University Teaching Hospital (UTH) in Zambia. A total of 400 rectal swabs were obtained and subjected to initial screening using MacConkey agar supplemented with cefotaxime. blaTEM, blaSHV and bla CTX-M genes in ESBL producing E. coli were detected using Polymerase Chain Reaction (PCR). All CTX-M positive isolates were subjected to sensitivity patterns using 11 different antibiotics: ampicillin (AMP), trimethoprim-sulphamethoxazole (SXT), streptomycin (STR), tetracycline (TET), gentamycin (GEN), nalidixic acid (NAL), ceftazidime (CAZ), chloramphenicol (CHL), norfloxacin (NOR), ciprofloxacin (CIP) and cefotaxime (CTX).
The prevalence of ESBL producing E. coli was 19% (76/400). Among the ESBL producing E. coli, 25 out of 76 (32.9%) were positive for CTX-M genes. Of the 25 CTX-M positive isolates, 9 (36%) isolates were positive for SHV genes and 9 (36%) were positive for TEM genes. The highest resistance was found to be to nalidixic acid (96%), followed by sulfamethoxazole-trimethoprim, tetracycline and ceftazidime (92% each). The least resistance was to ampicillin (60%). Male gender (p=0.014, 95% CI=1.198-4.813) and history of surgery (p=0.01, 95% CI=1.196-3.740) were found to be significant risk factors for ESBL presence. The findings emphasize that ESBL-producing bacteria are present among patients at the UTH, and that these organisms exhibit co-resistance to several classes of antibiotics.
Subjects/Keywords: Drug resistance, Microbial;
Drug resistance in microorganisms
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Shawa, M. (2015). Risk factors and Alleles of extended spectrum Beta-Lactamase(ESBL) producing Escherichia coli at the University Teaching Hospital, Zambia
. (Thesis). University of Zambia. Retrieved from http://dspace.unza.zm:8080/xmlui/handle/123456789/4464
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Shawa, Misheck. “Risk factors and Alleles of extended spectrum Beta-Lactamase(ESBL) producing Escherichia coli at the University Teaching Hospital, Zambia
.” 2015. Thesis, University of Zambia. Accessed October 23, 2019.
http://dspace.unza.zm:8080/xmlui/handle/123456789/4464.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Shawa, Misheck. “Risk factors and Alleles of extended spectrum Beta-Lactamase(ESBL) producing Escherichia coli at the University Teaching Hospital, Zambia
.” 2015. Web. 23 Oct 2019.
Vancouver:
Shawa M. Risk factors and Alleles of extended spectrum Beta-Lactamase(ESBL) producing Escherichia coli at the University Teaching Hospital, Zambia
. [Internet] [Thesis]. University of Zambia; 2015. [cited 2019 Oct 23].
Available from: http://dspace.unza.zm:8080/xmlui/handle/123456789/4464.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Shawa M. Risk factors and Alleles of extended spectrum Beta-Lactamase(ESBL) producing Escherichia coli at the University Teaching Hospital, Zambia
. [Thesis]. University of Zambia; 2015. Available from: http://dspace.unza.zm:8080/xmlui/handle/123456789/4464
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Technology, Sydney
3.
James, CE.
ABC transport proteins and drug resistance in nematodes.
Degree: 2009, University of Technology, Sydney
URL: http://hdl.handle.net/10453/30176
► Widespread resistance to chemotherapeutic agents is one of the biggest challenges facing human health and the agricultural industry, with resistance to all current anthelmintics now…
(more)
▼ Widespread resistance to chemotherapeutic agents is one of the biggest challenges facing human health and the agricultural industry, with resistance to all current anthelmintics now recorded. Understanding the development of drug resistance in parasitic nematodes is critical to prolonging the efficacy of current anthelmintics, developing markers for monitoring drug resistance and is beneficial in the design of new chemotherapeutic agents or targets. Multidrug resistance (MDR) is mediated by ATP-binding cassette (ABC) transport proteins including the multidrug resistance-associated proteins (MRPs) and P-glycoproteins, which confer resistance to structurally and functionally different drugs. This work characterizes the role of these proteins in drug resistance in nematodes.
Using the model nematode Caenorhabditis elegans, ivermectin resistant sublines were developed through step-wise exposure to increasing concentrations of ivermectin commencing with a non-toxic concentration of 1 ng/ml. Resistant strains displayed a MDR phenotype with cross-resistance not only to the related drug moxidectin, but also to other unrelated anthelmintics, levamisole, pyrantel and thiabendazole but not to albendazole. Resistance was stable after 3 months without tivermectin treatment.
Resistance to low levels of ivermectin (≤6 ng/ml) was associated with increased expression of mrp-1, mrp-6 and pgp-1 and decreased glutathione, while higher level resistance (10ng/ml) was primarily associated with the increased expression of P-glycoproteins. This resistance to ivermectin was reversible by the co-administration of MRP, P-glycoprotein and glutathione synthesis inhibitors confirming the involvement of these proteins in resistance. To show the relevance of this model, homologues of MRPs were identified in the gastrointestinal parasitic nematode of ruminants Haemonchus contortus. Increased expression of several MRPs identified in H. contortus was found in ivermectin resistant isolates, supporting the relevance of the C. elegans model.
The interaction of ivermectin with human P-glycoprotein and MRP-1 was also examined. lvermectin clearly inhibits the transport of P-glycoprotein substrates and can reverse resistance to both daunorubicin and taxol in resistant cells . An interaction with mammalian MRP-1 is less clear, with a 10-fold lower affinity. Therefore ivermectin and modulators of Pglycoprotein have the potential to interfere with the biodisposition and bioavailability of anthelmintics within parasitic hosts as well as parasites. Overall, this work demonstrated that low doses of ivermectin can induce resistance in nematodes through the increased expression of multidrug resistance transport proteins, adding further complexity of the development of drug resistance, and demonstrating the multi-factorial nature of MDR.
Subjects/Keywords: Nematodes.; Drug resistance.
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
James, C. (2009). ABC transport proteins and drug resistance in nematodes. (Thesis). University of Technology, Sydney. Retrieved from http://hdl.handle.net/10453/30176
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
James, CE. “ABC transport proteins and drug resistance in nematodes.” 2009. Thesis, University of Technology, Sydney. Accessed October 23, 2019.
http://hdl.handle.net/10453/30176.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
James, CE. “ABC transport proteins and drug resistance in nematodes.” 2009. Web. 23 Oct 2019.
Vancouver:
James C. ABC transport proteins and drug resistance in nematodes. [Internet] [Thesis]. University of Technology, Sydney; 2009. [cited 2019 Oct 23].
Available from: http://hdl.handle.net/10453/30176.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
James C. ABC transport proteins and drug resistance in nematodes. [Thesis]. University of Technology, Sydney; 2009. Available from: http://hdl.handle.net/10453/30176
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Stellenbosch University
4.
Fouche, Desire.
Drug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients.
Degree: MScMedSc, Medicine, 2012, Stellenbosch University
URL: http://hdl.handle.net/10019.1/20079
► ENGLISH ABSTRACT: Background: HIV-positive patients have a significantly weakened immune system which makes them highly susceptible for opportunistic infections, requiring additional treatment. Cryptococcal meningitis and…
(more)
▼ ENGLISH ABSTRACT: Background: HIV-positive patients have a significantly weakened immune system which
makes them highly susceptible for opportunistic infections, requiring additional treatment.
Cryptococcal meningitis and oropharyngeal candidiasis are treated with oral fluconazole. A
great potential for
drug-drug interactions (DDIs) between fluconazole and antiretrovirals
(ARVs), efavirenz, nevirapine, and lopinavir/ritonavir, exists due to interference in common
metabolic pathways. The outcome may result in the development of adverse
drug reactions
or
drug resistance and treatment failure.
Aim: The primary aim of this thesis was to evaluate the effect of fluconazole on the
pharmacokinetics of efavirenz, nevirapine and lopinavir/ritonavir in HIV-infected patients
diagnosed with cryptococcal meningitis or oropharyngeal candidiasis.
Methods: A prospective study was conducted in 80 HIV-positive, treatment experienced
adults (≥18 years old) treated in three different outpatient clinics in the Western Cape region.
Patients were subdivided according to ARV regimen and the use of fluconazole. A sparse
sampling design was used and corresponding ARV serum concentrations were determined by
established HPLC and GC methods. Fluconazole serum concentrations were determined by a
newly developed HPLC method. Patient characteristics, concomitant medications, clinical
test data and ARV serum concentrations were included in a NONMEM generated, onecompartment,
open pharmacometric model with first order elimination to detect any drugdrug
interactions between fluconazole and the studied ARVs. The secondary outcome was to
establish which patient characteristics influence ARV pharmacokinetics.
Results: From 80 outpatients, a total of 276 ARV serum samples (137 efavirenz, 67
nevirapine and 72 lopinavir) were collected for pharmacokinetic evaluation. Efavirenz
clearance was correlated with race and concomitant use of rifampicin. No significant
covariates were established in the nevirapine model. In the lopinavir model, concomitant use
of clotrimazole and the antituberculosis combination isoniazid, pyrazinamide and rifampicin
were identified as significant covariates.
Discussion: No significant effects of fluconazole on the pharmacokinetics of any of the
studied ARVs were observed. Varying efavirenz plasma concentrations in different ethnic
populations may be due to differences in gene expression particularly CYP2B6. Coloured patients had significantly lower efavirenz serum concentrations (56.8% decrease in
clearance), which has not been previously described in the South African context. Although
gender was not a significant covariate in the nevirapine model, female patients tended to have
higher nevirapine serum concentrations. TB treatment in all patients receiving lopinavir
consisted of a combination of isoniazid, pyrazinamide and rifampicin, each with different
effects on CYP isoenzymes. The exact contributing factor of each
drug in the ultimate
decrease in lopinavir clearance (46.4%) can therefore not…
Advisors/Committee Members: Rosenkranz, Bernd, Stellenbosch University. Faculty of Health Sciences. Dept. of Medicine. Pharmacology..
Subjects/Keywords: Pharmacology; Drug resistance
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Fouche, D. (2012). Drug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients. (Masters Thesis). Stellenbosch University. Retrieved from http://hdl.handle.net/10019.1/20079
Chicago Manual of Style (16th Edition):
Fouche, Desire. “Drug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients.” 2012. Masters Thesis, Stellenbosch University. Accessed October 23, 2019.
http://hdl.handle.net/10019.1/20079.
MLA Handbook (7th Edition):
Fouche, Desire. “Drug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients.” 2012. Web. 23 Oct 2019.
Vancouver:
Fouche D. Drug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients. [Internet] [Masters thesis]. Stellenbosch University; 2012. [cited 2019 Oct 23].
Available from: http://hdl.handle.net/10019.1/20079.
Council of Science Editors:
Fouche D. Drug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients. [Masters Thesis]. Stellenbosch University; 2012. Available from: http://hdl.handle.net/10019.1/20079
University of Notre Dame
5.
Mark Aaron Wacker.
Impacts of Drug Resistance on the Fitness and Metabolism of
Plasmodium falciparum</h1>.
Degree: PhD, Biological Sciences, 2011, University of Notre Dame
URL: https://curate.nd.edu/show/9880vq30153
► Malaria effects nearly a quarter of a billion people each year. Efforts to control the disease have been hampered by the development of drug…
(more)
▼ Malaria effects nearly a quarter of a billion
people each year. Efforts to control the disease have been hampered
by the development of
drug resistance in the Plasmodium parasite.
This history of
drug selections on the parasite have shaped its
genome, enhancing
drug resistance and compensating for fitness
costs associated with the
resistance phenotype.
The reshaping of
drug resistant parasite genomes
will constrain loci particularly important to parasite fitness.
Consistent with the hypothesis that the genome of the
drug
resistant Dd2 parent has been fined tuned to compensate for the
effects of
drug resistantce we found that parental allele
combinations were found at a greater frequency in the progeny of a
genetic cross. Growth dynamics of individual
parasite clones in mixed infections were further investigated
through the development of a quantitative competition assay that
allowed for precise quantitifiation of growth dynamics,
specifically the absolute quantification of each parasite within a
multiclonal infection. In a mixed infection consisting of
drug
sensitive and
drug resistant parasites the application of
drug
pressure leads to the competitive release of the
drug resistant
parasite. Impact of
drug selection on parasite
physiology was investigated by coupling global metabolite analysis
and QTL mapping. We propose that the endogenous function of pfcrt
is the transport of these small peptides from the digestive vacuole
of the parasite to cytoplasm. Knowledge of the endogenous fuction
of pfcrt is necessary to begin to understand how
drug resistant
parasites may have adapted to compensate for any fitness costs
associated with
resistance mutations. The
compiliation of this work strongly supports the existence of, and
identifies key molecular components of, the relationship between
past
drug selection bottlenecks and growth/fitness traits. These
compensatory changes could play critical roles in the origin,
persistence and spread of
drug resistant parasite populations that
have been argued to be more virulent and prone to rapid
resistance
to new drugs. Knowledge of these pathways and mechanisms will also
reveal new
drug targets, unique to
drug resistant parasites, and
could facilitate the rational design of
drug combinations to thwart
the ever-emerging scourge of multi-
drug resistant
malaria.
Advisors/Committee Members: Dave Severson, Committee Member, Jeff Feder, Committee Member, Mary Ann McDowell, Committee Member, Mike Ferdig, Committee Chair.
