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Song M.S.,Beth Israel Deaconess Medical Center | Salmena L.,Beth Israel Deaconess Medical Center | Salmena L.,Ontario Cancer Institute | Pandolfi P.P.,Beth Israel Deaconess Medical Center
Nature Reviews Molecular Cell Biology | Year: 2012

The importance of the physiological function of phosphatase and tensin homologue (PTEN) is illustrated by its frequent disruption in cancer. By suppressing the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway through its lipid phosphatase activity, PTEN governs a plethora of cellular processes including survival, proliferation, energy metabolism and cellular architecture. Consequently, mechanisms regulating PTEN expression and function, including transcriptional regulation, post-transcriptional regulation by non-coding RNAs, post-translational modifications and proteing-protein interactions, are all altered in cancer. The repertoire of PTEN functions has recently been expanded to include phosphatase-independent activities and crucial functions within the nucleus. Our increasing knowledge of PTEN and pathologies in which its function is altered will undoubtedly inform the rational design of novel therapies. © 2012 Macmillan Publishers Limited. All rights reserved.


McIlwain D.R.,Ontario Cancer Institute
Cold Spring Harbor perspectives in biology | Year: 2013

Caspases are a family of endoproteases that provide critical links in cell regulatory networks controlling inflammation and cell death. The activation of these enzymes is tightly controlled by their production as inactive zymogens that gain catalytic activity following signaling events promoting their aggregation into dimers or macromolecular complexes. Activation of apoptotic caspases results in inactivation or activation of substrates, and the generation of a cascade of signaling events permitting the controlled demolition of cellular components. Activation of inflammatory caspases results in the production of active proinflammatory cytokines and the promotion of innate immune responses to various internal and external insults. Dysregulation of caspases underlies human diseases including cancer and inflammatory disorders, and major efforts to design better therapies for these diseases seek to understand how these enzymes work and how they can be controlled.


Simpson J.T.,Ontario Cancer Institute
Bioinformatics | Year: 2014

Motivation: The de novo assembly of large, complex genomes is a significant challenge with currently available DNA sequencing technology. While many de novo assembly software packages are available, comparatively little attention has been paid to assisting the user with the assembly. Results: This article addresses the practical aspects of de novo assembly by introducing new ways to perform quality assessment on a collection of sequence reads. The software implementation calculates per-base error rates, paired-end fragment-size distributions and coverage metrics in the absence of a reference genome. Additionally, the software will estimate characteristics of the sequenced genome, such as repeat content and heterozygosity that are key determinants of assembly difficulty. © The Author 2013. Published by Oxford University Press.


Khokha R.,Ontario Cancer Institute
Cold Spring Harbor perspectives in biology | Year: 2011

The adult mammary structure provides for the rapid growth, development, and immunological protection of the live-born young of mammals through its production of milk. The dynamic remodeling of the branched epithelial structure of the mammary gland in response to physiological stimuli that allow its programmed branching morphogenesis at puberty, cyclical turnover during the reproductive cycle, differentiation into a secretory organ at parturition, postlactational involution, and ultimately, regression with age is critical for these processes. Extracellular metalloproteinases are essential for the remodeling programs that operate in the tissue microenvironment at the interface of the epithelium and the stroma, coupling form with function. Deregulated proteolytic activity drives the transition of a physiological mammary microenvironment into a tumor microenvironment, facilitating malignant transformation.


Stein L.D.,Ontario Cancer Institute
Genome Biology | Year: 2010

With DNA sequencing now getting cheaper more quickly than data storage, the time may have come to use cloud computing for genome informatics. © 2010 BioMed Central Ltd.


