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Rony A.,Sudbury Regional Hospital | Chiu R.C.J.,McGill University
Stem Cells Translational Medicine | Year: 2012

Stem cell transplantation is a promising approach for improving cardiac function after severe myocardial damage, for which the use of autologous donor cells has been preferred to avoid immune rejection. Recently, however, rodent as well as human mesenchymal stem cells have been reported to be uniquely immune-tolerant, in both in vitro and in vivo transplant models. In this review, we explore in detail the current understanding of the underlying immunologic mechanisms, which can facilitate the use of such cells as "universal donor cells" with fascinating clinical implications. © AlphaMed Press.


Knockleby J.W.,Sudbury Regional Hospital | Lee H.,Sudbury Regional Hospital | Lee H.,University of Ottawa
Cell Cycle | Year: 2010

Genome replication is the most fundamental element of the continuity of life. In eukaryotes, DNA replication is regulated by an elegant network of many different protein factors to ensure the timely and accurate copying of their entire genome once per cell cycle. The replication factors include the origin recognition complex (ORC), minichromosome maintenance (MCM) proteins, Cdt1, Cdc6, Cdc7, Cdc45 and geminin. All of these proteins are involved in the regulation of DNA replication at the initiation step. Interestingly, recent studies have shown that some of these replication proteins also localize to the centrosome, often throughout the entire cell cycle. These centrosomally localized replication proteins appear to play essential roles in the regulation of centrosome biogenesis, suggesting that genome replication and segregation are regulated interdependently. In this review, we summarize and discuss the inter-dependent regulation played by some of the replication proteins. © 2010 Landes Bioscience.


Alipour M.,Laurentian University | Suntres Z.E.,Laurentian University | Suntres Z.E.,Lakehead University | Lafrenie R.M.,Laurentian University | And 2 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2010

Objectives: This study examined the activities of tobramycin and bismuth against quorum sensing, virulence factors and biofilms of Pseudomonas aeruginosa by co-encapsulating the agents in liposomes in order to achieve greater delivery of the agents. Methods: The inhibitory effects of the agents, in either their conventional (free) or vesicle-entrapped (liposomal) formulations, were assessed by measuring the changes in the quorum-sensing signal molecule N-acyl homoserine lactone, pyoverdine, pyocyanin, elastase, protease, chitinase, bacterial attachment and biofilms in vitro. Results: The effectiveness of tobramycin and bismuth was superior when they were co-administered as a liposomal formulation as measured by their ability to attenuate the production of N-acyl homoserine lactone, elastase (P<0.01), protease (P<0.05) and chitinase (P<0.01). In the presence of non-lethal concentrations of free and liposomal tobramycin and bismuth, bacterial attachment was attenuated. Biofilm formation was also attenuated with free tobramycin and bismuth, yet, in the presence of liposomal tobramycin and bismuth, biofilm complexes could form but contained mostly dead bacteria. When established biofilms were treated with higher concentrations, free tobramycin and bismuth killed and detached bacteria, while the liposomal tobramycin and bismuth penetrated and killed bacteria in the cores of the biofilms. Conclusions: These data suggest that treatment of P. aeruginosa with tobramycin and bismuth, as measured by the changes in quorum sensing, virulence factors and biofilms, is most effective when delivered as a liposomal formulation at a lower concentration compared with the free formulation. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.


Bewick M.A.,Sudbury Regional Hospital | Lafrenie R.M.,Sudbury Regional Hospital | Conlon M.S.C.,Sudbury Regional Hospital
Journal of Cancer Research and Clinical Oncology | Year: 2011

