Net Results EXPRESS (NRx) is an award-winning, monthly e-newsletter highlighting medical and scientific breakthroughs, major grants and honours awarded, and other research-related events at UHN. Through NRx you can read about ongoing research at our four research institutes, the Ontario Cancer Institute (OCI), the Toronto General Research Institute (TGRI), the Toronto Western Research Institute (TWRI) and the Toronto Rehabilitation Institute (TRI).

We hope you will find this newsletter informative and helpful. If you have feedback or questions, please contact www@uhnresearch.ca.

Christopher J. Paige, PhD, FCAHS
Vice President, Research
UHN

UHN and the Toronto Rehabilitation Institute (TRI) have given final approval for the integration of these two hospitals, effective July 1, 2011. TRI is a leading academic provider of adult rehabilitation services, complex continuing care and long-term care, and is revolutionizing rehabilitation knowledge and practice through research and education to maximize life.

The combination of TRI and UHN will provide a wide range of translational research and services. “Quite simply becoming part of the University Health Network makes good sense,” said TRI President & CEO Mark Rochon. “Bringing these two organizations together will enable clinicians to initiate rehabilitation much sooner in the acute care phase of treatment which will enhance both the quality and continuity of care as well as outcomes for patients.”

As of July 1, UHN will have approximately 14,000 employees, providing a wide range of health care services on the sites of theToronto General Hospital, Toronto Western Hospital, Princess Margaret Hospital and the five sites that make up TRI.

For more information, please visit the integration website.

TWRI’s Drs. Elena Moro and Andres Lozano have conducted a study to explore whether symptoms of movement disorders could be improved through electrical stimulation of the brain. Patients with the neurological conditions examined in this study, specifically essential tremor (ET) and Parkinson’s disease (PD), presented with severe tremor of the arms. The group implanted electrodes above the motor cortex—the region of the brain involved in motor function—in patients with ET and PD and examined the effect of varying degrees of electrical stimulation on the severity of hand tremor.

Over a period of one year, motor cortex stimulation led to decreased hand tremor in patients with ET. PD patients, however, did not show signs of improvement. “The potential advantage of cortical stimulation is that it is less complex to perform than conventional therapies, is safer for the patient and, for patients with ET, it can decrease hand tremor symptoms,” says Dr. Moro.

Unilateral subdural motor cortex stimulation improves essential tremor but not Parkinson's disease. Moro E, Schwalb JM, Piboolnurak P, Poon YY, Hamani C, Hung SW, Arenovich T, Lang AE, Chen R, Lozano AM. Brain. 2011 Jun 6. [Pubmed abstract]

This work was supported by Parkinson Society Canada.

Research into the development of acute myelogenous leukemia (AML), the most common form of leukemia in adults, is hindered by the fact that leukemic cells are not a uniform population but are in fact at different stages of development, with different growth properties. These mixed cell populations prevent investigators from identifying the genetic components involved in the growth and differentiation of leukemia cells. A recent study from the labs of OCI Senior Scientist Dr. Norman Iscove and Sunnybrook Research Institute Scientist Dr. Richard Wells has described the isolation of a new genetic factor controlling the growth of leukemic stem cells. A population of leukemia cells is thought to be composed of leukemia stem cells (LSC) and non-stem leukemia cells (NSLC). LSCs are the actively dividing cells of the disease, while NSLCs are differentiated from LSCs and are non-dividing. A novel strategy based on the analysis of single isolated cells was devised which allows these two leukemia cell types to be resolved.

By analyzing the expression of genes in leukemic cells derived from AML patients, they identified EAR-2, a gene with no previously characterized role, as being associated with the ability of these leukemic cells to survive and grow under artificial conditions. The investigators were able to show that elevated expression of EAR-2 in cells led to a prolonged growth, while decreases in EAR-2 expression led to differentiation and arrest in growth.

“The results of this study provide two major findings. The first is the identification of a new factor controlling the ability of leukemic cells to grow and differentiate,” says Dr. Iscove. “The second finding is that we now have a new potential therapeutic target in leukemia. By inhibiting EAR-2 we may be able to promote the terminal differentiation of leukemic cells and stop the growth of the disease.”

Identification of a role for the nuclear receptor EAR-2 in the maintenance of clonogenic status within the leukemia cell hierarchy. Ichim CV, Atkins HL, Iscove NN, Wells RA. Leukemia. 2011 Jun 3. [Pubmed abstract]

This work was supported by a donation from the estate of J Douglas Crashley, the Canadian Institutes of Health Research, the Terry Fox Foundation, the Princess Margaret Hospital Foundation, the Health Sciences Centre Foundation and the Ontario Ministry of Health and Long-Term Care.

Researchers at TGRI and OCI have discovered a protein switch that can trigger a cascade of events leading to heart failure. The findings, published in the Proceedings of the National Academy of Sciences, show that the absence of PINK1, a protein involved in cell metabolism, induces heart cells to produce less energy. This lack of energy causes some heart cells to die, forcing the remaining cells to work harder to keep the heart going. In response to this stress the heart muscle cells thicken, a condition known as hypertrophy.

