PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-5 (5)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  Multiple mechanisms underlying acquired resistance to taxanes in selected docetaxel-resistant MCF-7 breast cancer cells 
BMC Cancer  2014;14:37.
Background
Chemoresistance is a major factor involved in a poor response and reduced overall survival in patients with advanced breast cancer. Although extensive studies have been carried out to understand the mechanisms of chemoresistance, many questions remain unanswered.
Methods
In this research, we used two isogenic MCF-7 breast cancer cell lines selected for resistance to doxorubicin (MCF-7DOX) or docetaxel (MCF-7TXT) and the wild type parental cell line (MCF-7CC) to study mechanisms underlying acquired resistance to taxanes in MCF-7TXT cells. Cytotoxicity assay, immunoblotting, indirect immunofluorescence and live imaging were used to study the drug resistance, the expression levels of drug transporters and various tubulin isoforms, apoptosis, microtubule formation, and microtubule dynamics.
Results
MCF-7TXT cells were cross resistant to paclitaxel, but not to doxorubicin. MCF-7DOX cells were not cross-resistant to taxanes. We also showed that multiple mechanisms are involved in the resistance to taxanes in MCF-7TXT cells. Firstly, MCF-7TXT cells express higher level of ABCB1. Secondly, the microtubule dynamics of MCF-7TXT cells are weak and insensitive to the docetaxel treatment, which may partially explain why docetaxel is less effective in inducing M-phase arrest and apoptosis in MCF-7TXT cells in comparison with MCF-7CC cells. Moreover, MCF-7TXT cells express relatively higher levels of β2- and β4-tubulin and relatively lower levels of β3-tubulin than both MCF-7CC and MCF-7DOX cells. The subcellular localization of various β-tubulin isoforms in MCF-7TXT cells is also different from that in MCF-7CC and MCF-7DOX cells.
Conclusion
Multiple mechanisms are involved in the resistance to taxanes in MCF-7TXT cells. The high expression level of ABCB1, the specific composition and localization of β-tubulin isoforms, the weak microtubule dynamics and its insensitivity to docetaxel may all contribute to the acquired resistance of MCF-7TXT cells to taxanes.
doi:10.1186/1471-2407-14-37
PMCID: PMC3900991  PMID: 24447372
Breast cancer; Taxane; Doxorubicin; Chemoresistance; MCF-7 cell; ABC proteins; β-tubulin isoforms; Microtubule dynamics
2.  Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Aβ Reduction 
ACS medicinal chemistry letters  2012;3(11):897-902.
Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approach to the treatment of Alzheimer’s disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aβ levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aβ40 levels when administered orally to rats.
doi:10.1021/ml3001165
PMCID: PMC3568987  PMID: 23412139
BACE1; inhibitor; Alzheimer’s disease; Aβ40; iminopyrimidinone; X-ray crystallography
3.  Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS Aβ Reduction 
ACS Medicinal Chemistry Letters  2012;3(11):897-902.
Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approach to the treatment of Alzheimer’s disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aβ levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aβ40 levels when administered orally to rats.
doi:10.1021/ml3001165
PMCID: PMC3568987  PMID: 23412139
BACE1; inhibitor; Alzheimer’s disease; Aβ40; iminopyrimidinone; X-ray crystallography
4.  Toll-like Receptor 4 Polymorphisms and Aspergillosis in Stem-Cell Transplantation 
The New England journal of medicine  2008;359(17):1766-1777.
BACKGROUND
Toll-like receptors (TLRs) are essential components of the immune response to fungal pathogens. We examined the role of TLR polymorphisms in conferring a risk of invasive aspergillosis among recipients of allogeneic hematopoietic-cell transplants.
METHODS
We analyzed 20 single-nucleotide polymorphisms (SNPs) in the toll-like receptor 2 gene (TLR2), the toll-like receptor 3 gene (TLR3), the toll-like receptor 4 gene (TLR4), and the toll-like receptor 9 gene (TLR9) in a cohort of 336 recipients of hematopoietic-cell transplants and their unrelated donors. The risk of invasive aspergillosis was assessed with the use of multivariate Cox regression analysis. The analysis was replicated in a validation study involving 103 case patients and 263 matched controls who received hematopoietic-cell transplants from related and unrelated donors.
RESULTS
In the discovery study, two donor TLR4 haplotypes (S3 and S4) increased the risk of invasive aspergillosis (adjusted hazard ratio for S3, 2.20; 95% confidence interval [CI], 1.14 to 4.25; P = 0.02; adjusted hazard ratio for S4, 6.16; 95% CI, 1.97 to 19.26; P = 0.002). The haplotype S4 was present in carriers of two SNPs in strong linkage disequilibrium (1063 A/G [D299G] and 1363 C/T [T399I]) that influence TLR4 function. In the validation study, donor haplotype S4 also increased the risk of invasive aspergillosis (adjusted odds ratio, 2.49; 95% CI, 1.15 to 5.41; P = 0.02); the association was present in unrelated recipients of hematopoietic-cell transplants (odds ratio, 5.00; 95% CI, 1.04 to 24.01; P = 0.04) but not in related recipients (odds ratio, 2.29; 95% CI, 0.93 to 5.68; P = 0.07). In the discovery study, seropositivity for cytomegalovirus (CMV) in donors or recipients, donor positivity for S4, or both, as compared with negative results for CMV and S4, were associated with an increase in the 3-year probability of invasive aspergillosis (12% vs. 1%, P = 0.02) and death that was not related to relapse (35% vs. 22%, P = 0.02).
CONCLUSIONS
This study suggests an association between the donor TLR4 haplotype S4 and the risk of invasive aspergillosis among recipients of hematopoietic-cell transplants from unrelated donors.
doi:10.1056/NEJMoa0802629
PMCID: PMC2656610  PMID: 18946062
5.  Dignity in the care of older people – a review of the theoretical and empirical literature 
BMC Nursing  2008;7:11.
Background
Dignity has become a central concern in UK health policy in relation to older and vulnerable people. The empirical and theoretical literature relating to dignity is extensive and as likely to confound and confuse as to clarify the meaning of dignity for nurses in practice. The aim of this paper is critically to examine the literature and to address the following questions: What does dignity mean? What promotes and diminishes dignity? And how might dignity be operationalised in the care of older people?
This paper critically reviews the theoretical and empirical literature relating to dignity and clarifies the meaning and implications of dignity in relation to the care of older people. If nurses are to provide dignified care clarification is an essential first step.
Methods
This is a review article, critically examining papers reporting theoretical perspectives and empirical studies relating to dignity. The following databases were searched: Assia, BHI, CINAHL, Social Services Abstracts, IBSS, Web of Knowledge Social Sciences Citation Index and Arts & Humanities Citation Index and location of books a chapters in philosophy literature. An analytical approach was adopted to the publications reviewed, focusing on the objectives of the review.
Results and discussion
We review a range of theoretical and empirical accounts of dignity and identify key dignity promoting factors evident in the literature, including staff attitudes and behaviour; environment; culture of care; and the performance of specific care activities. Although there is scope to learn more about cultural aspects of dignity we know a good deal about dignity in care in general terms.
Conclusion
We argue that what is required is to provide sufficient support and education to help nurses understand dignity and adequate resources to operationalise dignity in their everyday practice. Using the themes identified from our review we offer proposals for the direction of future research.
doi:10.1186/1472-6955-7-11
PMCID: PMC2483981  PMID: 18620561

Results 1-5 (5)