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Rybak A.P.,McMaster University | Bristow R.G.,University Health Network | Bristow R.G.,University of Toronto | Kapoor A.,McMaster University
Oncotarget | Year: 2015

The cells of the prostate gland are dependent on cell signaling pathways to regulate their growth, maintenance and function. However, perturbations in key signaling pathways, resulting in neoplastic transformation of cells in the prostate epithelium, are likely to generate subtypes of prostate cancer which may subsequently require different treatment regimes. Accumulating evidence supports multiple sources of stem cells in the prostate epithelium with distinct cellular origins for prostate tumorigenesis documented in animal models, while human prostate cancer stem-like cells (PCSCs) are typically enriched by cell culture, surface marker expression and functional activity assays. As future therapies will require a deeper understanding of its cellular origins as well as the pathways that drive PCSC maintenance and tumorigenesis, we review the molecular and functional evidence supporting dysregulation of PI3K/AKT, RAS/MAPK and STAT3 signaling in PCSCs, the development of castration resistance, and as a novel treatment approach for individual men with prostate cancer. Source


Zhu C.-Q.,University Health Network | Tsao M.-S.,University Health Network | Tsao M.-S.,University of Toronto
Translational Lung Cancer Research | Year: 2014

Non-small cell lung cancer (NSCLC) is a heterogeneity disease and to date, specific clinical factors and tumor stage are established as prognostic markers. Nevertheless, prognosis within stage may vary significantly. During the last 3 decades, genes/proteins that drive tumor initiation and progression, such as oncogenes and tumor suppressor genes have been studied as additional potential prognostic markers. The protein markers as evaluated by immunohistochemistry (IHC) have previously dominated these studies. However, with the development of high-throughput techniques to interrogate genome wide genetic or gene expression changes, DNA (copy number and mutation) and RNA (mRNA and microRNA) based markers have more recently been studied as prognostic markers. Largely due to the heterogeneity and complexity of NSCLC, single gene markers including KRAS mutation has not been validated as strong prognostic markers. In contrast, several gene expression signatures representing mRNA levels of multiple genes have been developed and validated in multiple microarray datasets of independent patient cohorts. The salient features of these gene signatures and their potential value to predict benefit from adjuvant chemotherapy is discussed. © Translational lung cancer research. All rights reserved. Source