Subjects/Keywords: malaria; drug resistance
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Wacker, M. A. (2011). Impacts of Drug Resistance on the Fitness and Metabolism of
Plasmodium falciparum</h1>. (Doctoral Dissertation). University of Notre Dame. Retrieved from https://curate.nd.edu/show/9880vq30153
Chicago Manual of Style (16th Edition):
Wacker, Mark Aaron. “Impacts of Drug Resistance on the Fitness and Metabolism of
Plasmodium falciparum</h1>.” 2011. Doctoral Dissertation, University of Notre Dame. Accessed October 23, 2019.
https://curate.nd.edu/show/9880vq30153.
MLA Handbook (7th Edition):
Wacker, Mark Aaron. “Impacts of Drug Resistance on the Fitness and Metabolism of
Plasmodium falciparum</h1>.” 2011. Web. 23 Oct 2019.
Vancouver:
Wacker MA. Impacts of Drug Resistance on the Fitness and Metabolism of
Plasmodium falciparum</h1>. [Internet] [Doctoral dissertation]. University of Notre Dame; 2011. [cited 2019 Oct 23].
Available from: https://curate.nd.edu/show/9880vq30153.
Council of Science Editors:
Wacker MA. Impacts of Drug Resistance on the Fitness and Metabolism of
Plasmodium falciparum</h1>. [Doctoral Dissertation]. University of Notre Dame; 2011. Available from: https://curate.nd.edu/show/9880vq30153
Queens University
6.
McClure, Nathan.
Assessing strategies for managing drug resistance in treatment of infectious disease: insights from queueing theory
.
Degree: Biology, 2013, Queens University
URL: http://hdl.handle.net/1974/8099
► Antimicrobials have been instrumental in the treatment of infectious disease: responsible for worldwide infection control and reductions in disease-induced morbidity, and mortality. However, in every…
(more)
▼ Antimicrobials have been instrumental in the treatment of infectious disease: responsible for worldwide infection control and reductions in disease-induced morbidity, and mortality. However, in every case where new chemotherapeutic agents have been introduced, resistance to them has eventually evolved. Principally, the current strategy for dealing with this problem is to invest heavily in drug development, with the hope that new drugs become available before all existing drugs lose their efficacy. Instead of focusing on the ‘development side’ of the problem, another possible strategy is to invest in methods of slowing evolution of resistance.
We use a novel application of queueing theory to demonstrate that, when comparing equivalent changes in drug development versus evolution management, the latter has a much greater effect on ensuring a continued supply of effective antimicrobial agents. Our results therefore call for a reappraisal of the current emphasis on enhancing drug development as a means of managing resistance.
Subjects/Keywords: drug resistance;
evolution
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
McClure, N. (2013). Assessing strategies for managing drug resistance in treatment of infectious disease: insights from queueing theory
. (Thesis). Queens University. Retrieved from http://hdl.handle.net/1974/8099
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
McClure, Nathan. “Assessing strategies for managing drug resistance in treatment of infectious disease: insights from queueing theory
.” 2013. Thesis, Queens University. Accessed October 23, 2019.
http://hdl.handle.net/1974/8099.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
McClure, Nathan. “Assessing strategies for managing drug resistance in treatment of infectious disease: insights from queueing theory
.” 2013. Web. 23 Oct 2019.
Vancouver:
McClure N. Assessing strategies for managing drug resistance in treatment of infectious disease: insights from queueing theory
. [Internet] [Thesis]. Queens University; 2013. [cited 2019 Oct 23].
Available from: http://hdl.handle.net/1974/8099.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
McClure N. Assessing strategies for managing drug resistance in treatment of infectious disease: insights from queueing theory
. [Thesis]. Queens University; 2013. Available from: http://hdl.handle.net/1974/8099
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Addis Ababa University
7.
Ahmed, Esmael.
Drug resistance pattern of Mycobacterium tuberculosis and its association with patients` Knowledge, Attitude and Practice towards tuberculosis in Eastern Amhara Region
.
Degree: 2012, Addis Ababa University
URL: http://etd.aau.edu.et/dspace/handle/123456789/3214
► Background: Tuberculosis (TB) remains a serious public health problem, worsened by the emergence and spread of drug resistance particularly multi-drug resistance that threat global TB…
(more)
▼ Background: Tuberculosis (TB) remains a serious public health problem, worsened by the
emergence and spread of
drug resistance particularly multi-
drug resistance that threat global TB
control. Data obtained from KAP survey is essential to plan, implement and evaluate Advocacy,
Communication and Social Mobilization (ACSM) work.
Objectives: The aim of this study was to assess the magnitude of
drug resistance pattern of
M.tuberculosis, knowledge, perception and practice of patients` towards TB in Eastern Amhara
Region, North East Ethiopia.
Methods: A cross sectional survey was conducted among new and re-treatment patients (age >
18 years old) from September 2010 to February 2011. A structure and pre-validate
questionnaires was used to collect data. Primary isolation and DST were carried out on egg based
LJ media using indirect proportion method. Chi-Square and multivariate logistic regression was
used.
Results: Out of 230 study participants for DST, 165 were new cases while 65 were previously
treated cases. From these, 66.5% of isolates were sensitive and 4.4%
resistance to four first line
anti-tuberculosis drugs (HRSE) while the remaining 33.5% was
resistance to at least for single
drug. MDR-TB was detected in 6.5 % isolates, of which 4.4% were
resistance to all four first
line drugs. Overall
resistance to S, R, H and E was found in 27 % (62), 10 % (23), 17.8 % (41),
and 6.5 % (15) respectively. Mono
resistance was found in 17.4 % (40) of all isolates
Among new cases primary
drug resistance for one or more drugs was observed in 23.6 % (39)
cases. Primary MDR-TB was found in 3 (1.81%) cases. Similarly among previously treated cases
resistance to any
drug was found in 58.5 % (38) cases. MDR-TB in previously treated cases was
found in 18.46 % (12) Cases; the highest being in failure cases 9.23% (6).
More over the mean and median knowledge score of respondents about PTB was 6.81 and 7
respectively. Majority (53.6%) of study subjects had poor knowledge score, feels not well
informed about TB and had several misconceptions that need to be clarified. Majority (66.6%) of
xv
study subjects heard about TB for the first time from health workers. Of study participants,
79.9% mentioned that TB transmits by respiratory droplets through coughing and sneezing and
prevents by covering mouth and nose (66.6%). The four common symptoms mentioned by
respondents were cough (65.6%), weight loss (33.2%), cough > = 2 weeks (32.7%) and shortness
of breath (29.4%). About half of respondent not knew current free cost of TB diagnosis and
treatment. Majority of respondents also worried about the disease due to it might transmits to
their family, might not be cure, social interact (fear of stigma) and unable to do work. Cost (69.9
%) and difficulties in transportation (54.5 %) mentioned as the main reason for their delaines to
seeking care.
Previous
drug exposure and 1+ bacterial load independently contribute for the development of
drug resistance TB strains. Similarly Illiteracy, rural residence, non-previous history of
contracting TB, experiencing…
Advisors/Committee Members: Mr. Kassue Desta (BSc, MSc (advisor).
Subjects/Keywords: Mycobacterium tuberculosis;
Drug resistance
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Ahmed, E. (2012). Drug resistance pattern of Mycobacterium tuberculosis and its association with patients` Knowledge, Attitude and Practice towards tuberculosis in Eastern Amhara Region
. (Thesis). Addis Ababa University. Retrieved from http://etd.aau.edu.et/dspace/handle/123456789/3214
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Ahmed, Esmael. “Drug resistance pattern of Mycobacterium tuberculosis and its association with patients` Knowledge, Attitude and Practice towards tuberculosis in Eastern Amhara Region
.” 2012. Thesis, Addis Ababa University. Accessed October 23, 2019.
http://etd.aau.edu.et/dspace/handle/123456789/3214.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Ahmed, Esmael. “Drug resistance pattern of Mycobacterium tuberculosis and its association with patients` Knowledge, Attitude and Practice towards tuberculosis in Eastern Amhara Region
.” 2012. Web. 23 Oct 2019.
Vancouver:
Ahmed E. Drug resistance pattern of Mycobacterium tuberculosis and its association with patients` Knowledge, Attitude and Practice towards tuberculosis in Eastern Amhara Region
. [Internet] [Thesis]. Addis Ababa University; 2012. [cited 2019 Oct 23].
Available from: http://etd.aau.edu.et/dspace/handle/123456789/3214.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Ahmed E. Drug resistance pattern of Mycobacterium tuberculosis and its association with patients` Knowledge, Attitude and Practice towards tuberculosis in Eastern Amhara Region
. [Thesis]. Addis Ababa University; 2012. Available from: http://etd.aau.edu.et/dspace/handle/123456789/3214
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Addis Ababa University
8.
BERHAN, MENGISTE.
ANTIPLASMODIAL ACTIVITY OF EXTRACTS FROM DODONAEA ANGUSTIFOLIA L.F. AND BERSAMA ABYSSINICA FRESEN AGAINST PLASMODIUM BERGHEI IN MICE MODEL
.
Degree: 2008, Addis Ababa University
URL: http://etd.aau.edu.et/dspace/handle/123456789/6503
► The seed of Dodonaea angustifolia and root bark of Bersama abyssinica are traditionally used for the treatment/prophylaxis of malaria in some malarous areas in Ethiopia.…
(more)
▼ The seed of Dodonaea angustifolia and root bark of Bersama abyssinica are traditionally used for the treatment/prophylaxis of malaria in some malarous areas in Ethiopia. The aim of this study is to evaluate antiplasmodial activity and study acute toxicity of Dodonaea angustifolia and Bersama abyssinica in P. berghei infected mice. In the present study, aqueous and methanol extracts of D. angustifolia and B. abyssinica were investigated for their antimalarial activity using Peters’ 4-day suppressive test against P. berghei infection in mice. The crude extracts and the fractions of the most active extract were orally administered to screen their antimalarial properties. The extracts significantly inhibited parasitemia and prevented PCV fall (p <0.05) dose-dependently. They increased the survival time of the infected mice. However, the extracts from both plants did not prevent body weight loss. The aqueous extract of D. angustifolia was found to be most active producing 35.79% chemosuppression. From this extract, three fractions were produced and tested in vivo against P. berghei in mice. The butanol fraction was found to be the most active producing percentage inhibition of 48.6% at 100 mg/kg. This fraction was also found to prevent PCV, body weight and temperature reduction significantly. The test substances showed only low toxicity (LD50=5044 mg/kg for B. abyssinica and no mortality for D. angustifolia up to 4500 mg/kg). The results obtained from the present work support the traditional use of these plants for treatment of malaria. Key words: Malaria, Drug resistance, Dodonaea angustifolia, Bersama abyssinica, Plasmodium berghei and
Subjects/Keywords: Malaria; Drug resistance; Dodonaea angustifolia
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
BERHAN, M. (2008). ANTIPLASMODIAL ACTIVITY OF EXTRACTS FROM DODONAEA ANGUSTIFOLIA L.F. AND BERSAMA ABYSSINICA FRESEN AGAINST PLASMODIUM BERGHEI IN MICE MODEL
. (Thesis). Addis Ababa University. Retrieved from http://etd.aau.edu.et/dspace/handle/123456789/6503
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
BERHAN, MENGISTE. “ANTIPLASMODIAL ACTIVITY OF EXTRACTS FROM DODONAEA ANGUSTIFOLIA L.F. AND BERSAMA ABYSSINICA FRESEN AGAINST PLASMODIUM BERGHEI IN MICE MODEL
.” 2008. Thesis, Addis Ababa University. Accessed October 23, 2019.
http://etd.aau.edu.et/dspace/handle/123456789/6503.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
BERHAN, MENGISTE. “ANTIPLASMODIAL ACTIVITY OF EXTRACTS FROM DODONAEA ANGUSTIFOLIA L.F. AND BERSAMA ABYSSINICA FRESEN AGAINST PLASMODIUM BERGHEI IN MICE MODEL
.” 2008. Web. 23 Oct 2019.
Vancouver:
BERHAN M. ANTIPLASMODIAL ACTIVITY OF EXTRACTS FROM DODONAEA ANGUSTIFOLIA L.F. AND BERSAMA ABYSSINICA FRESEN AGAINST PLASMODIUM BERGHEI IN MICE MODEL
. [Internet] [Thesis]. Addis Ababa University; 2008. [cited 2019 Oct 23].
Available from: http://etd.aau.edu.et/dspace/handle/123456789/6503.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
BERHAN M. ANTIPLASMODIAL ACTIVITY OF EXTRACTS FROM DODONAEA ANGUSTIFOLIA L.F. AND BERSAMA ABYSSINICA FRESEN AGAINST PLASMODIUM BERGHEI IN MICE MODEL
. [Thesis]. Addis Ababa University; 2008. Available from: http://etd.aau.edu.et/dspace/handle/123456789/6503
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Ottawa
9.
Camellato, Brendan.
Gene Regulatory Networks are a Mechanism for Drug Resistance
.