Integrin α11β1 is a stromal cell-specific receptor for fibrillar collagens and is overexpressed in carcinoma-associated fibroblasts (CAFs). We have investigated its direct role in cancer progression by generating severe combined immune deficient (SCID) mice deficient in integrin α11 (α11) expression. The growth of A549 lung adenocarcinoma cells and two patient-derived non-small cell lung carcinoma (NSCLC) xenografts in these α11 knockout (α11-/-) mice was significantly impeded, as compared with wild-type (α11+/+) SCID mice. Orthotopic implantation of a spontaneously metastatic NCI-H460SM cell line into the lungs of α11-/- and α11+/+ mice showed significant reduction in the metastatic potential of these cells in the α11-/- mice. We identified that collagen cross-linking is associated with stromal α11 expression, and the loss of tumor stromal α11 expression was correlated with decreased collagen reorganization and stiffness. This study shows the role of integrin α11β1, a receptor for fibrillar collagen in differentiation of fibroblasts into CAFs. Furthermore, our data support an important role for α11 signaling pathway in CAFs, promoting tumor growth and metastatic potential of NSCLC cells and being closely associated with collagen cross-linking and the organization and stiffness of fibrillar collagen matrices.Oncogene advance online publication, 6 July 2015; doi:10.1038/onc.2015.254. © 2015 Macmillan Publishers Limited


Asa S.L.,Ontario Cancer Institute
Modern Pathology | Year: 2011

The endocrine cells of the pancreas and their related cells throughout the gastrointestinal tract give rise to a variety of tumors that pose a diagnostic challenge. There has been progress in understanding their histogenesis, morphology, immunohistochemistry, molecular biology and classifications. This review will focus on nomenclature/terminology, classification, the role of immunohistochemistry, molecular advances, including genetic predisposition, and potential therapeutic targets to define the role of pathology in the application of prognostic and predictive markers for this disease. © 2011 USCAP, Inc. All rights reserved.


Watson I.D.G.,Ontario Cancer Institute | Dean Toste F.D.,University of California at Berkeley
Chemical Science | Year: 2012

This review describes important recent advancements in asymmetric cycloisomerization reactions. A wide variety of catalytic and asymmetric strategies have been applied to these reactions over the past twenty years. Cycloisomerization reactions have the ability to produce diverse polycyclic compounds in excellent yields and selectivity. They constitute a powerful and efficient strategy for asymmetric carbon-carbon bond formation in cyclic compounds. Enyne and related olefin cyclizations comprise the majority of reactions of this type and important advances have recently occurred in this area. However, significant changes have also occurred in the area of classical cyclization as well as intramolecular hydroacylation and C-H activation initiated cyclization and these will also be described. © 2012 The Royal Society of Chemistry.


Dancey J.,Ontario Cancer Institute
Nature Reviews Clinical Oncology | Year: 2010

Mammalian target of rapamycin (mTOR) is a protein kinase of the PI3K/Akt signaling pathway. Activation of mTOR in response to growth, nutrient and energy signals leads to an increase in protein synthesis, which is required for tumor development. This feature makes mTOR an attractive target for cancer therapy. First-generation mTOR inhibitors are sirolimus derivatives (rapalogs), which have been evaluated extensively in cancer patients. Everolimus and temsirolimus are already approved for the treatment of renal-cell carcinoma. Temsirolimus is also approved for the treatment of mantle-cell lymphoma. These drugs, in addition to ridaforolimus (formerly deforolimus) and sirolimus, are currently being evaluated in clinical trials of various cancers. Second-generation mTOR inhibitors are small molecules that target the kinase domain, and have also entered clinical development. Clinical trials are underway to identify additional malignancies that respond to mTOR inhibitors, either alone or in combination with other therapies. Future research should evaluate the optimal drug regimens, schedules, patient populations, and combination strategies for this novel class of agents. © 2010 Macmillan Publishers Limited. All rights reserved.


Patent
Ontario Cancer Institute | Date: 2015-01-16

There is provided herein, systems, devices and methods for determining a risk of recurrence of cancer following a cancer therapy of a patient by determining genomic instability of a tumour. There is further provided systems, devices and methods for categorizing a patient into a prognostic cancer sub-group by using copy number alterations.

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