Purpose: Inter-individual variations in treatment efficacy may be influenced by polymorphisms in DNA repair genes. We investigated the association of 3 functional polymorphisms in the nucleotide excision repair (NER) pathway with survival outcome of 95 patients with metastatic breast cancer (MBC) treated with DNA-damaging chemotherapy. Methods: ERCC1 8092 C/A, ERCC2 Asp312Asn and ERCC2 Lys751Gln were determined using Taqman-based genotyping assays. Genotype associations with breast cancer-specific survival (BCSS) and progression-free survival (PFS) were evaluated using Kaplan-Meier estimates and hazard ratios calculated using Cox regression analysis. Tests for trend were conducted by calculating P-values for the HR coefficient in proportional hazards regression models. Results: ERCC2 Lys751Gln was significantly associated with BCSS (median: 24.8 months for AA/AC combined and 14.2 months for CC, HR: 1.9 (95% CI 1.06-3.26)). Median BCSS decreased with increasing number of designated adverse genotypes for the 3 polymorphisms (Ptrend = 0.003). Risk estimates for PFS were nonsignificantly elevated and were significantly elevated for BCSS for patients with 2 (HR = 2.21, 95% CI: 1.04-4.72) or 3 (HR = 6.67, 95% CI: 2.19-20.29) adverse genotypes. In treatment subgroup analysis, risk estimates for BCSS were significantly elevated for patients with 3 adverse genotypes treated with cyclophosphamide, mitoxantrone and vinblastine (HR: 11.9, 95% CI 1.77-79.51) and Ptrend = 0.02 for increasing number of adverse genotypes. Risk of progression was significantly increased for patients with 1 adverse genotype treated with cyclophosphamide, mitoxantrone and carboplatin (HR: 3.5, 95% CI 1.19-10.6) and Ptrend = 0.02 for increasing number of adverse genotypes. Conclusion: Polymorphisms in NER pathway may impact survival outcome for patients with MBC following treatment with DNA-damaging chemotherapy. These results provide support for a polygenic pathway approach for assessing the prognostic and predictive potential of polymorphisms in treatment outcome. © Springer-Verlag 2010.


Naryzhny S.N.,Sudbury Regional Hospital | Naryzhny S.N.,RAS Petersburg Nuclear Physics Institute | Lee H.,Sudbury Regional Hospital
FEBS Letters | Year: 2010

Proliferating cell nuclear antigen (PCNA) is involved in a wide range of functions in the nucleus. However, a substantial amount of PCNA is also present in the cytoplasm, although their function is unknown. Here we show, through Far-Western blotting and mass spectrometry, that PCNA is associated with several cytoplasmic oncoproteins, including elongation factor, malate dehydrogenase, and peptidyl-prolyl isomerase. Surprisingly, PCNA is also associated with six glycolytic enzymes that are involved in the regulation of steps 4-9 in the glycolysis pathway. Structured summary: MINT-7995351: G3P (uniprotkb:. P04406) and PCNA (uniprotkb:. P12004) colocalize (MI:. 0403) by fluorescence microscopy (MI:. 0416)MINT-7995334: ENOA (uniprotkb:. P06733) and PCNA (uniprotkb:. P12004) colocalize (MI:. 0403) by fluorescence microscopy (MI:. 0416)MINT-7995368: ALDOA (uniprotkb:. P04075) and PCNA (uniprotkb:. P12004) colocalize (MI:. 0403) by fluorescence microscopy (MI:. 0416)MINT-7995141: G3P (uniprotkb:. P04406) binds (MI:. 0407) to PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995182: ENOA (uniprotkb:. P06733) binds (MI:. 0407) to PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995132: G3P (uniprotkb:. P04406) physically interacts (MI:. 0915) with PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995228: PRDX6 (uniprotkb:. P30041) physically interacts (MI:. 0915) with PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995220: CAH2 (uniprotkb:. P00918) physically interacts (MI:. 0915) with PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995114: Triosephosphate isomerase (uniprotkb:. P60174) binds (MI:. 0407) to PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995244: K2C7 (uniprotkb:. P08729) physically interacts (MI:. 0915) with PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995252: ANXA2 (uniprotkb:. P07355) physically interacts (MI:. 0915) with PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995122: Triosephosphate isomerase (uniprotkb:. P60174) physically interacts (MI:. 0915) with PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995093: ALDOA (uniprotkb:. P04075) physically interacts (MI:. 0915) with PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995148: PGK1 (uniprotkb:. P00558) physically interacts (MI:. 0915) with PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995158: PGAM1 (uniprotkb:. P18669)physically interacts (MI:. 0915) with PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995166: PGAM1 (uniprotkb:. P18669) binds (MI:. 0407) to PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995105: ALDOA (uniprotkb:. P04075) binds (MI:. 0407) to PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995260: PPIA (uniprotkb:. P62937) physically interacts (MI:. 0915) with PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995173: ENOA (uniprotkb:. P06733) physically interacts (MI:. 0915) with PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995268: EF1A (uniprotkb:. P68104) physically interacts (MI:. 0915) with PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995236: MDHM (uniprotkb:. P40926) physically interacts (MI:. 0915) with PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995189: RSSA (uniprotkb:. P08865) physically interacts (MI:. 0915) with PCNA (uniprotkb:. P12004) by far western blotting (MI:. 0047)MINT-7995282: PCNA (uniprotkb:. P12004) physically interacts (MI:. 0915) with ALDOA (uniprotkb:. P00883) and G3P (uniprotkb:. P46406) by anti bait coimmunoprecipitation (MI:. 0006). © 2010 Federation of European Biochemical Societies.


