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Barnett D.A.,Atlantic Cancer Research Institute | Barnett D.A.,Mount Allison University | Ouellette R.J.,Atlantic Cancer Research Institute | Ouellette R.J.,Université de Sherbrooke
Rapid Communications in Mass Spectrometry | Year: 2011

Cylindrical geometry high-field asymmetric waveform ion mobility spectrometry (FAIMS) focuses and separates gas-phase ions at atmospheric pressure and room (or elevated) temperature. Addition of helium to a nitrogen-based separation medium offers significant advantages for FAIMS including improved resolution, selectivity and sensitivity. Aside from gas composition, ion transmission through FAIMS is governed by electric field strength (E/N) that is determined by the applied voltage, the analyzer gap width, atmospheric pressure and electrode temperature. In this study, the analyzer width of a cylindrical FAIMS device is varied from 2.5 to 1.25 mm to achieve average electric field strengths as high as 187.5 Townsend (Td). At these electric fields, the performance of FAIMS in an N 2 environment is dramatically improved over a commercial system that uses an analyzer width of 2.5 mm in 1:1 N 2/He. At fields of 162 Td using electrodes at room temperature, the average effective temperature for the [M + 2 H] 2+ ion of angiotensin II reaches 365 K. This has a dramatic impact on the curtain gas flow rate, resulting in lower optimum flows and reduced turbulence in the ion inlet. The use of narrow analyzer widths in a N 2 carrier gas offers previously unattainable baseline resolution of the [M + 2 H] 2+ and [M + 3 H] 3+ ions of angiotensin II. Comparisons of absolute ion current with FAIMS to conventional electrospray ionization (ESI) are as high as 77% with FAIMS versus standard ESI-MS. Copyright © 2011 John Wiley & Sons, Ltd.


Culf A.S.,Atlantic Cancer Research Institute | Culf A.S.,Mount Allison University | Ouellette R.J.,Atlantic Cancer Research Institute
Molecules | Year: 2010

Peptoids (N-substituted polyglycines and extended peptoids with variant backbone amino-acid monomer units) are oligomeric synthetic polymers that are becoming a valuable molecular tool in the biosciences. Of particular interest are their applications to the exploration of peptoid secondary structures and drug design. Major advantages of peptoids as research and pharmaceutical tools include the ease and economy of synthesis, highly variable backbone and side-chain chemistry possibilities. At the same time, peptoids have been demonstrated as highly active in biological systems while resistant to proteolytic decay. This review with 227 references considers the solid-phase synthetic aspects of peptoid preparation and utilization up to 2010 from the instigation, by R. N. Zuckermann et al., of peptoid chemistry in 1992. © 2010 by the authors; licensee MDPI, Basel, Switzerland.


Culf A.S.,Atlantic Cancer Research Institute | Cuperlovic-Culf M.,National Research Council Canada | Leger D.A.,Atlantic Cancer Research Institute | Decken A.,University of New Brunswick
Organic Letters | Year: 2014

A convenient and efficient methodology for the head-to-tail macrocyclization of small 3-mer, 4-mer, and 5-mer α-peptoid acids (9-, 12-, and 15-atom N-substituted glycine oligomers) is described. The cyclic trimer has a ccc amide sequence in the crystal structure, whereas the tetramer has ctct and the pentamer has ttccc stereochemistry. NMR analysis reveals rigid structures in solution. These synthetic macrocycles may prove useful in medicinal and materials applications. © 2014 American Chemical Society.


Cuperlovic-Culf M.,National Research Council Canada | Culf A.S.,Atlantic Cancer Research Institute | Touaibia M.,University of Moncton | Lefort N.,Atlantic Cancer Research Institute
Future Oncology | Year: 2012

The metabolism of tumors is remarkably different from the metabolism of corresponding normal cells and tissues. Metabolic alterations are initiated by oncogenes and are required for malignant transformation, allowing cancer cells to resist some cell death signals while producing energy and fulfilling their biosynthetic needs with limiting resources. The distinct metabolic phenotype of cancers provides an interesting avenue for treatment, potentially with minimal side effects. As many cancers show similar metabolic characteristics, drugs targeting the cancer metabolic phenotype are, perhaps optimistically, expected to be 'magic bullet treatments. Over the last few years there have been a number of potential drugs developed to specifically target cancer metabolism. Several of these drugs are currently in clinical and preclinical trials. This review outlines examples of drugs developed for different targets of significance to cancer metabolism, with a focus on small molecule leads, chemical biology and clinical results for these drugs. © 2012 Future Medicine Ltd.


Gillis L.D.,Atlantic Cancer Research Institute | Lewis S.M.,Atlantic Cancer Research Institute | Lewis S.M.,Dalhousie University | Lewis S.M.,University of New Brunswick
Oncogene | Year: 2013

eIF3e/Int6 is a component of the multi-subunit eIF3 complex, which binds directly to the 40S ribosome to facilitate ribosome recruitment to mRNA and hence protein synthesis. Reduced expression of eIF3e/Int6 has been found in up to 37% of human breast cancers, and expression of a truncated mutant version of the mouse eIF3e/Int6 protein leads to malignant transformation of normal mammary cells. These findings suggest that eIF3e/Int6 is a tumor suppressor; however, a recent study has reported that a reduction of eIF3e/Int6 expression in breast cancer cells leads to reduced translation of oncogenes, suggesting that eIF3e/Int6 may in fact have an oncogenic role in breast cancer. To gain a better understanding of the role of eIF3e/Int6 in breast cancer, we have examined the effects of decreased eIF3e/Int6 expression in an immortalized breast epithelial cell line, MCF-10A. Surprisingly, we find that decreased expression of eIF3e/Int6 causes breast epithelial cells to undergo epithelial-to-mesenchymal transition (EMT). We show that EMT induced by a decrease in eIF3e/Int6 expression imparts invasive and migratory properties to breast epithelial cells, suggesting that regulation of EMT by eIF3e/Int6 may have an important role in breast cancer metastasis. Furthermore, we show that reduced eIF3e/Int6 expression in breast epithelial cells causes a specific increase in the expression of the key EMT regulators Snail1 and Zeb2, which occurs at both the transcriptional and post-transcriptional levels. Together, our data indicate a novel role of eIF3e/Int6 in the regulation of EMT in breast epithelial cells and support a tumor suppressor role of eIF3e/Int6. © 2013 Macmillan Publishers Limited.