News Article
Site: http://www.rdmag.com/rss-feeds/all/rss.xml/all

Researchers have developed a new way of growing realistic human tissues outside the body. Their “person-on-a-chip” technology, called AngioChip, is a powerful platform for discovering and testing new drugs, and could eventually be used to repair or replace damaged organs. University of Toronto Professor Milica Radisic (IBBME, ChemE), graduate student Boyang Zhang and their collaborators are among those research groups around the world racing to find ways to grow human tissues in the lab under conditions that mimic a real person’s body. They have developed unique methods for manufacturing small, intricate scaffolds for individual cells to grow on. These artificial environments produce cells and tissues that resemble the real thing more closely than those grown lying flat in a petri dish. The team’s recent creations have included Biowire — an innovative method of growing heart cells around a silk suture — as well as a scaffold for heart cells that snaps together like sheets of Velcro. But AngioChip takes tissue engineering to a whole new level. “It’s a fully three-dimensional structure complete with internal blood vessels,” says Radisic. “It behaves just like vasculature, and around it there is a lattice for other cells to attach and grow.” The work — which is published in the journal Nature Materials — was produced collaboratively with researchers from across U of T, including Professor Michael Sefton (ChemE, IBBME), Professor Aaron Wheeler (Chemistry, IBBME) and their research teams, as well as researchers from Toronto General Hospital and University Health Network. Zhang built the scaffold out of POMaC, a polymer that is both biodegradable and biocompatible. The scaffold is built out of a series of thin layers, stamped with a pattern of channels that are each about 50 to 100 micrometers wide. The layers, which resemble the computer microchips, are then stacked into a 3-D structure of synthetic blood vessels. As each layer is added, UV light is used to cross-link the polymer and bond it to the layer below. When the structure is finished, it is bathed in a liquid containing living cells. The cells quickly attach to the inside and outside of the channels and begin growing just as they would in the human body. “Previously, people could only do this using devices that squish the cells between sheets of silicone and glass,” says Radisic. “You needed several pumps and vacuum lines to run just one chip. Our system runs in a normal cell culture dish, and there are no pumps; we use pressure heads to perfuse media through the vasculature. The wells are open, so you can easily access the tissue.” Using the platform, the team has built model versions of both heart and liver tissues that function like the real thing. “Our liver actually produced urea and metabolized drugs,” says Radisic. They can connect the blood vessels of the two artificial organs, thereby modelling not just the organs themselves, but the interactions between them. They’ve even injected white blood cells into the vessels and watched as they squeezed through gaps in the vessel wall to reach the tissue on the other side, just as they do in the human body. AngioChip has great potential in the field of pharmaceutical testing. Current drug-testing methods, such as animal testing and controlled clinical trials, are costly and fraught with ethical concerns. Testing on lab-grown human tissues would provide a realistic model at a fraction of the cost, but this area of research is still in its infancy. “In the last few years, it has become possible to order cultures of human cells for testing, but they’re grown on a plate, a two-dimensional environment,” says Radisic. “They don’t capture all the functional hallmarks of a real heart muscle, for example.” A more realistic platform like AngioChip could enable drug companies to detect dangerous side effects and interactions between organ compartments long before their products reach the market, saving countless lives. It could also be used to understand and validate the effectiveness of current drugs and even to screen libraries of chemical compounds to discover new drugs. Through TARA Biosystems, a spin-off company co-founded by Radisic, the team is already working on commercializing the technology. In the future, Radisic envisions her lab-grown tissues being implanted into the body to repair organs damaged by disease. Because the cells used to seed the platform can come from anyone, the new tissues could be genetically identical to the intended host, reducing the risk of organ rejection. Even in its current form, the team has shown that the AngioChip can be implanted into a living animal, its artificial blood vessels connected to a real circulatory system. The polymer scaffolding itself simply biodegrades after several months. The team still has much work to do. Each AngioChip is currently made by hand; if the platform is to be used industrially, the team will need to develop high-throughput manufacturing methods to create many copies at once. Still, the potential is obvious. “It really is multifunctional, and solves many problems in the tissue engineering space,” says Radisic. “It’s truly next-generation.”


News Article | August 19, 2016
Site: http://www.cemag.us/rss-feeds/all/rss.xml/all

The emerging field of nanomedicine holds great promise in the battle against cancer. Particles the size of protein molecules can be customized to carry tumor-targeting drugs and destroy cancer cells without harming healthy tissue. But here’s the problem: when nanoparticles are administered into the body, more than 99 percent of them become trapped in non-targeted organs, such as the liver and spleen. These nanoparticles are not delivered to the site of action to carry out their intended function. To solve this problem, researchers at the University of Toronto and the University Health Network have figured out how the liver and spleen trap intact nanoparticles as they move through the organ. “If you want to unlock the promise of nanoparticles, you have to understand and solve the problem of the liver,” says Dr. Ian McGilvray, a transplant surgeon at the Toronto General Hospital and scientist at the Toronto General Research Institute (TGRI). In a recent paper in the journal Nature Materials, the researchers say that as nanoparticles move through the liver sinusoid, the flow rate slows down 1,000 times, which increases the interaction of the nanoparticles all of types of liver cells. This was a surprising finding because the current thought is that Kupffer cells, responsible for toxin breakdown in the liver, are the ones that gobbles up the particles.  This study found that liver B-cells and liver sinusoidal endothelial cells are also involved and that the cell phenotype also matters. “We know that the liver is the principle organ controlling what gets absorbed by our bodies and what gets filtered out — it governs our everyday biological functions,” says Dr. Kim Tsoi, a U of T orthopaedic surgery resident, and a first author of the paper, who completed her PhD in biomedical engineering with Warren Chan (IBBME). “But nanoparticle drug delivery is a newer approach and we haven’t had a clear picture of how they interact with the liver — until now.” Tsoi and MacParland first examined both the speed and location of their engineered nanoparticles as they moved through the liver. “This gives us a target to focus on,” says MacParland, an immunology post-doctoral fellow at U of T and TGRI. “Knowing the specific cells to modify will allow us to eventually deliver more of the nanoparticles to their intended target, attacking only the pathogens or tumors, while bypassing healthy cells.” “Many prior studies that have tried to reduce nanomaterial clearance in the liver have focused on the particle design itself,” says Chan. “But our work now gives greater insight into the biological mechanisms underpinning our experimental observations — now we hope to use our fundamental findings to help design nanoparticles that work with the body, rather than against it.”