“Our research suggests that PINK1 is an important switch that sets off a cascade of events affecting heart cell metabolism,” says lead author Dr. Phyllis Billia, Clinical Investigator at OCI and at the Peter Munk Cardiac Centre. “The discovery of PINK1's role in the development of heart failure may lead to a new treatment approach to prevent heart failure in those at risk. This discovery represents a novel and as yet, untapped mechanism to fight the battle against heart failure," adds Dr. Vivek Rao, co-author of the study and Senior Scientist at the TGRI.

PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function. Billia F, Hauck L, Konecny F, Rao V, Shen J, Mak TW. Proceedings of the National Academy of Sciences. 2011 May 23. [Pubmed abstract]

This work was supported by a grant from the Canadian Institutes of Health Research.

Multiple myeloma (MM) is a cancer of B lymphocytes, the immune cells responsible for the production of antibodies, and is diagnosed in over 2,000 Canadians every year. Elevated expression of insulin-like growth factor 1 receptor (IGF-1R) is associated with aggressive conditions of MM and poor prognosis for patient survival. IGF-1R is a special receptor for the hormone IGF-1 that plays an important role in childhood growth and metabolism in adults. OCI Scientist Dr. Suzanne Trudel and Senior Scientist I George Fantus have recently conducted a study examining the effects of a new anti-IGF-1R inhibitor drug (named GTx-134) on MM.

The team examined the effect of GTx-134 on the inhibition of growth in 14 different types of MM cancer cells, which serve as an experimental model for cancer. They observed that 11 out of the 14 types of cancer cells responded favourably to GTx-134 treatment through arrest of growth and cell death. The researchers hypothesized that the lack of response in the remaining MM cancer cells was due to a development of resistance to GTx-134. To avoid this potential problem, they examined the effect of co-treatment of MM cell lines with this drug and other conventional chemotherapy agents. This was observed to have a synergistic effect (the drugs had a greater total effect when used together than the sum of individual effects of each drug) in inhibiting cancer growth.

“By targeting IGF-1R, we are developing a drug that could better serve patients with an aggressive form of this disease,” says Dr. Trudel. “The findings from this study, combined with data showing that GTx-134 is safe and tolerable, indicate that it could serve as an effective treatment alone or in combination with other therapies.”

Molecular target characterization and anti-myeloma activity of then novel, insulin-like growth factor 1 receptoriInhibitor, GTx-134. Liang SB, Yang XZ, Trieu Y, Li ZH, Zive J, Leung-Hagesteijn C, Wei E, Zozulya S, Coss CC, Dalton JT, Fantus IG, Trudel S. Clinical Cancer Research. 2011 Jun 1. [Pubmed abstract]

This study was supported by grants from the Ontario Institute for Cancer Research, the Multiple Myeloma Research Foundation and the Canadian Institutes of Health Research.

The use of neural stem cells, cells that can develop into the different types of brain cells, to repair injured regions of the central nervous system is a promising potential therapeutic approach, however its successful use requires a better understanding of the underlying mechanisms and standardized techniques for neural cell maturation. TWRI and McEwen Centre for Regenerative Medicine’s Dr. Michael Fehlings recently published study characterizing the differentiation of stem cells into neuronal cells transplanted into a mouse model of spinal cord impairment may shed new light upon this.

“Our method of stem cell maturation follows the model of ‘default mechanism’,” says Dr. Fehlings. “In the absence of any factors directing changes of stem cells into a specific cell type, stem cells will intrinsically develop into neuronal cells.” Following this model, his group characterized the changes in gene expression of definitive neural stem cells (dNSC) as they mature into neuronal cells when transplanted into shiverer mice. Shiverer mice are an experimental strain of mice with dysfunctional oligodendrocytes, causing improper spinal cord function. Oligodendrocytes are a type of neuronal cell that insulates, or myelinates, the signaling axons of nerve cells and are critical for the function of the nervous system.

In addition to characterizing the changes that occur during the maturation process of dNSCs, they observed that they did indeed produce oligodendrocytes that became integrated with the nervous system of the mouse and expressed proteins associated with myelination. “This is the first study to show the differentiation of transplanted neural stem cells into oligodendrocytes in an animal model through the default mechanism,” added Dr. Fehlings. “This approach is a very promising potential strategy for repairing spinal cord injury.”

Generation of neural stem cells from embryonic stem cells using the default mechanism: in vitro and in vivo characterization. Rowland JW, Lee JJ, Salewski RP, Eftekharpour E, van der Kooy D, Fehlings MG. Stem Cells and Development. 2011 May 23. [Pubmed abstract]

This work was supported by the Multiple Sclerosis Society of Canada, the Canadian Institutes of Health Research, the Krembil Neuroscience Fund and the Krembil Foundation.