Degree: 2018, University of Ottawa
URL: http://hdl.handle.net/10393/37099
► Multidrug resistance has become a major issue in the treatment of both microbial infections and cancers. While genetically encoded drug resistance is fairly well understood,…
(more)
▼ Multidrug resistance has become a major issue in the treatment of both microbial infections and cancers. While genetically encoded drug resistance is fairly well understood, it cannot explain all observed cases of resistance, namely the ability of a subset of disease cells to persist in an otherwise susceptible population. This non-genetic resistance requires the heterogeneous expression of a drug resistance phenotype, which can be produced by certain gene regulatory network architectures. Two particular network motifs, the coherent feedforward loop (CFFL) and the positive feedback loop (PFL), have functional properties that implicate them in the development of non-genetic heterogeneity and response to changing conditions. Motivated by the observation that CFFL and PFL motifs are involved in the transcriptional regulation of multiple pleiotropic drug resistance (PDR) genes in yeast, it has been hypothesized that CFFLs and PFLs could contribute to the development of drug resistance. This hypothesis was based on model simulations and has not been tested experimentally. In this thesis, it is demonstrated experimentally that the PDR5 gene is indeed expressed heterogeneously within an isogenic population of yeast cells, and that this cell-to-cell variability enables a subset of cells to persist drug treatment. While these observations agree with model predictions, it is also observed that the resistant phenotype occurs within a subset of cells that are morphologically distinct. This subpopulation has previously been linked to abnormal mitochondrial function, which cannot be ruled out as a likely cause of the observed drug resistance. To validate the hypothesis that CFFLs and PFLs contribute to drug resistance, the expression of the PDR5 gene was placed under the control of synthetic gene regulatory networks constructed to contain different combinations of direct activation, indirect activation, and positive feedback. These networks are used to show that direct activation can provide a selective advantage enabling rapid responses, while indirect activation and positive feedback can provide a selective advantage by maintaining favourable gene expression states. These results demonstrate that a gene regulatory network combining CFFLs and PFLs can contribute to the development of drug resistance, and highlight plausible means by which cells can exploit certain network features to gain a fitness advantage.
Subjects/Keywords: Gene regulatory networks;
Drug resistance
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Camellato, B. (2018). Gene Regulatory Networks are a Mechanism for Drug Resistance
. (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/37099
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Camellato, Brendan. “Gene Regulatory Networks are a Mechanism for Drug Resistance
.” 2018. Thesis, University of Ottawa. Accessed October 23, 2019.
http://hdl.handle.net/10393/37099.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Camellato, Brendan. “Gene Regulatory Networks are a Mechanism for Drug Resistance
.” 2018. Web. 23 Oct 2019.
Vancouver:
Camellato B. Gene Regulatory Networks are a Mechanism for Drug Resistance
. [Internet] [Thesis]. University of Ottawa; 2018. [cited 2019 Oct 23].
Available from: http://hdl.handle.net/10393/37099.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Camellato B. Gene Regulatory Networks are a Mechanism for Drug Resistance
. [Thesis]. University of Ottawa; 2018. Available from: http://hdl.handle.net/10393/37099
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Hong Kong
10.
陳穎芊; Chan, Wing-tsin, Alison.
Comparative genotypic study of viral RNA and proviral DNA
in HIV-1 patients.
Degree: Master of Medical Sciences, 2015, University of Hong Kong
URL: Chan,
W.
A.
[陳穎芊].
(2015).
Comparative
genotypic
study
of
viral
RNA
and
proviral
DNA
in
HIV-1
patients.
(Thesis).
University
of
Hong
Kong,
Pokfulam,
Hong
Kong
SAR.
Retrieved
from
http://dx.doi.org/10.5353/th_b5616177
;
http://hdl.handle.net/10722/221510
► Highly Active Antiretroviral Therapy (HAART) has been used for HIV-1 treatment for more than a decade. Prior identification of drug resistance associated mutations and viral…
(more)
▼ Highly Active Antiretroviral Therapy (HAART) has
been used for HIV-1 treatment for more than a decade. Prior
identification of drug resistance associated mutations and viral
tropism provides valuable information for physicians in optimizing
the best HAART regimens for each patient. Plasma RNA has long been
used as the major laboratory marker as it reflects the status of
circulating virus. However, it might not be as informative in
patients with low viral loads. Proviral DNA was therefore suggested
as an additional maker for this purpose.
This project aimed to
compare the concordance of resistance interpretation and tropism
prediction between plasma RNA and proviral DNA. Peripheral blood
samples from 45 HIV-1 patients were collected by Integrated
Treatment Centre. Drug resistance mutations (DRMs) of Protease
Inhibitors (PIs), Nucleoside Analogue Reverse transcriptase
Inhibitors (NRTIs), Non- Nucleoside Analogue Reverse transcriptase
Inhibitors (NNRTIs) and Integrase Inhibitors (INIs), and viral
tropism were identified with bi-directional Sanger sequencing and
interpreted with Stanford HIVdB and Geno2Phenocoreceptor,
respectively.
The DRMs identified from plasma RNA and proviral
DNA had high concordances among PIs (83.3%), NRTIs (100%), NNRTIs
(83.3%) and INIs (91.7%). Major PI mutations were more frequently
detected by proviral DNA. In contrast, more NNRTI and accessory INI
mutations were detected in plasma RNA. The concordance was lower in
HIV-1 tropism test (73.7%). In general, proviral DNA identified
more non-R5 variants than plasma RNA. Ten discordant cases were
only found in subtype B and CRF01_AE and were mainly contributed by
cases (6 out of 10) with R5 tropic variants detected in plasma RNA
and non-R5 tropic variants detected in proviral DNA (R5/non-R5).
False positive rate (FPR) values obtained were compared and found
high concordance that correlation coefficient r equals to 0.83.
In conclusion, proviral DNA and plasma RNA were highly concordant
in DRMs interpretation. Since mutations exclusively detected in
each genotype, proviral DNA was suggested to be used as a
supplementary source of DRMs detection. Frequent non-R5 variant
detection in proviral DNA could discourage usage of CCR5
antagonists. Before clinical relevance of proviral DNA tropism is
validated, plasma RNA tropism identification was
preferred.
published_or_final_version
Microbiology
Master
Master of Medical Sciences
Subjects/Keywords: Drug resistance; HIV (Viruses)
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
陳穎芊; Chan, Wing-tsin, A. (2015). Comparative genotypic study of viral RNA and proviral DNA
in HIV-1 patients. (Masters Thesis). University of Hong Kong. Retrieved from Chan, W. A. [陳穎芊]. (2015). Comparative genotypic study of viral RNA and proviral DNA in HIV-1 patients. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5616177 ; http://hdl.handle.net/10722/221510
Chicago Manual of Style (16th Edition):
陳穎芊; Chan, Wing-tsin, Alison. “Comparative genotypic study of viral RNA and proviral DNA
in HIV-1 patients.” 2015. Masters Thesis, University of Hong Kong. Accessed October 23, 2019.
Chan, W. A. [陳穎芊]. (2015). Comparative genotypic study of viral RNA and proviral DNA in HIV-1 patients. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5616177 ; http://hdl.handle.net/10722/221510.
MLA Handbook (7th Edition):
陳穎芊; Chan, Wing-tsin, Alison. “Comparative genotypic study of viral RNA and proviral DNA
in HIV-1 patients.” 2015. Web. 23 Oct 2019.
Vancouver:
陳穎芊; Chan, Wing-tsin A. Comparative genotypic study of viral RNA and proviral DNA
in HIV-1 patients. [Internet] [Masters thesis]. University of Hong Kong; 2015. [cited 2019 Oct 23].
Available from: Chan, W. A. [陳穎芊]. (2015). Comparative genotypic study of viral RNA and proviral DNA in HIV-1 patients. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5616177 ; http://hdl.handle.net/10722/221510.
Council of Science Editors:
陳穎芊; Chan, Wing-tsin A. Comparative genotypic study of viral RNA and proviral DNA
in HIV-1 patients. [Masters Thesis]. University of Hong Kong; 2015. Available from: Chan, W. A. [陳穎芊]. (2015). Comparative genotypic study of viral RNA and proviral DNA in HIV-1 patients. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5616177 ; http://hdl.handle.net/10722/221510
University of Illinois – Chicago
11.
Logan, Latania K.
Resistance Determinants and Factors associated with Multi-drug Resistant Enterobacteriaceae in Children.
Degree: 2017, University of Illinois – Chicago
URL: http://hdl.handle.net/10027/22220
► Background: National studies have found an increase in multi-drug resistant (MDR) Enterobacteriaceae (Ent) infections in children over the last decade; however, there is a paucity…
(more)
▼ Background: National studies have found an increase in multi-
drug resistant (MDR) Enterobacteriaceae (Ent) infections in children over the last decade; however, there is a paucity of literature on the antibiotic
resistance determinants associated with these increases, and, regarding the children most impacted by these dangerous pathogens.
Objectives: 1) To determine the genetic basis of extended-spectrum beta-lactam (ESBL), carbapenem, and fluoroquinolone
resistance (FQR) phenotypes in Enterobacteriaceae isolates from children cared for by multiple centers in the Chicago area; 2) To identify which exposures and host factors serve as predictors of infection within dominant genotypes of resistant Enterobacteriaceae recovered from children from multiple centers.
Methods: Objective 1: A retrospective cohort study of 276 GNB isolates from unique patients, phenotypically identified as beta-lactamases producers, was performed. Isolates from 5 Chicago hospitals were recovered from children ages 0-18 years hospitalized between 2011- 2015. DNA microarray (Check-Points™) was used to query the genetic background associated with beta-lactam
resistance. Determinants of quinolone
resistance (e.g., QRDR and PMFQR) were investigated. Objective 2: A case-control study of children cared for by 3 Chicago area hospitals during 2011-14 was performed. Cases were 53 children diagnosed with PMFQR containing beta-lactam resistant isolates. Controls were 131 children with antibiotic susceptible Ent infections matched by hospital, age and source. Demographics; comorbidities; device, antibiotic, and healthcare exposures; and the impact of location of patient residence were evaluated. Race categories were white, black, Hispanic, and other. Multivariable logistic regression was used to explore associations between predictors and PMFQR infection. Data were analyzed in SAS 9.4.
Results: Median age was 4.8 years, 59% were female, and 46% were outpatients. Most isolates (69%) were from urine. E. coli (62%) was most frequently recovered; and of 272 bla genes detected, the most common was blaCTX-M-1 (49%); 1.9% were CRE (4- blaKPC and 1- blaIMP-13). PMFQR was found in 56/82 (66%) and associated with QRDR mutations in 84% of cases. Overall, pAmpC were found in 12% (34/276). The blaKPC harboring K. pneumoniae were mainly non-ST258 strains, which differs from adults.
Children with PMFQR Ent infections were more likely to be diagnosed in an outpatient clinic (OR 33.1; CI 7.1, 154.7) and of race “other” (OR 6.5; CI 1.9, 22.2). Residents of Southwest Chicago were 5 times more likely to have a PMFQR Ent infection than those residing in other regions (OR 5.3; CI 1.8, 15.2); while residence in Central Chicago was associated with a 97% decreased risk (OR 0.03; CI 0.002, 0.3). Significant differences in other demographics; comorbidities; invasive devices; antibiotic use; or recent healthcare were not found.
Conclusions: Complex bla genotypes were responsible for the beta-lactam resistant phenotypes in children. Transmissible plasmid mediated
resistance may be…
Advisors/Committee Members: Hershow, Ronald (advisor).
Subjects/Keywords: Children; Microbial Drug Resistance
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Logan, L. K. (2017). Resistance Determinants and Factors associated with Multi-drug Resistant Enterobacteriaceae in Children. (Thesis). University of Illinois – Chicago. Retrieved from http://hdl.handle.net/10027/22220
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Logan, Latania K. “Resistance Determinants and Factors associated with Multi-drug Resistant Enterobacteriaceae in Children.” 2017. Thesis, University of Illinois – Chicago. Accessed October 23, 2019.
http://hdl.handle.net/10027/22220.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Logan, Latania K. “Resistance Determinants and Factors associated with Multi-drug Resistant Enterobacteriaceae in Children.” 2017. Web. 23 Oct 2019.
Vancouver:
Logan LK. Resistance Determinants and Factors associated with Multi-drug Resistant Enterobacteriaceae in Children. [Internet] [Thesis]. University of Illinois – Chicago; 2017. [cited 2019 Oct 23].
Available from: http://hdl.handle.net/10027/22220.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Logan LK. Resistance Determinants and Factors associated with Multi-drug Resistant Enterobacteriaceae in Children. [Thesis]. University of Illinois – Chicago; 2017. Available from: http://hdl.handle.net/10027/22220
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Montana State University
12.
Eby, Anne Kathryn.
Factors affecting medical-surgical area nurses' compliance with contact precautions.
Degree: College of Nursing, 2009, Montana State University
URL: https://scholarworks.montana.edu/xmlui/handle/1/1217
► Multidrug-resistant organisms are a significant threat in health care facilities, and are associated with many adverse consequences for infected patients. However, despite these concerns and…
(more)
▼ Multidrug-resistant organisms are a significant threat in health care facilities, and are associated with many adverse consequences for infected patients. However, despite these concerns and the evidence that contact precautions are an effective way to address them, compliance with contact precautions guidelines among health care workers remains low (Farr, 2000). The primary goal of this study was to examine factors affecting medical-surgical nurses' compliance with contact precautions guidelines when caring for patients colonized by or infected with multidrug-resistant organisms. A secondary purpose of this study was to describe demographic characteristics of medical-surgical nurses to determine if certain characteristics (e.g. age, time in practice, level of education) had a relationship with their compliance in using contact precautions guidelines. Finally, this study examined barriers to the use of contact precautions and consequences for failure to follow contact precautions guidelines. A survey tool was developed by the researcher for this study to examine these questions, and an exploratory, cross-sectional, correlation descriptive study was conducted. The study group was made up primarily of female nurses with associate or bachelor degrees. Nurses from the orthopedic and neurosurgery unit made up the largest percentage of respondents. All respondents indicated that they were familiar with CP guidelines. Eight primary barriers to the use of contact precautions were listed by participants. Half of the participants listed one of the time management categories ("no time" or "urgency") as the primary barrier to compliance with contact precautions. Participants' age, years experience and level of education were not statistically significant predictors of the participants' level of compliance. There was not a statistically significant difference between the barriers to compliance groups (no time/urgency versus other) on their ability to comply with contact precautions. Lastly, there was not a statistically significant relationship among the primary consequence of non-compliance with CP guidelines (medical versus other) and the participants' level of compliance (low versus high).