Mariani M.,Sudbury Regional Hospital | Shammi P.,Baycrest Center
Clinical Neuropsychologist | Year: 2010

We present a case study of an individual diagnosed with isolated neurosarcoidosis, a rare granulomatous condition of unknown aetiology. Although the extant medical literature on this disease is adequate, no study has focused on the neuropsychological sequelae involved with such an inflammatory disorder. The case described herein is of a 57-year-old woman who participated in a neuropsychological evaluation following complaints of recurring cognitive difficulties. Results of the assessment revealed moderate difficulties in effortful word retrieval and recall of unstructured verbal information, as well as some mild mental rigidity, slowing, and subtle difficulties with attention. Her neuropsychological profile is discussed in terms of neuroanatomic lesion localization and clinical diagnostic implications.


Background This phase ii clinical trial examined the activity of a metronomic dosing schedule of docetaxel and capecitabine chemotherapy in patients with advanced breast cancer. Patients also received daily oral celecoxib in an effort to improve outcome measures and to ameliorate some of the common side effects of chemotherapy. Methods Patients received docetaxel at a starting dose of 15 mg/m 2 weekly, oral capecitabine 1250 mg/m 2 once daily, and oral celecoxib 200 mg twice daily. The primary endpoint was clinical benefit: percentage of patients experiencing either an objective response or stable disease (sd) for more than 6 months. In the absence of significant neutropenia, the dose of docetaxel was escalated after 4 and 8 weeks of treatment. Therapy was given until disease progression or development of unacceptable toxicity. The level of thymidine phosphorylase expression in peripheral white blood cells of patients was measured before and during treatment to determine the effect on this capecitabine-activating enzyme. Results Of 47 patients enrolled, 38 (81%) completed treatment to a disease endpoint. No complete responses were achieved, but 13 of the 38 patients (34%) experienced a partial response, and another 3 patients (8%) experienced sd for more than 6 months. The clinical benefit rate was therefore 42% (95% confidence interval: 27% to 57%). The median time to disease progression for all evaluable patients was 3.6months (range: 0.9-21.7 months). The most common nonhematologic toxicities were diarrhea, plantar-palmar erythrodysesthesia, fatigue, mucositis, and vomiting. Most patients (89%) received combination chemotherapy until disease progression. Conclusions The present study demonstrates that metronomic docetaxel-capecitabine chemotherapy with daily celecoxib can produce significant anticancer activity, with predictable toxicity. Efficacy fell short of expectations, with outcome measures being similar to those obtained when the study agents are given in conventional dosing. Furthermore, there is mounting evidence to indicate that a low dose of taxanes fails to induce thymidine phosphorylase expression, an effect believed to be important in achieving therapeutic synergism when taxanes are given concurrently with capecitabine. © 2012 Multimed Inc.


Santi S.A.,University of Ottawa | Santi S.A.,Sudbury Regional Hospital | Lee H.,University of Ottawa | Lee H.,Sudbury Regional Hospital
American Journal of Physiology - Cell Physiology | Year: 2010

