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Hickey J.L.,University of Western Ontario | Simpson E.J.,University of Western Ontario | Hou J.,London Regional Cancer Program | Luyt L.G.,University of Western Ontario
Chemistry - A European Journal | Year: 2015

β-Sheets account for over 30% of all secondary structural conformations found in proteins. The intramolecular hydrogen bonding that exists between the two peptide strands is imperative in maintaining this secondary structure. With the proper design, cyclic peptides may act as scaffolds emulating active β-sheet regions, enabling investigation of their importance in molecular recognition and protein aggregation. Starting from Fmoc-Lys(Fmoc)-OH, macrocyclic peptides were synthesized on a solid support, with peptidechain elongation extending from both the alpha and epsilon amines of the lysine. The branching peptides were cyclized with a pyridyl tridentate chelation core followed by coordination using [99mTc/Re(CO)3(H2O)3]+. Variable temperature 1H NMR spectroscopy studies were performed, demonstrating that intramolecular hydrogen bonding exists between the two sides of the uncoordinated macrocyclic peptide scaffolds. Additionally, computational modelling and circular dichroism spectroscopic analysis revealed that the peptide backbone exists in a similar conformation both before and after metal coordination. The ability to seamlessly incorporate a tridentate chelation core into the backbone of a macrocyclic peptide, without disrupting the secondary structure, can greatly assist in the design of metal-centric peptidomimetic imaging agents. This novel integrated imaging probe approach may facilitate the investigation into protein-protein interactions using macrocyclic β-sheet scaffolds. © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Dranitsaris G.,Caduceus Information Systems Inc. | Vincent M.D.,London Regional Cancer Program | Yu J.,Bayer AG | Huang L.,Bayer AG | And 2 more authors.
Annals of Oncology | Year: 2012

Background: This study describes a repeated measures prediction index to identify patients at high risk of ≥ grade 2 hand-foot skin reaction (HFSR) before each week of sorafenib therapy. Methods: Data from 451 patients who received a sorafenib (400 mg bid) as part of a clinical trial were reviewed (Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: 125-134). Generalized estimating equations were used to develop the final risk model. A risk-scoring algorithm (range 0-58) was then derived from the final model coefficients. External validation was then carried out on a new sample of 1145 patients who received sorafenib under an expanded access program. Results: Pretreatment white blood cell count, female gender, good performance status, presence of lung and liver metastases and number of affected organs were predictors for ≥ grade 2 HFSR. A nonlinear association between HFSR risk and treatment duration was also identified where risk was maximized at week 5 followed by a gradual decline. Before each week of therapy, patients with risk scores >40 would be considered at high risk for developing ≥ grade 2 HFSR. Conclusions: The application and planned continued refinement of this prediction tool will be an important source of patient-specific risk information for the development of moderate to severe HFSR. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Vincent M.,London Regional Cancer Program
Current Drug Targets | Year: 2010

Platinum-based doublet chemotherapy is now established as a standard of care in the adjuvant treatment of resected stage II and stage IIIA nonsmall cell lung cancer, and seems reasonable also in resected stage IB when the primary tumor measures ≥4 cm. Several issues remain unresolved, however, including individualized selection of both the optimal platinum (cisplatin vs carboplatin), and the optimal nonplatinum drug; and identification of patients who will not need chemotherapy ("surgically cured"), as well as patients who cannot benefit because of inherently drug resistant disease. Furthermore, while efficacy remains a priority, it is also necessary to improve the management of toxicity, both because it may compromise dose intensity and because it carries a risk of morbidity and even mortality. Other issues, such as the role of postoperative radiotherapy, the choice between neoadjuvant and adjuvant approaches, the role of targeted agents, and the possibility of harm and how it can be mediated, also merit serious attention. Finally the durability of benefit, the question of late toxicity, and the importance of smoking cessation are also open questions. I will discuss a potential role for pemetrexed in the adjuvant treatment of early stage nonsmall cell lung cancer with some of these issues in mind. © 2010 Bentham Science Publishers Ltd.

Vujovic O.,London Regional Cancer Program
Current Oncology | Year: 2010

Radiation recall is a well-known phenomenon that involves the "recall" of an acute inflammatory reaction in a previously irradiated region after administration of certain drugs. The most common type of radiation recall is radiation recall dermatitis, which involves the reoccurrence of an acute inflammatory skin reaction in previously irradiated skin. Most radiation recall reactions are attributable to chemotherapeutic agents. One previously reported case of radiation recall dermatitis occurred after administration of an antibiotic. The present case report is the second of radiation recall dermatitis involving an antibiotic: azithromycin.

Mattonen S.A.,University of Western Ontario | Palma D.A.,London Regional Cancer Program | Haasbeek C.J.A.,VU University Amsterdam | Senan S.,VU University Amsterdam | Ward A.D.,University of Western Ontario
Acta Oncologica | Year: 2013

Background. For patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer, benign computed tomography (CT) changes due to radiation-induced lung injury (RILI) can be difficult to differentiate from recurrence. We measured the utility of CT image feature analysis in differentiating RILI from recurrence, compared to Response Evaluation Criteria In Solid Tumours (RECIST). Materials and methods. Twenty-two patients with 24 lesions treated with SABR were selected (11 with recurrence, 13 with substantial RILI). On each follow-up CT, consolidative changes and ground glass opacities (GGO) were contoured. For each lesion, contoured regions were analysed for mean and variation in Hounsfield units (HU), 3D volume, and RECIST size during follow-up. Results. One hundred and thirty-six CT scans were reviewed, with a median imaging follow-up of 26 months. The 3D volume and RECIST measures of consolidative changes could significantly distinguish recurrence from RILI, but not until 15 months post-SABR; mean volume at 15 months [all values ± 95% confidence interval (CI)] of 30.1 ± 19.3 cm vs. 5.1 ± 3.6 cm (p = 0.030) and mean RECIST size at 15 months of 4.34 ± 1.13 cm vs. 2.63 ± 0.84 cm (p = 0.028) respectively for recurrence vs. RILI. At nine months post-SABR, patients with recurrence had significantly higher-density consolidative changes (mean at nine months of -96.4 ± 32.7 HU vs. -143.2 ± 28.4 HU for RILI; p = 0.046). They also had increased variability of HU, an image texture metric, measured as the standard deviation (SD) of HU, in the GGO areas (SD at nine months of 210.6 ± 14.5 HU vs. 175.1 ± 18.7 HU for RILI; p = 0.0078). Conclusions. Quantitative changes in mean HU and GGO textural analysis have the potential to distinguish RILI from recurrence as early as nine months post-SABR, compared to 15 months with RECIST and 3D volume. If validated, this approach could allow for earlier detection and salvage of recurrence, and result in fewer unnecessary investigations of benign RILI. © 2013 Informa Healthcare.

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