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Tarhonskaya H.,University of Oxford | Szollossi A.,University of Oxford | Leung I.K.H.,University of Oxford | Bush J.T.,University of Oxford | And 8 more authors.
Biochemistry | Year: 2014

Deacetoxycephalosporin C synthase (DAOCS) catalyzes the oxidative ring expansion of penicillin N (penN) to give deacetoxycephalosporin C (DAOC), which is the committed step in the biosynthesis of the clinically important cephalosporin antibiotics. DAOCS belongs to the family of non-heme iron(II) and 2-oxoglutarate (2OG) dependent oxygenases, which have substantially conserved active sites and are proposed to employ a consensus mechanism proceeding via formation of an enzyme·Fe(II)·2OG·substrate ternary complex. Previously reported kinetic and crystallographic studies led to the proposal of an unusual "ping-pong" mechanism for DAOCS, which was significantly different from other members of the 2OG oxygenase superfamily. Here we report pre-steady-state kinetics and binding studies employing mass spectrometry and NMR on the DAOCS-catalyzed penN ring expansion that demonstrate the viability of ternary complex formation in DAOCS catalysis, arguing for the generality of the proposed consensus mechanism for 2OG oxygenases. © 2014 American Chemical Society.

Northcott P.A.,German Cancer Research Center | Jones D.T.W.,German Cancer Research Center | Kool M.,German Cancer Research Center | Robinson G.W.,St Jude Childrens Research Hospital | And 11 more authors.
Nature Reviews Cancer | Year: 2012

The division of medulloblastoma into different subgroups by microarray expression profiling has dramatically changed our perspective of this malignant childhood brain tumour. Now, the availability of next-generation sequencing and complementary high-density genomic technologies has unmasked novel driver mutations in each medulloblastoma subgroup. The implications of these findings for the management of patients are readily apparent, pinpointing previously unappreciated diagnostic and therapeutic targets. In this Review, we summarize the 'explosion' of data emerging from the application of modern genomics to medulloblastoma, and in particular the recurrent targets of mutation in medulloblastoma subgroups. These data are currently making their way into clinical trials as we seek to integrate conventional and molecularly targeted therapies. © 2012 Macmillan Publishers Limited. All rights reserved.

Nanau R.M.,University of Toronto | Neuman M.G.,01 College Street
Digestive Diseases and Sciences | Year: 2012

In vitro and animals models have long been used to study human diseases and identify novel therapeutic approaches that can be applied to combat these conditions. Ulcerative colitis and Crohn's disease are the two main entities of inflammatory bowel disease (IBD). There is an intricate relationship between IBD features in human patients, in vitro and animal colitis models, mechanisms and possible therapeutic approaches in these models, and strategies that can be extrapolated and applied in humans. Malnutrition, particularly protein-energy malnutrition and vitamin and micronutrient deficiencies, as well as dysregulation of the intestinal microbiota, are common features of IBD. Based on these observations, dietary supplementation with essential nutrients known to be in short supply in the diet in IBD patients and with other molecules believed to provide beneficial anti-inflammatory effects, as well as with probiotic organisms that stimulate immune functions and resistance to infection has been tested in colitis models. Here we review current knowledge on nutritional and probiotic supplementation in in vitro and animal colitis models. While some of these strategies require further fine-tuning before they can be applied in human IBD patients, their intended purpose is to prevent, delay or treat disease symptoms in a non-pharmaceutical manner. © Springer Science+Business Media, LLC 2012.

Hojjat S.-P.,Sunnybrook Research Institute | Foltz W.,01 College Street | Wise-Milestone L.,Sunnybrook Research Institute | Whyne C.M.,Sunnybrook Research Institute
Medical Physics | Year: 2012

Purpose: Multimodal microimaging in preclinical models is used to examine the effect of spinal metastases on bony structure; however, the evaluation of tumor burden and its effect on microstructure has thus far been mainly qualitative or semiquantitative. Quantitative analysis of multimodality imaging is a time consuming task, motivating automated methods. As such, this study aimed to develop a low complexity semiautomated multimodal μCT/μMR based approach to segment rat vertebral structure affected by mixed osteolytic/osteoblastic destruction. Methods: Mixed vertebral metastases were developed via intracardiac injection of Ace-1 canine prostate cancer cells in three 4-week-old rnu/rnu rats. μCT imaging (for high resolution bone visualization), T1-weighted μMR imaging (for bone registration), and T2-weighted μMR imaging (for osteolytic tumor visualization) were conducted on one L1, three L2, and one L3 vertebrae (excised). One sample (L1-L3) was processed for undecalcified histology and stained with Goldner's trichome. The μCT and μMR images were registered using a 3D rigid registration algorithm with a mutual information metric. The vertebral microarchitecture was segmented from the μCT images using atlas-based demons deformable registration, levelset curvature evolution, and intensity-based thresholding techniques. The μCT based segmentation contours of the whole vertebrae were used to mask the T2-weighted μMR images, from which the osteolytic tumor tissue was segmented (intensity-based thresholding). Results: Accurate registration of μCT and μMRI modalities yielded precise segmentation of whole vertebrae, trabecular centrums, individual trabeculae, and osteolytic tumor tissue. While the algorithm identified the osteoblastic tumor attached to the vertebral pereosteal surfaces, it was limited in segmenting osteoblastic tissue located within the trabecular centrums. Conclusions: This semiautomated segmentation method yielded accurate registration of μCT and μMRI modalities with application to the development of mathematical models analyzing the mechanical stability of metastatically involved vertebrae and in preclinical applications evaluating new and existing treatment effects on tumor burden and skeletal microstructure. © 2012 American Association of Physicists in Medicine.

Neuman M.G.,University of Toronto | Neuman M.G.,01 College Street | Neuman M.G.,Institute of Drug Research | Schneider M.,Alcohol and Drug Abuse Research Unit | And 4 more authors.
AIDS Research and Treatment | Year: 2012

The present paper describes the possible connection between alcohol consumption and adherence to medicine used to treat human deficiency viral (HIV) infection. Highly active antiretroviral therapy (HAART) has a positive influence on longevity in patients with HIV, substantially reducing morbidity and mortality, including resource-poor settings such as South Africa. However, in a systematic comparison of HAART outcomes between low-income and high-income countries in the treatment of HIV-patients, mortality was higher in resource-poor settings. Specifically, in South Africa, patients often suffer from concomitant tuberculosis and other infections that may contribute to these results. Alcohol influences the use of medicine for opportunistic infections (e.g., pneumonia, tuberculosis), or coinfections HIV-hepatitis viruses-B (HBV) and C (HCV), cytomegalovirus, or herpes simplex virus. Furthermore, alcohol use may negatively impact on medication adherence contributing to HIV progression. The materials used provide a data-supported approach. They are based on analysis of published (2006-2011) world literature and the experience of the authors in the specified topic. Intended for use by health care professionals, these recommendations suggest approaches to the therapeutic and preventive aspects of care. Our intention was to fully characterize the quality of evidence supporting recommendations, which are reflecting benefit versus risk, and assessing strength or certainty. © 2012 Manuela G. Neuman et al.

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