Advisors/Committee Members: Chairperson, Graduate Committee: Christina Sieloff. (advisor).
Subjects/Keywords: Nurses.; Drug resistance in microorganisms.
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Eby, A. K. (2009). Factors affecting medical-surgical area nurses' compliance with contact precautions. (Thesis). Montana State University. Retrieved from https://scholarworks.montana.edu/xmlui/handle/1/1217
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Eby, Anne Kathryn. “Factors affecting medical-surgical area nurses' compliance with contact precautions.” 2009. Thesis, Montana State University. Accessed October 23, 2019.
https://scholarworks.montana.edu/xmlui/handle/1/1217.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Eby, Anne Kathryn. “Factors affecting medical-surgical area nurses' compliance with contact precautions.” 2009. Web. 23 Oct 2019.
Vancouver:
Eby AK. Factors affecting medical-surgical area nurses' compliance with contact precautions. [Internet] [Thesis]. Montana State University; 2009. [cited 2019 Oct 23].
Available from: https://scholarworks.montana.edu/xmlui/handle/1/1217.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Eby AK. Factors affecting medical-surgical area nurses' compliance with contact precautions. [Thesis]. Montana State University; 2009. Available from: https://scholarworks.montana.edu/xmlui/handle/1/1217
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Massey University
13.
Omar, Sharina.
Molecular epidemiology of Salmonella typhimurium DT160 in New Zealand.
Degree: Master of Veterinary Studies, Public Health, 2010, Massey University
URL: http://hdl.handle.net/10179/2681
► Salmonellosis is a zoonotic bacterial disease of national and international importance. In New Zealand (NZ), the most common foodborne notifiable disease is campylobacteriosis, which is…
(more)
▼ Salmonellosis is a zoonotic bacterial disease of national and international importance. In New Zealand (NZ), the most common foodborne notifiable disease is campylobacteriosis, which is followed by salmonellosis. In 1998, Salmonella enterica subsp. enterica serotype Typhimurium Definitive Type 160 (DT160) was identified in NZ. Since first reported, S. Typhimurium DT160 has caused several epidemics in the country but has not produced significant illness worldwide.
Therefore, the objectives of the project were to investigate the molecular epidemiology of S. Typhimurium DT160 and the association between isolates from human and animal origin. Ninety Salmonella isolates obtained in the period between 1999 and 2009 from the Institute of Environmental Science and Research, NZ were assessed for colony morphology, serotype, susceptibility to 11 antimicrobials, virulotyped using Polymerase Chain Reaction (PCR) and the Pulsed Field Gel Electrophoresis (PFGE) patterns were also determined. In addition, 4 isolates were further assessed with Triple Sugar Agar, API20E biochemical and motility tests.
All 90 isolates were confirmed as Salmonella spp. with no indications for resistance to multiple antimicrobials. All isolates were susceptible to the antimicrobials used in this study with the exception of 26 and 8 isolates that had intermediate susceptibility against tetracycline and oxytetracycline, respectively. In an attempt to discriminate between potentially pathogenic and pathogenic Salmonella isolates, PCR-based virulotyping was performed based on 12 potential virulence genes. Results revealed that all isolates were positive for at least 10 of the 12 virulence genes. Two of the six isolates negative for one of the virulence genes (invA, iroN, pefA or sifA) were of human origin and the remaining four were sparrow
isolates. The PFGE patterns determined with restriction enzymes XbaI and SpeI demonstrated that the genotype profile AA1 accounted for 78/90 (86.7%) of the isolates, whilst the second most common profile, AA2, was found in only three isolates (3.3%), comprising two isolates from sparrows and one from a human. The remaining nine profiles were found in single isolates. All isolates of AA2 profile were PCR negative for sifA.
In conclusion, no obvious correlation was observed between the phenol- and geno-type and the isolates, year and month of isolation, and source of the samples. There was no obvious evidence for multidrug resistance among DT160 isolates. The PFGE and virulotyping profiles suggest close relation among majority of isolates with predominant and epidemiologically important genotype persistent in multiple hosts. Finally, the few genotypes with low prevalence in multiple hosts may indicate emergence of sporadic genomic variants in the population.
Subjects/Keywords: Salmonellosis;
Zoonoses;
Drug resistance
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Omar, S. (2010). Molecular epidemiology of Salmonella typhimurium DT160 in New Zealand. (Masters Thesis). Massey University. Retrieved from http://hdl.handle.net/10179/2681
Chicago Manual of Style (16th Edition):
Omar, Sharina. “Molecular epidemiology of Salmonella typhimurium DT160 in New Zealand.” 2010. Masters Thesis, Massey University. Accessed October 23, 2019.
http://hdl.handle.net/10179/2681.
MLA Handbook (7th Edition):
Omar, Sharina. “Molecular epidemiology of Salmonella typhimurium DT160 in New Zealand.” 2010. Web. 23 Oct 2019.
Vancouver:
Omar S. Molecular epidemiology of Salmonella typhimurium DT160 in New Zealand. [Internet] [Masters thesis]. Massey University; 2010. [cited 2019 Oct 23].
Available from: http://hdl.handle.net/10179/2681.
Council of Science Editors:
Omar S. Molecular epidemiology of Salmonella typhimurium DT160 in New Zealand. [Masters Thesis]. Massey University; 2010. Available from: http://hdl.handle.net/10179/2681
The Ohio State University
14.
Gibbs, Seth.
Microrna regulation of anthracycline drug resistance in
leukemia through MIR-221, MIR-222, MIR-26a, and MIR-21.
Degree: PhD, Pharmacy, 2008, The Ohio State University
URL: http://rave.ohiolink.edu/etdc/view?acc_num=osu1204309177
► Drug resistance takes many forms with P-gp-mediated efflux of chemotherapeutic drugs being one of the most common. Anthracyclines contain a sugar moiety important in…
(more)
▼ Drug resistance takes many forms with
P-gp-mediated efflux of chemotherapeutic drugs being one of the
most common. Anthracyclines contain a sugar moiety important in the
drug’s efficacy. These sugar moieties alter pharmacokinetic
profiles, target specificity, and
drug resistance. Through
modification of the sugar moiety we propose to overcome
P-gp-related
drug resistance and determine if alternative
drug
resistance forms exist. We created daunorubicin derivatives with
sugar structure alterations. Changing the amino group to an azido
group or conversion of a monosaccharide to a disaccharide made P-gp
binding less favorable. Modification changes the compound's
specificity during DNA interchelation which changes microRNA
expression. We identified two new analogs (ADNR, ADNR3) which avert
P-gp binding and overcome
resistance. These studies provide an
understanding of the critical sugar moiety elements of
anthracyclines, and provide a starting point for more effective
drug design. To study other mechanisms of
resistance in leukemia, doxorubicin, daunorubicin, ADNR, and ADNR3
were used to induce microRNA associated
drug resistance. We found
that 5-15 microRNAs were up-regulated by at least 1.5-fold, and
2-122 microRNAs were down-regulated by 2 to 4852-fold in the
resistant cells by doxorubicin, daunorubicin, ADNR, and ADNR3.
miR-221 and miR-222 were down-regulated by 2 to 15-fold in all four
resistant cells. miR-221 and miR-222 in these
drug-resistant cells
up-regulate 4 to 8-fold expression of Kit, a receptor tyrosine
kinase for cell survival. Transfection of miR-221 and miR-222 into
drug-resistant cells regained
drug sensitivity indicating that
down-regulation of miR-221 and miR-222 and subsequent up-regulation
of Kit provides a novel mechanism for
drug resistance in leukemia.
miR-26a was down-regulated by 1.49 to 3.60-fold
in doxorubicin and daunorubicin resistant K562 cells. miR-26a in
the two cell lines up-regulate the expression of cdk6 by 3.65 and
4.42-fold. The miR-26a/cdk6 regulation mechanism was confirmed
through transfection of miR-26a into resistant cells where cdk6
expression was knocked out, and
drug sensitivity restored. DOX and
DNR IC50 values decreased by 11.01-fold and 12.97-fold,
respectively, indicating that down-regulation of miR-26a and
subsequent up-regulation of cdk6 provides a novel mechanism for
drug resistance. miR-26a regulation of cdk6 allows for research
into cell cycle regulation by microRNA.
Anthracycline treatment up-regulates microRNA, including
miR-21 which was up-regulated by 2.51 to 6.51-fold in the resistant
cells. miR-21 is important due to its regulation PTEN, a tumor
suppressor. Up-regulation led to no PTEN expression in the
resistant cells. AntimiR-21 transfection reduced miR-21 levels
which unblocked PTEN translation. The IC50 values of doxorubicin,
daunorubicin, ADNR, and ADNR3 were reduced by 2.81 to 13.12-fold in
the resistant cell lines after antimir-21 transfection. This use of
antimir therapy will increase PTEN levels and reverse
drug
resistance in…
Advisors/Committee Members: Sun, Duxin (Advisor).
Subjects/Keywords: Pharmaceuticals; MicroRNA; Leukemia; Drug Resistance
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Gibbs, S. (2008). Microrna regulation of anthracycline drug resistance in
leukemia through MIR-221, MIR-222, MIR-26a, and MIR-21. (Doctoral Dissertation). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1204309177
Chicago Manual of Style (16th Edition):
Gibbs, Seth. “Microrna regulation of anthracycline drug resistance in
leukemia through MIR-221, MIR-222, MIR-26a, and MIR-21.” 2008. Doctoral Dissertation, The Ohio State University. Accessed October 23, 2019.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1204309177.
MLA Handbook (7th Edition):
Gibbs, Seth. “Microrna regulation of anthracycline drug resistance in
leukemia through MIR-221, MIR-222, MIR-26a, and MIR-21.” 2008. Web. 23 Oct 2019.
Vancouver:
Gibbs S. Microrna regulation of anthracycline drug resistance in
leukemia through MIR-221, MIR-222, MIR-26a, and MIR-21. [Internet] [Doctoral dissertation]. The Ohio State University; 2008. [cited 2019 Oct 23].
Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1204309177.
Council of Science Editors:
Gibbs S. Microrna regulation of anthracycline drug resistance in
leukemia through MIR-221, MIR-222, MIR-26a, and MIR-21. [Doctoral Dissertation]. The Ohio State University; 2008. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1204309177
University of Cambridge
15.
Cassidy, John.
Studying the Clonal Origins of Drug Resistance in Human Breast Cancers
.
Degree: 2019, University of Cambridge
URL: https://www.repository.cam.ac.uk/handle/1810/290759
► Despite remarkable advances in our understanding of the drivers of human malignancies, new targeted therapies often fail to show sufficient efficacy in clinical trials. Indeed,…
(more)
▼ Despite remarkable advances in our understanding of the drivers of human malignancies, new targeted therapies often fail to show sufficient efficacy in clinical trials. Indeed, the cost of bringing a new agent to market has risen substantially in the last several decades, fuelled partly by lack of efficacy in late phase clinical trials. Even in cases where a new agent is deemed 'successful', the development of resistance is often seen as inevitable and clinical responses can be fleeting. Typically, resistance to targeted therapies is thought to arise from pre-existing populations within the tumour, rather than from de novo evolution, yet few studies have experimentally tested this understanding. Indeed, recent reports in the literature have described epigenetically regulated drug tolerant populations within cancers, defined by cell-cycle regulation and/or quiescent repopulation dynamics, drug induced chromatin remodelling or differential transcription factor binding, that can be transient or permanent in nature. This thesis will outline experiments using high complexity molecular barcodes to trace the fate of individual cellular clones in the development of drug resistance. With this technique, cellular clones can be uncoupled from their genomic backgrounds, giving a new depth to our understanding of clonal selection in cancer. In particular, high complexity barcodes are used to identify a pre-existing tamoxifen resistant population in the MCF7 cell line. This resistance phenotype is then linked to the induction of embryonic transcription factor OCT4. Finally, we use our molecular barcoding technique to interrogate the repopulation dynamics of a breast cancer PDX model, supporting their use as complex model systems suitable for studying the origins and consequences of tumour heterogeneity.
Subjects/Keywords: Cancer;
drug resistance;
clonal tracing
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Cassidy, J. (2019). Studying the Clonal Origins of Drug Resistance in Human Breast Cancers
. (Thesis). University of Cambridge. Retrieved from https://www.repository.cam.ac.uk/handle/1810/290759
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Cassidy, John. “Studying the Clonal Origins of Drug Resistance in Human Breast Cancers
.” 2019. Thesis, University of Cambridge. Accessed October 23, 2019.
https://www.repository.cam.ac.uk/handle/1810/290759.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Cassidy, John. “Studying the Clonal Origins of Drug Resistance in Human Breast Cancers
.” 2019. Web. 23 Oct 2019.
Vancouver:
Cassidy J. Studying the Clonal Origins of Drug Resistance in Human Breast Cancers
. [Internet] [Thesis]. University of Cambridge; 2019. [cited 2019 Oct 23].
Available from: https://www.repository.cam.ac.uk/handle/1810/290759.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Cassidy J. Studying the Clonal Origins of Drug Resistance in Human Breast Cancers
. [Thesis]. University of Cambridge; 2019. Available from: https://www.repository.cam.ac.uk/handle/1810/290759
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Cambridge
16.