Akt is involved in the regulation of diverse cellular functions such as cell proliferation, energy metabolism, and apoptosis. Although three Akt isoforms are known, the function of each isoform is poorly understood. To gain a better understanding of each Akt isoform, we examined the subcellular localization and expression of each isoform in transformed and nontransformed cells. Akt1 was localized in the cytoplasm, which is in agreement with the currently accepted model that cytoplasmic Akt is translocated and activated at the inner leaflet of the plasma membrane. Interestingly, HEK-293 and HEK-293T cells contained Akt1 in the nucleus and cytoplasm, respectively, suggesting that SV40 T-antigen plays a crucial role in the cytoplasmic localization and activation of Akt1 in HEK-293T. Akt2 was colocalized with the mitochondria, while Akt3 was localized in both the nucleus and nuclear membrane. The subcellular localization of the Akt isoforms was not substantially altered in response to ionizing radiation or EGF. Furthermore, the ablation of one Akt isoform by small interfering RNA (siRNA) did not alter the subcellular location of the remaining isoforms, suggesting that the major function of one isoform is not compensated for by other isoforms. Together, our data support the notion that Akt2 and Akt3 are regulated at the mitochondrial and nuclear membranes, respectively. The mitochondrial localization of Akt2 raises the possibility that this isoform may be involved in both glucose-based energy metabolism and suppression of apoptosis, two Akt functions previously identified with anti-pan-Akt antibodies. Copyright © 2010 American Physiological Society.


Mainville N.P.,Sudbury Regional Hospital | Jordan D.R.,University of Ottawa
Ophthalmic Plastic and Reconstructive Surgery | Year: 2014

PURPOSE:: To determine the incidence of new-onset diplopia and evolution of preexisting diplopia in patients with thyroid-related orbitopathy undergoing orbital decompression surgery. METHODS:: A retrospective chart review was conducted of patients who had undergone orbital decompression for thyroid-related orbitopathy between 1999 and 2008 in one of the authors' practice (D.J.). A total of 217 orbits in 123 patients were identified. The clinical indication for decompression surgery (i.e., exposure keratitis, optic neuropathy, or improvement of cosmesis) was recorded in each case, as was the presence of pre-and postoperative diplopia. The surgical technique (1-, 2-, or 3-wall decompression) was noted for each patient. RESULTS:: Review of the charts of patients who underwent orbital decompression surgery for thyroid-related orbitopathy revealed a preoperative prevalence of diplopia of 26% and a postoperative prevalence of 40.7%. Amongst the patients with preoperative diplopia (n = 32), 28.1% (n = 9) had complete resolution of their diplopia after decompression, while 65.6% (n = 21) remained stable and 6.3% (n = 2) worsened. The incidence of new-onset diplopia was 29.7% in this case series of orbital decompression using a transcaruncular and swinging eyelid approach for medial wall and strut-sparing floor decompression. Rates of new-onset diplopia were significantly higher when periorbita was opened (40.0%, n = 82) compared with when it was left intact (11.8%, n = 37) CONCLUSIONS:: It has previously been reported in the literature that orbital decompression for thyroid-related orbitopathy can cause diplopia in a significant number of cases. This provides the rational for performing orbital decompression prior to strabismus surgery in the management of thyroid-related orbitopathy. In this case series, the authors noted resolution of diplopia in a significant proportion (28.1%) of patients with preexisting diplopia. This is rarely commented on in other articles but is important in the preoperative discussion. An incidence of new-onset diplopia of 29.7% was identified. Opening the periorbita was associated with an increased incidence of new-onset diplopia. © 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.


Solomon V.R.,Sudbury Regional Hospital | Solomon V.R.,Laurentian University | Lee H.,Sudbury Regional Hospital | Lee H.,Laurentian University
Current Medicinal Chemistry | Year: 2011

Quinoline (1-azanaphthalene) is a heterocyclic aromatic nitrogen compound characterized by a double-ring structure that contains a benzene ring fused to pyridine at two adjacent carbon atoms. Quinoline compounds are widely used as "parental" compounds to synthesize molecules with medical benefits, especially with anti-malarial and anti-microbial activities. Certain quinoline-based compounds also show effective anticancer activity. This broad spectrum of biological and biochemical activities has been further facilitated by the synthetic versatility of quinoline, which allows the generation of a large number of structurally diverse derivatives. This includes numerous analogues derived from substitution of the quinoline ring system, and derivatization of quinoline ring structure. Quinoline and its analogs have recently been examined for their modes of function in the inhibition of tyrosine kinases, proteasome, tubulin polymerization and DNA repair. In this review, we have summarized our knowledge on quinoline compounds with respect to their anticancer activities, mechanisms of action, structure-activity relationship (SAR), and selective and specific activity against various cancer drug targets. In particular, we focus our review on in vitro and in vivo anticancer activities of quinoline and its analogs in the context of cancer drug development and refinement. © 2011 Bentham Science Publishers Ltd.

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