News Article
Site: http://www.scientificcomputing.com/rss-feeds/all/rss.xml/all

Adaptive Computing worked with High Performance Computing for Health Sciences (HPC4Health) — which consists of The Hospital for Sick Children (SickKids), University Health Network’s (UHN) Princess Margaret Cancer Center, Compute Canada and Compute Ontario — to create a converged HPC, cloud and big data environment that was capable of bringing multiple organizations together to share resources dynamically, securely and equitably. Together, we are building the engine that will help make personalized medicine and diagnostics a reality. To help bring these organizations together, Moab HPC Suite - Enterprise Edition 8.1 (Moab) was chosen for its elastic computing, advanced policies and accounting capabilities. HPC4Health has been an amazing project. We loved working with the HPC4 Health teams. They were so creative and dedicated to creating an environment that would really make a difference. Everyone knew they needed the power of HPC to analyze the massive data they were collecting and to extract the necessary data fast to make life-changing decisions. By coupling HPC with cloud, and its inherent sharing capabilities, you have this really cool, dynamic, scalable, powerful environment that can serve multiple organizations and deliver the necessary resources when each organization needs it. By creating this converged infrastructure of cloud, HPC and big data with Moab, SickKids and UHN’s Princess Margaret Cancer Center have the resources necessary to save lives! Adaptive was there from the beginning to help create technology that did not exist to make HPC4Heath’s vision a reality. We helped them build a converged data center that dynamically shared resources securely and allowed them to account for the workloads used by each organization involved in HPC4Health. The HPC4Health IT Infrastructure is configured as a single pool of resources, with each organization having dedicated resources, plus a common communal pool of resources. Each organization and their Admins manage their dedicated resources just as if it were a private data center. As workloads increase, Moab automates each organization’s growth requirements and dynamically obtains additional resources from the communal pool to handle the peak loads, and then relinquishes those resources back to the communal pool for the next peak workload requirement from any organization. All workloads are tracked per user/organization and accounted for with extensive reporting capabilities. Here are a few more details about elastic computing, advanced policies and accounting capabilities to better understand how HPC4Health is able to orchestrate their workloads and resources. Administrators from both SickKids and UHN’s Princess Margaret Cancer Centre must ensure that regularly scheduled workloads are completed, particularly during peak times. Each organization manages many users with countless needs, and the requirement to be responsive to those needs is imperative; therefore, the ability to burst workloads to other resources is extremely important. Moab tackles these challenges with elastic computing, which allows Admins to efficiently manage resource expansion by bursting to private clouds or other data center resources utilizing OpenStack. Elastic computing is triggered when a threshold set in Moab is exceeded. To determine this threshold, Moab surveys the system workload and calculates the combined completion time of these burstable workloads if no other workloads are running. Elastic computing bursts workloads, on an as-needed basis, into a communal pool of data center resources and then relinquishes these resources back to the shared pool. Using Openstack, Moab completely wipes each resource after use to help comply with Canadian privacy regulations. This added flexibility enables Admins to expand their own cluster while taking advantage of the elasticity of resources and scalability of the cloud. Some advanced policies, such as auto enforcement of Service Level Agreements (SLAs), dynamic provision of virtual resources, and job arrays, are key to the success of HPC4Health’s converged infrastructure. Usage accounting and budget enforcement enables tracking of resource usage, as well as the setting and enforcement of usage budgets by user, group, project or any custom organizational hierarchy. Resources are scheduled against that budget for a given period of time, including dynamic usage reports and a flexible conditional usage cost/charge structure. This allows HPC4Health to track usage for each organization and then each organization can further track internal usage by user, department or group. To hear more about HPC4Health, join us at SC15 in Austin, TX. Jorge Gonzalez-Outeirino, Ph.D., Facility Manager at the Centre for Computational Medicine at SickKids will be speaking in booth #833 on November 17 at 10:30 am. Also you can visit the Adaptive Computing Web site for additional information on the HPC4Health deployment.

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