Lee, Liam Changwoo.
Functional identification of molecular oncotargets associated with the resistance to ALK inhibition in neuroblastoma via genome-wide CRISPR-Cas9 screens
.
Degree: 2017, University of Cambridge
URL: https://www.repository.cam.ac.uk/handle/1810/267921
► Recent whole-exome sequencing studies of hundreds of high-risk neuroblastoma (hNB) patients have identified Anaplastic Lymphoma Kinase (ALK) as the only directly ‘druggable’ target with a…
(more)
▼ Recent whole-exome sequencing studies of hundreds of high-risk neuroblastoma (hNB) patients have identified Anaplastic Lymphoma Kinase (ALK) as the only directly ‘druggable’ target with a significant mutation rate (9%). ALK is a receptor tyrosine kinase whose dysregulation has been implicated as the driver lesion in a variety of cancer types, including Non-Small Cell Lung Cancer (NSCLC) and various paediatric malignancies. As a kinase normally only expressed during early development in the foetal brain, ALK is an ideal therapeutic target and it has proven relatively simple to target therapeutically. However, resistance to ALK-targeted therapy, particularly in ALK+ NSCLC patients has frequently been observed.
The majority of the acquired resistance mechanisms noted in NSCLC patients rely on bypass signalling pathways, which are tissue-context dependent. To proactively identify and develop strategies to counter these varied yet expected resistance mechanisms in other ALK-driven tumours, we must gain a better insight of the bypass-track mechanism(s) in a tumour-specific manner. The present study aimed to functionally identify putative resistance mechanisms against ALK inhibitors via extensive CRISPR/Cas9-based genome-wide knockout (GeCKO) or overexpression screens (SAM) in the human neuroblastoma cell line, SHSY-5Y, to develop novel therapeutic strategies for ALK mutant NBs.
The GeCKO screen identified a total of 39 genes and miRNAs, and the SAM overexpression screen identified 25 genes that induce resistance to ALK inhibitors. These putative resistance-inducing candidates were then aligned with a publicly available expression dataset of hNB patients (n = 476) to identify those with prognostic significance (Kaplan-Meier event-free survival analysis), specifically those that are indicative of relapse risk. Furthermore, all candidates identified from the screen were individually validated in vitro. Two of the candidates, one from each of the knockout and overexpression screens, were further investigated.
Inhibition of hsa-miR-1304-5p, identified from GeCKO screen, induced resistance to ALK inhibitors. Interestingly, interference of has-miR-1304-5p, in the absence of ALK inhibitors, also enabled enhanced cell viability whilst the transfection of its mimic led to a significant reduction of viability across 17 distinct NB cell lines. Through genome-wide cDNA microarrays, in silico predictions, and UTR-luciferase assays, this study identified hsa-miR-1304-5p to be a major regulator of the Ras/MAP Kinase pathway.
Overexpression of PIM1, identified from the SAM screen, in NB cell lines induced resistance to ALK inhibitors and this phenotype could be reversed on transducing cells with RNAi against PIM1. Interestingly, inhibition of PIM1 in wild-type cell lines via RNAi or pharmacological compounds led to substantially enhanced potency of ALK inhibitors suggesting PIM1 inhibitors as combinatorial agents with ALK inhibitors for the therapy of treatment-naive hNB. Through protein analysis of all identified…
Subjects/Keywords: CRISPR;
ALK;
Drug-resistance;
Neuroblastoma
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Lee, L. C. (2017). Functional identification of molecular oncotargets associated with the resistance to ALK inhibition in neuroblastoma via genome-wide CRISPR-Cas9 screens
. (Thesis). University of Cambridge. Retrieved from https://www.repository.cam.ac.uk/handle/1810/267921
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Lee, Liam Changwoo. “Functional identification of molecular oncotargets associated with the resistance to ALK inhibition in neuroblastoma via genome-wide CRISPR-Cas9 screens
.” 2017. Thesis, University of Cambridge. Accessed October 23, 2019.
https://www.repository.cam.ac.uk/handle/1810/267921.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Lee, Liam Changwoo. “Functional identification of molecular oncotargets associated with the resistance to ALK inhibition in neuroblastoma via genome-wide CRISPR-Cas9 screens
.” 2017. Web. 23 Oct 2019.
Vancouver:
Lee LC. Functional identification of molecular oncotargets associated with the resistance to ALK inhibition in neuroblastoma via genome-wide CRISPR-Cas9 screens
. [Internet] [Thesis]. University of Cambridge; 2017. [cited 2019 Oct 23].
Available from: https://www.repository.cam.ac.uk/handle/1810/267921.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Lee LC. Functional identification of molecular oncotargets associated with the resistance to ALK inhibition in neuroblastoma via genome-wide CRISPR-Cas9 screens
. [Thesis]. University of Cambridge; 2017. Available from: https://www.repository.cam.ac.uk/handle/1810/267921
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Cambridge
17.
Bartlett, Sean.
Synthesis and antibacterial evaluation of diverse small molecules
.
Degree: 2017, University of Cambridge
URL: https://www.repository.cam.ac.uk/handle/1810/270198
► Hospital-acquired infections are the most frequent adverse event in healthcare delivery worldwide. Seven in ten hospital-acquired infections exhibit resistance to at least one antibiotic, and…
(more)
▼ Hospital-acquired infections are the most frequent adverse event in healthcare delivery worldwide. Seven in ten hospital-acquired infections exhibit resistance to at least one antibiotic, and three in five doctors have encountered an infection unresponsive to any treatment at all. This prolongs hospitalisation, increases suffering, and causes long-term disability and unnecessary death. At present the antibiotic pipeline is unable to meet the demand for novel antibiotics needed to treat these infections. Herein I discuss how the lack of new scaffolds, limitations of target-based screening, and poor target validation each contribute to the current bottleneck in the antibiotic pipeline. In turn, I argue that the development and application of chemical probes is a more fruitful way to make progress towards new antibiotics with novel mechanisms of action. This dissertation describes a combined chemical-biology study in the search for novel inhibitors of the human pathogens Pseudomonas aeruginosa and Staphylococcus aureus. First we extend organocatalysis to the field of diversity-oriented synthesis as a powerful means to generate molecular diversity and complexity in small molecule screening collections. We then study a family of potential biofilm inhibitors identified from a diverse screening collection, and for which we suggest a possible mode of action upon the quorum sensing receptors LasR and RhlR. Thereafter we provide evidence that a novel macrocycle, based upon the cylindrocyclophane family of natural products, inhibits methicillin-resistant S. aureus through action upon the respiratory chain. Finally, we also report insights into the structure and small molecule inhibition of a key P. aeruginosa drug target, malate synthase G. Together the findings in this dissertation encourage the development and application of divergent synthesis and unbiased screening methods in antibacterial discovery.
Subjects/Keywords: antibiotics;
drug resistance;
synthesis
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Bartlett, S. (2017). Synthesis and antibacterial evaluation of diverse small molecules
. (Thesis). University of Cambridge. Retrieved from https://www.repository.cam.ac.uk/handle/1810/270198
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Bartlett, Sean. “Synthesis and antibacterial evaluation of diverse small molecules
.” 2017. Thesis, University of Cambridge. Accessed October 23, 2019.
https://www.repository.cam.ac.uk/handle/1810/270198.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Bartlett, Sean. “Synthesis and antibacterial evaluation of diverse small molecules
.” 2017. Web. 23 Oct 2019.
Vancouver:
Bartlett S. Synthesis and antibacterial evaluation of diverse small molecules
. [Internet] [Thesis]. University of Cambridge; 2017. [cited 2019 Oct 23].
Available from: https://www.repository.cam.ac.uk/handle/1810/270198.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Bartlett S. Synthesis and antibacterial evaluation of diverse small molecules
. [Thesis]. University of Cambridge; 2017. Available from: https://www.repository.cam.ac.uk/handle/1810/270198
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Columbia University
18.
Tzoneva, Gannie Valentinova.
The role of cytosolic 5'-nucleotidase II (NT5C2) in drug resistance and relapse of acute lymphoblastic leukemia.
Degree: 2016, Columbia University
URL: https://doi.org/10.7916/D85Q4W77
► Acute lymphoblastic leukemia (ALL) is an aggressive hematological cancer which arises from the malignant transformation of B-cell or T-cell progenitors. Despite recent pioneering improvements in…
(more)
▼ Acute lymphoblastic leukemia (ALL) is an aggressive hematological cancer which arises from the malignant transformation of B-cell or T-cell progenitors. Despite recent pioneering improvements in intensified combination chemotherapy, 20% of pediatric and 50% of adult ALL patients present with primary drug-resistant leukemia or develop relapse. Treatment of refractory and relapsed ALL has remained a significant clinical challenge with survival rates following relapse of only 40%, highlighting the need to understand the mechanisms which drive drug resistance and relapse of ALL.
Through extensive sequencing analyses of matched diagnostic, remission and relapsed DNA samples from patients with B-precursor ALL (B-ALL) and T-cell ALL (T-ALL) we have identified recurrent relapse-specific gain-of-function mutations in the cytosolic 5'-nucleotidase II (NT5C2) gene in 25% of relapsed T-ALLs and 6% of relapsed B-ALLs. NT5C2 is a highly conserved, ubiquitously expressed enzyme which regulates intracellular purine nucleotide levels by dephosphorylating purine monophosphates. NT5C2 also dephosphorylates key metabolites in the activation of purine analog prodrugs such as 6-mercaptopurine and 6-thioguanine which are routinely used in the treatment of ALL, allowing purine analog nucleosides to be readily exported out of the cell.
Here we show that mutant NT5C2 proteins have increased 5’-nucleotidase activity and confer resistance to 6-mercaptopurine and 6-thioguanine chemotherapy when expressed in leukemic cells. Consistently, NT5C2 mutations correlate with early relapse and relapse while under therapy. We present a novel T-ALL conditional inducible knock-in mouse model of the highly recurrent NT5C2 R367Q mutation and show that expression of one Nt5c2 R367Q allele from the endogenous locus in primary T-ALL lymphoblasts induces overt resistance and disease progression under therapy with 6-mercaptopurine in vivo, while surprisingly conferring reduced growth and decreased leukemia initiating activity in the absence of chemotherapy. Metabolically we show that the observed loss of fitness in Nt5c2 R367Q tumors can be explained by a severe depletion of endogenous purine monophosphate metabolites as a result of increased Nt5c2 5’-nucleotidase activity. Consistently, using ultra-sensitive mutation analyses we show that relapse-associated NT5C2 mutations are not detectable at initial disease presentation, indicating that NT5C2-mutant tumor cells are negatively selected by clonal competition in the early stages of disease development and only positively selected under prolonged 6-mercaptopruine chemotherapy which is the backbone treatment for ALL following remission. Our findings present the first known example of chemotherapy resistance and disease progression driven by a tumor clone with decreased leukemia initiating activity, highlighting the intense selective pressure of chemotherapy in the clonal evolution of tumors from diagnosis to relapse.
Through extensive biochemical and structural characterizations of recombinant…
Subjects/Keywords: Drug resistance; Lymphoblastic leukemia; Oncology
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Tzoneva, G. V. (2016). The role of cytosolic 5'-nucleotidase II (NT5C2) in drug resistance and relapse of acute lymphoblastic leukemia. (Doctoral Dissertation). Columbia University. Retrieved from https://doi.org/10.7916/D85Q4W77
Chicago Manual of Style (16th Edition):
Tzoneva, Gannie Valentinova. “The role of cytosolic 5'-nucleotidase II (NT5C2) in drug resistance and relapse of acute lymphoblastic leukemia.” 2016. Doctoral Dissertation, Columbia University. Accessed October 23, 2019.
https://doi.org/10.7916/D85Q4W77.
MLA Handbook (7th Edition):
Tzoneva, Gannie Valentinova. “The role of cytosolic 5'-nucleotidase II (NT5C2) in drug resistance and relapse of acute lymphoblastic leukemia.” 2016. Web. 23 Oct 2019.
Vancouver:
Tzoneva GV. The role of cytosolic 5'-nucleotidase II (NT5C2) in drug resistance and relapse of acute lymphoblastic leukemia. [Internet] [Doctoral dissertation]. Columbia University; 2016. [cited 2019 Oct 23].
Available from: https://doi.org/10.7916/D85Q4W77.
Council of Science Editors:
Tzoneva GV. The role of cytosolic 5'-nucleotidase II (NT5C2) in drug resistance and relapse of acute lymphoblastic leukemia. [Doctoral Dissertation]. Columbia University; 2016. Available from: https://doi.org/10.7916/D85Q4W77
University of Waterloo
19.
Dekker, Heather.
Characterising changes in adhesion and enzyme activity related to drug resistance in colon cancer cells.
Degree: 2018, University of Waterloo
URL: http://hdl.handle.net/10012/14278
► Metastatic colorectal cancer is often fatal, and drug resistance to chemotherapeutic agents is one of the primary contributing factors to this lethality. Drug resistance arises…
(more)
▼ Metastatic colorectal cancer is often fatal, and drug resistance to chemotherapeutic agents is one of the primary contributing factors to this lethality. Drug resistance arises from exposure to chemotherapies, and it can be mediated through a variety of mechanisms. One of these mechanisms is alteration of enzymes within the cancer cells to affect the processing or removal of the drug. Carboxylesterase is an example of an enzyme that converts irinotecan, a drug used in metastatic colorectal cancer treatments, into the active metabolite SN-38. Carboxylesterase enzymes are found in high quantities in both the liver and intestinal cells. The presence of carboxylesterase in intestinal and liver cells is an important consideration in the processing of colorectal cancer treatments. Glutathione S-transferase is another enzyme that has been implicated in drug resistance because of its ability to conjugate reduced glutathione to xenobiotic substances, facilitating their removal. Additionally, drug resistance can affect the behaviours of cells. Drug-resistant cells can exhibit changes in their motility and aggressiveness compared to drug-sensitive cells. In this study I investigated cellular behavioural changes in SN-38-resistant colon cancer cells compared to their SN-38-sensitive counterparts. In addition to behavioural changes, I also sought to determine if elevations in carboxylesterase and glutathione S-transferase enzymes were contributing to the drug resistance in these colon cancer cells.