Shukla P.K.,CSIR - Central Electrochemical Research Institute | Kumar A.,Atlantic Cancer Research Institute
Microbial Pathogenesis | Year: 2015

There has been an increase in the cases of fungal resistance against many antifungal drugs and an effective alternative mode in the form of immunotherapy is being considered as new hope. The adhesion of Aspergillus fumigatus conidia to the host components is one of the prime factors to cause aspergillosis. Carbohydrate components or glycoproteins present on the cell surface play an important role in interaction of the organism to the host and leads to adhesion. Any substance which is capable of disrupting this interaction may be a vital tool for the fungal clearance and hence may protect the host from infections caused by the fungus. In this study, a murine monoclonal antibody IgM generated against the secretory antigens of A.fumigatus, was found to be specific to a common epitope containing glyco-moieties of the various proteins and exhibited anti-adhesive potential invitro. © 2015 Elsevier Ltd.


Liwak U.,Ottawa Hospital Research Institute | Liwak U.,University of Ottawa | Thakor N.,Ottawa Hospital Research Institute | Jordan L.E.,Ottawa Hospital Research Institute | And 8 more authors.
Molecular and Cellular Biology | Year: 2012

Apoptosis can be regulated by extracellular signals that are communicated by peptides such as fibroblast growth factor 2 (FGF-2) that have important roles in tumor cell proliferation. The prosurvival effects of FGF-2 are transduced by the activation of the ribosomal protein S6 kinase 2 (S6K2), which increases the expression of the antiapoptotic proteins X chromosome-linked Inhibitor of Apoptosis (XIAP) and Bcl-xL. We now show that the FGF-2-S6K2 prosurvival signaling is mediated by the tumor suppressor programmed cell death 4 (PDCD4). We demonstrate that PDCD4 specifically binds to the internal ribosome entry site (IRES) elements of both the XIAP and Bcl-xL messenger RNAs and represses their translation by inhibiting the formation of the 48S translation initiation complex. Phosphorylation of PDCD4 by activated S6K2 leads to the degradation of PDCD4 and thus the subsequent derepression of XIAP and Bcl-xL translation. Our results identify PDCD4 as a specific repressor of the IRES-dependent translation of cellular mRNAs (such as XIAP and Bcl-xL) that mediate FGF-2-S6K2 prosurvival signaling and provide further insight into the role of PDCD4 in tumor suppression. © 2012, American Society for Microbiology.


O'Brien P.,University of Moncton | O'Brien P.,Atlantic Cancer Research Institute | Morin Jr. P.,University of Moncton | Ouellette R.J.,University of Moncton | And 3 more authors.
Cancer Research | Year: 2011

The Pax-5 oncogene encodes a potent transcription factor that plays a key role in B-cell development and cancerous processes. In normal B-lymphopoiesis, Pax-5 accomplishes a dual function by activating B-cell commitment genes while concomitantly repressing non-B-lineage genes. Given the pivotal importance of Pax-5-mediated processes in B-cell development, an aberrant regulation of Pax5 expression has consistently been associated with B-cell cancers, namely, lymphoma and lymphocytic leukemias. More recently, Pax-5 gene expression has been proposed to influence carcinogenic events in tissues of nonlymphoid origin by promoting cell growth and survival. However, in other cases, Pax-5 products have opposing effects on proliferative activity, thus redefining its generally accepted role as an oncogene in cancer. In this review, we attempt to summarize recent findings about the function and regulation of Pax-5 gene products in B-cell development and related cancers. In addition, we present new findings that highlight the pleiotropic effects of Pax-5 activity in a number of other cancer types. ©2011 AACR.


Patent
Atlantic Cancer Research Institute | Date: 2013-07-19

The present disclosure relates to a method for the isolation of microvesicles comprising contacting the sample with at least one polysaccharide to isolate the microvesicles.


Steeves C.H.,Dalhousie University | Potrykus J.,Dalhousie University | Barnett D.A.,Atlantic Cancer Research Institute | Bearne S.L.,Dalhousie University
Proteomics | Year: 2011

The anaerobic, Gram-negative bacillus Fusobacterium nucleatum plays a vital role in oral biofilm formation and the development of periodontal disease. The organism plays a central bridging role between early and late colonizers within dental plaque and plays a protective role against reactive oxygen species. Using a two-dimensional gel electrophoresis and mass spectrometry approach, we have annotated 78 proteins within the proteome of F. nucleatum subsp. nucleatum and identified those proteins whose apparent intracellular concentrations change in response to either O2- or H2O2-induced oxidative stress. Three major protein systems were altered in response to oxidative stress: (i) proteins of the alkyl hydroperoxide reductase/thioredoxin reductase system were increased in intracellular concentration; (ii) glycolytic enzymes were modified by oxidation (i.e. D-glyceraldehyde 3-phosphate dehydrogenase, and fructose 6-phosphate aldolase) or increased in intracellular concentration, with an accompanying decrease in ATP production; and (iii) the intracellular concentrations of molecular chaperone proteins and related proteins (i.e. ClpB, DnaK, HtpG, and HrcA) were increased. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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