Subjects/Keywords: drug resistance; colorectal cancer
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Dekker, H. (2018). Characterising changes in adhesion and enzyme activity related to drug resistance in colon cancer cells. (Thesis). University of Waterloo. Retrieved from http://hdl.handle.net/10012/14278
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Dekker, Heather. “Characterising changes in adhesion and enzyme activity related to drug resistance in colon cancer cells.” 2018. Thesis, University of Waterloo. Accessed October 23, 2019.
http://hdl.handle.net/10012/14278.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Dekker, Heather. “Characterising changes in adhesion and enzyme activity related to drug resistance in colon cancer cells.” 2018. Web. 23 Oct 2019.
Vancouver:
Dekker H. Characterising changes in adhesion and enzyme activity related to drug resistance in colon cancer cells. [Internet] [Thesis]. University of Waterloo; 2018. [cited 2019 Oct 23].
Available from: http://hdl.handle.net/10012/14278.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Dekker H. Characterising changes in adhesion and enzyme activity related to drug resistance in colon cancer cells. [Thesis]. University of Waterloo; 2018. Available from: http://hdl.handle.net/10012/14278
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of New South Wales
20.
Jiamsakul, Awachana.
HIV Drug Resistance and Adherence to Antiretroviral Therapy in Asia.
Degree: Kirby Institute, 2015, University of New South Wales
URL: http://handle.unsw.edu.au/1959.4/55477
;
https://unsworks.unsw.edu.au/fapi/datastream/unsworks:37799/SOURCE01?view=true
► The expansion of combination antiretroviral therapy (cART) in resource-limited settings has led to improved survival but also the emergence of HIV drug resistance associated mutations…
(more)
▼ The expansion of combination antiretroviral therapy (cART) in resource-limited settings has led to improved survival but also the emergence of HIV
drug resistance associated mutations (RAMs). As treatment strategies lean towards earlier cART initiation, it is expected that an increasing number of HIV-infected individuals will be exposed to cART for longer, potentially leading to higher prevalence of RAMs in both treatment naive, through transmitted RAMs, and treatment experienced individuals. This thesis aims to evaluate RAMs in recently infected individuals and those who have failed first-line cART in Asia. Additionally, adherence to cART, an important predictor of RAMs, was also investigated.Analysis datasets were obtained from the TREAT Asia HIV databases. Firstly, the applications of different types of
resistance interpretation systems on HIV-1 CRF01_AE were compared. Proportions of RAMs in recently-infected and treatment experienced individuals were then analysed, and the corresponding second-line virological outcome adjusting for adherence and genotypic susceptibility score were determined. Levels of suboptimal adherence utilising the self-reported questionnaire were evaluated. Additionally, the effects of unplanned treatment interruptions on treatment outcomes after cART resumption were investigated. Although developed from subtype B, genotypic and virtual phenotypic
resistance interpretation systems proved to be reliable in their predicted
resistance calls for non-B subtypes, particularly CRF01_AE. RAMs in recently infected individuals were below 15%, however, multi-
drug RAMs found in patients failing first-line cART existed in a high proportion but were not associated with second-line virological suppression. Adherence was the only factor showing a significant association, conferring the importance of high-level adherence beyond first-line therapy. Sites that assessed adherence more frequently, and longer time on cART, were associated with better adherence. Treatment interruptions due to adverse events did not have an effect on treatment response after cART had been resumed, possibly due to the shorter duration. Longer time off treatment was associated with higher hazard of treatment failure.Continued monitoring of RAMs in recently infected and treatment experienced individuals in Asia should be encouraged. Greater emphasis on adherence counselling at the early stages of cART is beneficial in promoting treatment and program retention.
Advisors/Committee Members: Law, Matthew, Kirby Institute, Faculty of Medicine, UNSW, Kerr, Stephen, HIV-NAT, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand;, Sungkanuparp, Somnuek, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand;.
Subjects/Keywords: Adherence; HIV; Drug resistance; Asia
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Jiamsakul, A. (2015). HIV Drug Resistance and Adherence to Antiretroviral Therapy in Asia. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/55477 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:37799/SOURCE01?view=true
Chicago Manual of Style (16th Edition):
Jiamsakul, Awachana. “HIV Drug Resistance and Adherence to Antiretroviral Therapy in Asia.” 2015. Doctoral Dissertation, University of New South Wales. Accessed October 23, 2019.
http://handle.unsw.edu.au/1959.4/55477 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:37799/SOURCE01?view=true.
MLA Handbook (7th Edition):
Jiamsakul, Awachana. “HIV Drug Resistance and Adherence to Antiretroviral Therapy in Asia.” 2015. Web. 23 Oct 2019.
Vancouver:
Jiamsakul A. HIV Drug Resistance and Adherence to Antiretroviral Therapy in Asia. [Internet] [Doctoral dissertation]. University of New South Wales; 2015. [cited 2019 Oct 23].
Available from: http://handle.unsw.edu.au/1959.4/55477 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:37799/SOURCE01?view=true.
Council of Science Editors:
Jiamsakul A. HIV Drug Resistance and Adherence to Antiretroviral Therapy in Asia. [Doctoral Dissertation]. University of New South Wales; 2015. Available from: http://handle.unsw.edu.au/1959.4/55477 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:37799/SOURCE01?view=true
Rutgers University
21.
Blankson, Gifty Ayensu, 1986-.
Structure-activity studies on bacterial efflux inhibitors.
Degree: PhD, Medicinal Chemistry, 2016, Rutgers University
URL: https://rucore.libraries.rutgers.edu/rutgers-lib/49914/
► Antibiotic resistance poses a significant challenge in anti-infective therapy. There are several mechanisms involved in antibiotic resistance with efflux being a major determinant. Overcoming efflux…
(more)
▼ Antibiotic resistance poses a significant challenge in anti-infective therapy. There are several mechanisms involved in antibiotic resistance with efflux being a major determinant. Overcoming efflux will allow for the reintroduction of old antibiotics and prevent the development of resistance to new antibiotics. Several bacterial efflux pump inhibitors (EPIs) have been discovered, but none of these compounds have been FDA-approved for use in humans. There is a need for a systematic study of some of these inhibitors to gain a better understanding of their structure activity relationship (SAR). This work focuses on the SAR studies conducted on two classes of known EPI inhibitors. Analogues of aryl piperazines (biphenyl piperazines and naphthalene amines) were synthesized and tested for their EPI activity. None of the compounds in this series exhibited EPI activity and thus no further exploration was done on their SAR. Structurally simpler analogues of phenylalanine-arginine β-naphthylamide (PAβN) were also designed and an SAR study conducted on the three different scaffolds proposed. The three scaffolds include the “normal” amides, the “reverse” amides and the secondary amine series. Although these scaffolds exhibited some similarities in their SAR, there were some differences. In all cases, the 1,5-diphenylpentane core was the preferred substituent on the right hand side of the molecules. For the left hand side, diaminopentane was the preferred substituent. Further studies revealed that N5 substitution was detrimental to EPI activity. The “reverse” amides had better activity when compared against their analogous “normal” amides. The data indicated that a bis-alkylaryl was necessary for activity and that there was preference for the aryl to be hydrophobic. A methylene insertion in the reverse amides series gave a compound that caused 512-fold reduction in the minimum inhibitory concentration (MIC) of clarithromycin (PAβN, the historical EPI standard offered a 4-fold reduction in MIC). The amine analogues also offered some active compounds with one of these compounds causing a 128-fold reduction in the MIC of clarithromycin. (These tests were done in E. coli). Some success was achieved in P. aeruginosa; two compounds when independently co-administered with levofloxacin resulted in a 32-fold decrease in the MIC of levofloxacin.
Advisors/Committee Members: LaVoie, Edmond J (chair), Rice, Joseph E (internal member), Hu, Longqin (internal member), Pilch, Daniel S (outside member).
Subjects/Keywords: Drug resistance in microorganisms; Antibiotics
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Blankson, Gifty Ayensu, 1. (2016). Structure-activity studies on bacterial efflux inhibitors. (Doctoral Dissertation). Rutgers University. Retrieved from https://rucore.libraries.rutgers.edu/rutgers-lib/49914/
Chicago Manual of Style (16th Edition):
Blankson, Gifty Ayensu, 1986-. “Structure-activity studies on bacterial efflux inhibitors.” 2016. Doctoral Dissertation, Rutgers University. Accessed October 23, 2019.
https://rucore.libraries.rutgers.edu/rutgers-lib/49914/.
MLA Handbook (7th Edition):
Blankson, Gifty Ayensu, 1986-. “Structure-activity studies on bacterial efflux inhibitors.” 2016. Web. 23 Oct 2019.
Vancouver:
Blankson, Gifty Ayensu 1. Structure-activity studies on bacterial efflux inhibitors. [Internet] [Doctoral dissertation]. Rutgers University; 2016. [cited 2019 Oct 23].
Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/49914/.
Council of Science Editors:
Blankson, Gifty Ayensu 1. Structure-activity studies on bacterial efflux inhibitors. [Doctoral Dissertation]. Rutgers University; 2016. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/49914/
Rutgers University
22.
Varghese, Nevin.
Characterization of the interaction of daptomycin with bacterial liposomal analogues.
Degree: MS, Biomedical Engineering, 2016, Rutgers University
URL: https://rucore.libraries.rutgers.edu/rutgers-lib/51486/
► Efforts to curb the prevalence of antibiotic resistant bacteria are unable to keep up with the aggressive adaptation of these bacterial species to existing antibiotics.…
(more)
▼ Efforts to curb the prevalence of antibiotic resistant bacteria are unable to keep up with the aggressive adaptation of these bacterial species to existing antibiotics. Therefore, examining the interaction of existing antibiotics with bacteria may reveal previously unknown bacterial susceptibilities. Daptomycin is a typical second-line treatment for antibiotic-resistant gram positive bacterial strains, like methicillin-resistant Staphylococcus aureus (MRSA). Its proposed mechanism of action is to bind to the negatively charged phosphatidyglycerol (PG) head groups of the bacterial cytoplasmic membrane via a calcium ion dependent process. However, the specific mechanisms by which daptomycin exerts its bacteriocidality are currently unknown. It has been hypothesized that bacterial membrane rigidity may have an effect on susceptibility to daptomycin. Additionally, there is evidence to suggest that the charge of the bacterial membrane charge affects daptomycin's mechanism of action. Our study aims to systematically analyze the interaction of daptomycin with liposomal bacterial analogues by varying the rigidity and the zeta potential of the liposomes. Our results show possible mechanisms for targeting daptomycin
resistance in gram positive bacteria.
Advisors/Committee Members: Sofou, Stavroula (chair), Pierce, Mark (internal member), Langrana, Noshir (internal member).
Subjects/Keywords: Liposomes; Drug resistance in microorganisms
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Varghese, N. (2016). Characterization of the interaction of daptomycin with bacterial liposomal analogues. (Masters Thesis). Rutgers University. Retrieved from https://rucore.libraries.rutgers.edu/rutgers-lib/51486/
Chicago Manual of Style (16th Edition):
Varghese, Nevin. “Characterization of the interaction of daptomycin with bacterial liposomal analogues.” 2016. Masters Thesis, Rutgers University. Accessed October 23, 2019.
https://rucore.libraries.rutgers.edu/rutgers-lib/51486/.
MLA Handbook (7th Edition):
Varghese, Nevin. “Characterization of the interaction of daptomycin with bacterial liposomal analogues.” 2016. Web. 23 Oct 2019.
Vancouver:
Varghese N. Characterization of the interaction of daptomycin with bacterial liposomal analogues. [Internet] [Masters thesis]. Rutgers University; 2016. [cited 2019 Oct 23].
Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/51486/.
Council of Science Editors:
Varghese N. Characterization of the interaction of daptomycin with bacterial liposomal analogues. [Masters Thesis]. Rutgers University; 2016. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/51486/
Rutgers University
23.
Lloyd, Nicole A.
Co-selection of metal and antibiotic resistance in the gut microbial community of the Mummichog fish (Fundulus heteroclitus).
Degree: PhD, Microbial Biology, 2018, Rutgers University
URL: https://rucore.libraries.rutgers.edu/rutgers-lib/59159/
► Microbial resistance to antibiotics is one of the most pressing health care concerns we are currently facing. Antibiotic resistance can be selected for by metals…
(more)
▼ Microbial resistance to antibiotics is one of the most pressing health care concerns we are currently facing. Antibiotic resistance can be selected for by metals through the process known as co-selection. Co-selection occurs through two primary mechanisms: i) co-resistance, when genes encoding both are located together in the genome and ii), cross-resistance, when the same mechanism provides resistance to both (e.g. efflux pump proteins). This thesis describes co-selection in the gut microbiota of a forage feeder fish, the mummichog (Fundulus heteroclitus). By comparing gut microbiota from fish from a mercury contaminated site and a relatively clean site, we established the mummichog gut as a reservoir of antibiotic and mercury resistant microbiota. We further examined three representative isolates with interesting antibiotic and metal resistant profiles. Genome analyses revealed few instance of co-resistance, and instead, presented various chromosomally-encoded resistance genes, including some of public health concern, (i.e. a blaOXA carbapenemase), and contributions from cross-resistance. All three organisms contained a large number of efflux pump proteins, including multiple RND efflux pump operons. Testing of the strains shows that RND efflux pumps may be involved in resistance to several classes of drugs. A transcriptomic study is in progress to understand the regulation of arsenate resistance and the potential involvement of RND efflux pumps under metal stress. Together, this work describes the abundance and inventory of antibiotic resistance genes and mechanisms in the mummichog gut microbiome and establishes the fish gut as a reservoir of such genes. This work further adds to the understanding of the role of RND efflux pumps in resistance to antibiotics, which is critical in understanding multi-drug resistance in Gram negative bacteria.
Advisors/Committee Members: Barkay, Tamar (chair), Fahrenfeld, Nicole (internal member), Zylstra, Gerben (internal member), Nazaret, Sylvie (outside member), School of Graduate Studies.
Subjects/Keywords: Drug resistance in microorganisms
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Lloyd, N. A. (2018). Co-selection of metal and antibiotic resistance in the gut microbial community of the Mummichog fish (Fundulus heteroclitus). (Doctoral Dissertation). Rutgers University. Retrieved from https://rucore.libraries.rutgers.edu/rutgers-lib/59159/
Chicago Manual of Style (16th Edition):
Lloyd, Nicole A. “Co-selection of metal and antibiotic resistance in the gut microbial community of the Mummichog fish (Fundulus heteroclitus).” 2018. Doctoral Dissertation, Rutgers University. Accessed October 23, 2019.
https://rucore.libraries.rutgers.edu/rutgers-lib/59159/.
MLA Handbook (7th Edition):
Lloyd, Nicole A. “Co-selection of metal and antibiotic resistance in the gut microbial community of the Mummichog fish (Fundulus heteroclitus).” 2018. Web. 23 Oct 2019.
Vancouver:
Lloyd NA. Co-selection of metal and antibiotic resistance in the gut microbial community of the Mummichog fish (Fundulus heteroclitus). [Internet] [Doctoral dissertation]. Rutgers University; 2018. [cited 2019 Oct 23].
Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/59159/.
Council of Science Editors:
Lloyd NA. Co-selection of metal and antibiotic resistance in the gut microbial community of the Mummichog fish (Fundulus heteroclitus). [Doctoral Dissertation]. Rutgers University; 2018. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/59159/
24.
LOWRY, MICHELLE.
Investigating mechanisms of anti-cancer drug resistance in breast cancer cells and extracellular vesicles.
Degree: School of Pharmacy & Pharma. Sciences. Discipline of Pharmacy, 2019, Trinity College Dublin
URL: http://hdl.handle.net/2262/86081
► Breast cancer is the most common female cancer diagnosed worldwide. In 2018 alone, there were over 2 million new breast cancer cases diagnosed. In Ireland,…
(more)
▼ Breast cancer is the most common female cancer diagnosed worldwide. In 2018 alone, there were over 2 million new breast cancer cases diagnosed. In Ireland, breast cancer is the most commonly diagnosed cancer in women. In Ireland, breast cancer accounts for approximately 3,141 cases each year. Of which, a subtype of breast cancer called HER2overexpressing/HER2+ breast cancer accounts for 15-25% of breast cancers. This subtype of breast cancer has a genetic mutation that causes the cancer cells to produce larger amounts of the protein called HER2. HER2 promotes the growth of cancer cells and patients with this type of breast cancer often have high levels of metastasis, or spread of the cancer to other organs. Unfortunately, like with many cancer therapies, some patients do not respond to anti-HER2 therapies, i.e. patients are or become resistant to therapy. Some patient?s tumours will immediately not respond to therapy (innate
resistance), whereas, other patient tumour?s will initially respond well to the therapies but overtime the cancer cells can find ways to overcome the effects of the therapy i.e. the tumours become resistant to therapy (adaptive
resistance). Innate and adaptive
resistance to anticancer therapies are the main reasons that anti-cancer drugs fail in the clinic. It is imperative that we investigate the mechanisms of
drug resistance, find ways to overcome this
resistance and find ways to predict and/or find predictive biomarkers.
The focus of this PhD is on a
drug that stops HER2 working, it is called Neratinib. Neratinib prevents HER2 functioning and in doing so it can prevent cancer cell growth. Neratinib was approved by the Food and
Drug Administration (FDA) in July 2017. Neratinib is showing promise in the clinic but, like most therapies, the issue of
resistance prevails. We have developed HER2+ breast cancer cell lines that are resistant to neratinib i.e. neratinib does not kill them. When we compared cells that die from neratinib with cells that do not die after neratinib treatment, we found that the resistant cell lines produce very large amounts of a protein called PROTEIN X. The cells that are sensitive to neratinib or the cells that die after neratinib treatment, do not produce large amounts of PROTEIN X. We believe that PROTEIN X acts like a defence system for breast cancer cells.
This discoveries made in this PhD may be imperative to overcoming neratinib
resistance in the future, for predicting response to therapy (so that patients can be stratified into those who are likely versus unlikely to respond to HER-targeting), and so improving the survival rates of patients treated with neratinib and other HER2-targeted therapies. We also believe that PROTEIN X has potential as a predictive biomarker for HER2 therapies such as lapatinib and trastuzumab, but most notably for neratinib. PROTEIN X may be an important marker for future therapeutic decisions in clinics.
Advisors/Committee Members: O'Driscoll, Lorraine.
Subjects/Keywords: Breast cancer; Cancer drug resistance
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
LOWRY, M. (2019). Investigating mechanisms of anti-cancer drug resistance in breast cancer cells and extracellular vesicles. (Thesis). Trinity College Dublin. Retrieved from http://hdl.handle.net/2262/86081
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
LOWRY, MICHELLE. “Investigating mechanisms of anti-cancer drug resistance in breast cancer cells and extracellular vesicles.” 2019. Thesis, Trinity College Dublin. Accessed October 23, 2019.
http://hdl.handle.net/2262/86081.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
LOWRY, MICHELLE. “Investigating mechanisms of anti-cancer drug resistance in breast cancer cells and extracellular vesicles.” 2019. Web. 23 Oct 2019.
Vancouver:
LOWRY M. Investigating mechanisms of anti-cancer drug resistance in breast cancer cells and extracellular vesicles. [Internet] [Thesis]. Trinity College Dublin; 2019. [cited 2019 Oct 23].
Available from: http://hdl.handle.net/2262/86081.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
LOWRY M. Investigating mechanisms of anti-cancer drug resistance in breast cancer cells and extracellular vesicles. [Thesis]. Trinity College Dublin; 2019. Available from: http://hdl.handle.net/2262/86081
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Debrecen
25.
Géczy, Katalin Éva.
Aminoglikozidokkal szembeni rezisztenciamechanizmusok baktériumokban
.
Degree: DE – TEK – Természettudományi és Technológiai Kar – Biológiai és Ökológiai Intézet, 2013, University of Debrecen
URL: http://hdl.handle.net/2437/177289
► Az aminoglikozidok leginkább a gram-negatív aerob baktériumokkal szemben hatásosak. A baktériumok az aminoglikozidok szelekciós nyomása miatt idővel rezisztenssé váltak vagy válhatnak, emiatt a különböző rezisztenciamechanizmusok…
(more)
▼ Az aminoglikozidok leginkább a gram-negatív aerob baktériumokkal szemben hatásosak. A baktériumok az aminoglikozidok szelekciós nyomása miatt idővel rezisztenssé váltak vagy válhatnak, emiatt a különböző rezisztenciamechanizmusok megértése elengedhetetlen a rezisztens baktériumok ellen biztosan használó antibiotikus terápiák kifejlesztéséhez. A jelenleg ismert mechanizmusok közé tartozik (i) az aminoglikozidot inaktiváló transzferáz enzimek termelése, (ii) az aminoglikozidok sejtbe jutásának és szétterjedésének megakadályozása, (iii) az antibiotikum aktív eltávolítása a baktériumsejtből (például proton pumpa, efflux), és (iv) az aminoglikozidok támadáspontján, a riboszómális 30S-alegység fehérjéjén bekövetkezett mutáció. Az aminoglikozidok, mint régóta használt antibiotikumok, általános tulajdonságait és a velük szemben kialakult leggyakoribb rezisztenciamechanizmusokat foglalom össze néhány klinikailag fontos baktériumtörzs vonatkozásában. A multirezisztens fajok kialakulása és fékezhetetlen terjedése és a magas dózis miatti toxikus hatás elkerülése érdekében a kutatók figyelmét különböző, rezisztens baktériumokkal szembeni újabb hatásos, de kevésbé toxikus aminoglikozidok vagy azokhoz hasonló antibakteriális vegyületek fejlesztésére kell irányítani, koncentrálva a kémiai módosításokra és az aminoglikozid-módosító enzimek gátlóira.
Advisors/Committee Members: Megyeri, Attila (advisor).
Subjects/Keywords: rezisztencia;
aminoglikozid;
drug resistance;
aminoglycoside
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Géczy, K. . (2013). Aminoglikozidokkal szembeni rezisztenciamechanizmusok baktériumokban
. (Thesis). University of Debrecen. Retrieved from http://hdl.handle.net/2437/177289
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Géczy, Katalin Éva. “Aminoglikozidokkal szembeni rezisztenciamechanizmusok baktériumokban
.” 2013. Thesis, University of Debrecen. Accessed October 23, 2019.
http://hdl.handle.net/2437/177289.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Géczy, Katalin Éva. “Aminoglikozidokkal szembeni rezisztenciamechanizmusok baktériumokban
.” 2013. Web. 23 Oct 2019.
Vancouver:
Géczy K. Aminoglikozidokkal szembeni rezisztenciamechanizmusok baktériumokban
. [Internet] [Thesis]. University of Debrecen; 2013. [cited 2019 Oct 23].
Available from: http://hdl.handle.net/2437/177289.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Géczy K. Aminoglikozidokkal szembeni rezisztenciamechanizmusok baktériumokban
. [Thesis]. University of Debrecen; 2013. Available from: http://hdl.handle.net/2437/177289
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Bowling Green State University
26.
Pristas, Erica V.
Adolescents’ Anticipated Emotional and Behavioral Responses
to Alcohol and Drug Offers.
Degree: PhD, Psychology/Clinical, 2007, Bowling Green State University
URL: http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1136342177
► Theories of adolescent experimental substance use note that proximal influences, including refusal skills and substance use decisions in response to drug offers, are more amenable…
(more)
▼ Theories of adolescent experimental substance use note
that proximal influences, including refusal skills and substance
use decisions in response to
drug offers, are more amenable to
change than distal influences. However, research on adolescents’
responses to offers of alcohol or drugs has not addressed whether
resistance responses vary by type of
drug, or whether emotional
reactions to an offer of drugs or alcohol are associated with
adolescents’ intentions to use
resistance strategies. Therefore, I
assessed whether type of
drug (alcohol vs. marijuana), relationship
with the offerer (close friends vs. acquaintance), and
drug refusal
policy (uniform rejection, marijuana-only refusal, open-to-offers)
affected anticipated emotional reactions and intended use of a
broad range of
resistance responses. I administered a questionnaire
to high school students to assess
resistance responses adolescents
have used in the past,
resistance responses adolescents expect to
use in the future, and expected emotional reactions to
drug offers.
Although there was statistically significant variation in
anticipated use of different types of strategies according to
drug
and offerer, two particular strategies (“say no,” “say don’t want
it”) were endorsed most often regardless of the
drug/offerer
condition. Participants who had made an a priori decision to refuse
offers of alcohol or marijuana more often anticipated that an offer
would be a negative experience, and more often anticipated that
they would use various types of
resistance strategies in response
to the offer. Background characteristics such as age, gender, race,
grade, locality, grade point average, and intentions of going to
college had little association with endorsement of emotional
reactions or
resistance strategies. However, prior experience of
receiving
drug offers predicted anticipation of less negative
emotional reactions and lower endorsement of
resistance strategies.
Emotional reactions were correlated with
resistance strategies,
indicating that participants more frequently endorsed using
resistance responses to an offer when they expected that the offer
would be a negative emotional experience. This study has
contributed to the field of substance use prevention by identifying
proximal intrapersonal factors associated with endorsement of
resistance strategies (anticipation of negative emotions in
response to a
drug offer, prior decision to refuse an offer) and by
identifying factors associated with rejection of
resistance
strategies (anticipation of positive emotions in response to a
drug
offer, past history of
drug offers).
Advisors/Committee Members: Rosenberg, Harold (Advisor).
Subjects/Keywords: Psychology, Clinical; adolescents; drug offers; resistance strategies; drug resistance; emotional responses
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Pristas, E. V. (2007). Adolescents’ Anticipated Emotional and Behavioral Responses
to Alcohol and Drug Offers. (Doctoral Dissertation). Bowling Green State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1136342177
Chicago Manual of Style (16th Edition):
Pristas, Erica V. “Adolescents’ Anticipated Emotional and Behavioral Responses
to Alcohol and Drug Offers.” 2007. Doctoral Dissertation, Bowling Green State University. Accessed October 23, 2019.
http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1136342177.
MLA Handbook (7th Edition):
Pristas, Erica V. “Adolescents’ Anticipated Emotional and Behavioral Responses
to Alcohol and Drug Offers.” 2007. Web. 23 Oct 2019.
Vancouver:
Pristas EV. Adolescents’ Anticipated Emotional and Behavioral Responses
to Alcohol and Drug Offers. [Internet] [Doctoral dissertation]. Bowling Green State University; 2007. [cited 2019 Oct 23].
Available from: http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1136342177.
Council of Science Editors:
Pristas EV. Adolescents’ Anticipated Emotional and Behavioral Responses
to Alcohol and Drug Offers. [Doctoral Dissertation]. Bowling Green State University; 2007. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1136342177
University of Guelph
27.
Ward, David.
Characterizing drug interactions in the substrate binding pocket of the P-glycoprotein multidrug efflux pump
.
Degree: 2012, University of Guelph
URL: https://atrium.lib.uoguelph.ca/xmlui/handle/10214/3309
► P-glycoprotein (Pgp, ABCB1) is a polyspecific efflux transporter implicated in multidrug resistance in human cancers. In this study, tetramethylrhodamine-5-carbonyl azide (AzTMR) was covalently crosslinked to…
(more)
▼ P-glycoprotein (Pgp, ABCB1) is a polyspecific efflux transporter implicated in multidrug
resistance in human cancers. In this study, tetramethylrhodamine-5-carbonyl azide (AzTMR) was covalently crosslinked to the Pgp
drug binding pocket with a stoichiometry of 1. The Pgp-AzTMR adduct was functionally equivalent to unlabelled Pgp and retained its ability to transport Hoechst 33342. The binding site of AzTMR in Pgp was nonpolar, with a similar environment to that of propanol. Pgp-AzTMR could bind a second
drug molecule, with a higher affinity for H-site drugs and lower affinity for other R-site drugs. Unlabelled Pgp interacted with dimeric versions of known Pgp modulators, binding them with higher affinity than the monomer. These compounds were also found to either stimulate or inhibit Pgp ATPase activity depending on the concentration. Pgp-AzTMR was able to bind dimeric drugs, indicating that 3 substrate moieties can fit into the binding pocket.
Advisors/Committee Members: Sharom, Frances J (advisor).
Subjects/Keywords: P-glycoprotein;
Pgp;
drug resistance;
cancer;
tumour;
MDR;
drug binding;
drug transport;
multidrug resistance;
chemotherapy
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Ward, D. (2012). Characterizing drug interactions in the substrate binding pocket of the P-glycoprotein multidrug efflux pump
. (Thesis). University of Guelph. Retrieved from https://atrium.lib.uoguelph.ca/xmlui/handle/10214/3309
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Ward, David. “Characterizing drug interactions in the substrate binding pocket of the P-glycoprotein multidrug efflux pump
.” 2012. Thesis, University of Guelph. Accessed October 23, 2019.
https://atrium.lib.uoguelph.ca/xmlui/handle/10214/3309.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Ward, David. “Characterizing drug interactions in the substrate binding pocket of the P-glycoprotein multidrug efflux pump
.” 2012. Web. 23 Oct 2019.
Vancouver:
Ward D. Characterizing drug interactions in the substrate binding pocket of the P-glycoprotein multidrug efflux pump
. [Internet] [Thesis]. University of Guelph; 2012. [cited 2019 Oct 23].
Available from: https://atrium.lib.uoguelph.ca/xmlui/handle/10214/3309.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Ward D. Characterizing drug interactions in the substrate binding pocket of the P-glycoprotein multidrug efflux pump
. [Thesis]. University of Guelph; 2012. Available from: https://atrium.lib.uoguelph.ca/xmlui/handle/10214/3309
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Edinburgh
28.
Huijben, Silvie.
Experimental studies on the ecology and evolution of drug-resistant malaria parasites.
Degree: PhD, 2010, University of Edinburgh
URL: http://hdl.handle.net/1842/3945
► 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’…
(more)
▼ 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.
Subjects/Keywords: 616.9883; Drug resistance; malaria treatment; drug-resistant parasites; drug treatments
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Huijben, S. (2010). Experimental studies on the ecology and evolution of drug-resistant malaria parasites. (Doctoral Dissertation). University of Edinburgh. Retrieved from http://hdl.handle.net/1842/3945
Chicago Manual of Style (16th Edition):
Huijben, Silvie. “Experimental studies on the ecology and evolution of drug-resistant malaria parasites.” 2010. Doctoral Dissertation, University of Edinburgh. Accessed October 23, 2019.
http://hdl.handle.net/1842/3945.
MLA Handbook (7th Edition):
Huijben, Silvie. “Experimental studies on the ecology and evolution of drug-resistant malaria parasites.” 2010. Web. 23 Oct 2019.
Vancouver:
Huijben S. Experimental studies on the ecology and evolution of drug-resistant malaria parasites. [Internet] [Doctoral dissertation]. University of Edinburgh; 2010. [cited 2019 Oct 23].
Available from: http://hdl.handle.net/1842/3945.
Council of Science Editors:
Huijben S. Experimental studies on the ecology and evolution of drug-resistant malaria parasites. [Doctoral Dissertation]. University of Edinburgh; 2010. Available from: http://hdl.handle.net/1842/3945
University of Edinburgh
29.
Modrzynska, Katarzyna Kinga.
Genetics of drug resistance in malaria : identification of genes conferring chloroquine and artemisinin resistance in rodent malaria parasite Plasmodium chabaudi.
Degree: 2011, University of Edinburgh
URL: http://hdl.handle.net/1842/4888
► Resistance to antimalarial drugs continues to be a major obstacle in controlling and eradicating malaria. The identification of genetic markers of resistance is vital for…
(more)
▼ Resistance to antimalarial drugs continues to be a major obstacle in controlling and eradicating malaria. The identification of genetic markers of resistance is vital for disease management but they can be difficult to predict before resistance arises in the field. This thesis describes an alternative approach to gene identification, combining an in vivo experimental evolution model, Linkage Group Selection (LGS) and Solexa genome re-sequencing. Here this model was used to resolve the genetic basis of chloroquine and artemisinin resistance in the rodent malaria parasite Plasmodium chabaudi. AS-30CQ is a parasite with high resistance to chloroquine and resistance to artemisinin. It was crossed with the genetically different drug-sensitive strain AJ. The resulting progeny were selected with drugs and backcrossed to the sensitive parent. Both crosses were treated with increasing concentrations of chloroquine and artemisinin. The frequency of markers from the sensitive parasite were analysed in order to characterize the signatures of drug selection. Three loci involved progressively in chloroquine resistance were identified on chromosomes 11, 3 and 2. One main locus on chromosome 2 was identified with artemisinin selection. The Solexa platform was used to re-sequence the genomes of both AS-30CQ and its sensitive progenitor, AS-sens. The differences between the two genomes were integrated with the LGS data to identify: 1) a strong candidate for the main CQresistance determinant - a putative amino acid transporter on chromosome 11 (aat1) 2) two candidates for high level chloroquine resistance on chromosome 3. and 3) a mutation in ubp1 gene on chromosome 2 that is likely to contribute to the highest level of chloroquine resistance and be main determinant of the artemisinin resistance phenotype. In addition the last section of this thesis describes two otherwise isogenic clones showing low- and high levels of chloroquine resistance were grown competitively to evaluate the effect of these mutations on parasite fitness. The highly resistant strain demonstrated a loss of fitness in relation to its more sensitive progenitor and was outcompeted in untreated and low-treated infections.
Subjects/Keywords: 616.9883; drug resistance; malaria; artemisinin resistance; chloroquine resistance; Plasmodium chabaudi
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Modrzynska, K. K. (2011). Genetics of drug resistance in malaria : identification of genes conferring chloroquine and artemisinin resistance in rodent malaria parasite Plasmodium chabaudi. (Doctoral Dissertation). University of Edinburgh. Retrieved from http://hdl.handle.net/1842/4888
Chicago Manual of Style (16th Edition):
Modrzynska, Katarzyna Kinga. “Genetics of drug resistance in malaria : identification of genes conferring chloroquine and artemisinin resistance in rodent malaria parasite Plasmodium chabaudi.” 2011. Doctoral Dissertation, University of Edinburgh. Accessed October 23, 2019.
http://hdl.handle.net/1842/4888.
MLA Handbook (7th Edition):
Modrzynska, Katarzyna Kinga. “Genetics of drug resistance in malaria : identification of genes conferring chloroquine and artemisinin resistance in rodent malaria parasite Plasmodium chabaudi.” 2011. Web. 23 Oct 2019.
Vancouver:
Modrzynska KK. Genetics of drug resistance in malaria : identification of genes conferring chloroquine and artemisinin resistance in rodent malaria parasite Plasmodium chabaudi. [Internet] [Doctoral dissertation]. University of Edinburgh; 2011. [cited 2019 Oct 23].
Available from: http://hdl.handle.net/1842/4888.
Council of Science Editors:
Modrzynska KK. Genetics of drug resistance in malaria : identification of genes conferring chloroquine and artemisinin resistance in rodent malaria parasite Plasmodium chabaudi. [Doctoral Dissertation]. University of Edinburgh; 2011. Available from: http://hdl.handle.net/1842/4888
Victoria University of Wellington
30.
Coorey, Namal.
A Novel High-Throughput Screening Tool in Saccharomyces Cerevisiae.
Degree: 2012, Victoria University of Wellington
URL: http://hdl.handle.net/10063/2750
► The elucidation of drug targets and their biological effects can be aided by the identification of yeast deletion mutants that confer hypersensitivity to the drug.…
(more)
▼ The elucidation of
drug targets and their biological effects can be aided by the identification of yeast deletion mutants that confer hypersensitivity to the
drug. However, the biological activities of some compounds are reduced by the mechanisms of the pleotropic
drug resistance (PDR) network. For this reason a PDR-deficient strain with deletions in the master transcriptional regulators of the PDR network, PDR1 and PDR3 was created. This double deletion mutant strain was robotically mass mated against the non-essential deletion mutant array (DMA) to create genome wide nonessential PDR-deficient DMA (PD-DMA). No phenotypic enhancements were observed with Δpdr1Δpdr3 double mutant and the various deletion strains of the DMA.
Increased genome-wide sensitivity of the PDR-deficient mutants was demonstrated by screening pools of PD-DMA and the DMA against cycloheximide, a Pdr5p substrate and rapamycin which is not. Similar sensitivities were observed for the non-PDR substrate rapamycin for the two deletion mutant pools while sensitivity to Pdr5p substrate cycloheximide was significantly more sensitive in the PD-DMA.
The genome-wide increased sensitivity of the PDR-deficient mutants was further assessed by screening the LOPAC library of pharmacologically active compounds against pools of PD-DMA and the wild-type background DMA. The DMA screen identified 5 of 1280 compounds having bioactivity whilst the PD-DMA screen identified 25 compounds including the 5 identified by the DMA. The 20 additional compounds identified in the PDR-deficient background were inactive at the concentrations used in the wild-type background. The PD-DMA was then used in chemical genetic profiling assays; namely solid-phase chemical genetic profiling and DNA barcode microarray experiments. The PD-DMA was screened against natural products, rapamycin and cycloheximide with well characterized chemical genetic profiles. The PDR-deficient strains hypersensitivity to rapamycin and cycloheximide were indicative of TORC1 pathway inhibition and translational elongation inhibition, respectively. This was consistent with literature as rapamycin is an inhibitor of TORC1 and it mimics nutrient starvation response and cycloheximide inhibits eukaryotic translational elongation. These results validated the
utility of PD-DMA as a hypersensitive genome-wide deletion reagent for chemical genetic profiling.
Following validation of the PD-DMA, biochemical assays were performed on latrunculin-A, a less well characterised marine natural product and Plakortide-T a marine natural product with novel activity. These inhibitory drugs were shown to be PDR substrates with biological activity at low nanomolar concentrations. Latrunculin-A, was ~28 fold more potent in the PDR-deficient strain. In contrast, plakortide-T was biologically active only in the PDR-deficient background and the PDR mediated efflux did not involve the major efflux transporters.
DNA barcode microarray experiments performed with latrunculin-A identified several hypersensitive deletion mutants consistent with…
Advisors/Committee Members: Atkinson, Paul.
Subjects/Keywords: Pleiotropic drug resistance; Chemical genetics; DMA
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Coorey, N. (2012). A Novel High-Throughput Screening Tool in Saccharomyces Cerevisiae. (Masters Thesis). Victoria University of Wellington. Retrieved from http://hdl.handle.net/10063/2750
Chicago Manual of Style (16th Edition):
Coorey, Namal. “A Novel High-Throughput Screening Tool in Saccharomyces Cerevisiae.” 2012. Masters Thesis, Victoria University of Wellington. Accessed October 23, 2019.
http://hdl.handle.net/10063/2750.
MLA Handbook (7th Edition):
Coorey, Namal. “A Novel High-Throughput Screening Tool in Saccharomyces Cerevisiae.” 2012. Web. 23 Oct 2019.
Vancouver:
Coorey N. A Novel High-Throughput Screening Tool in Saccharomyces Cerevisiae. [Internet] [Masters thesis]. Victoria University of Wellington; 2012. [cited 2019 Oct 23].
Available from: http://hdl.handle.net/10063/2750.
Council of Science Editors:
Coorey N. A Novel High-Throughput Screening Tool in Saccharomyces Cerevisiae. [Masters Thesis]. Victoria University of Wellington; 2012. Available from: http://hdl.handle.net/10063/2750
◁ [1] [2] [3] [4] [5] … [38] ▶
. 
Open Access Theses and Dissertations