April 2007

Inside this issue...

Research Breakthroughs
Discovering the Cancer "On Ramp"

New Research Breakthroughs at UHN

Cancer: Looking for the Switch

Researchers from OCI and The Campbell Family Institute for Breast Cancer Research have determined a potential “on ramp” of a cancer pathway involving p53—a master gene implicated in many human cancers.

The investigation by Drs. Hitoshi Okada and Tak Mak shows that the Bat3 protein is responsible for activating the p53 protein. Activation of p53 organizes the stress response system of a cell in order to deal with DNA damage. Bat3 signals the cell to stop growing—for DNA repair to occur—or to commit cell suicide, which ultimately suppresses tumour growth.

“Our continued efforts will investigate if mutations in the Bat3 protein are associated with specific human cancers,” says Dr. Okada. “These findings may prove Bat3’s feasibility as a cancer marker or a prognostic tool.”

Genes and Development 2007 Apr 1;21(7):848-6. [Pubmed abstract] Research was supported by The Campbell Family Institute for Breast Cancer Research, the Ontario Cancer Institute, the National Institutes of Health and the National Cancer Institute of Canada.

Heart Failure: Knowing the Signs of Failure

A recent UHN-led study provides insight into the series of events involved in f heart failure, the fastest growing epidemic in cardiovascular disease, the number one killer of Canadians. Drs. Peter Liu, Thomas Parker and Rama Khokha have determined the importance of tumour necrosis factor alpha (TNFa)—usually involved in many cell processes such as growth and survival—in regulating cardiac repair and remodeling.

Using a mouse model, researchers compared the effects of pressure load on the left ventricle of the heart in the presence and absence of TNFa. In the presence of TNFa, pressure-overloaded cardiac cells are riddled with high levels of inflammatory proteins, leading to heart dilation, and the cells eventually succumb to TNF effects, contributing to cardiac dysfunction.

When TNFa was removed, adverse heart effects were reduced. “Based on this effect, TNFa could be used to alert physicians when heart repair processes threaten to deteriorate into heart failure,” says Dr. Liu. “Even more exciting is its potential as a therapeutic tool in the treatment of patients. We stumbled upon this finding quite unexpectedly, and were surprised at its absolutely potent effect.”

Circulation. 2007 Mar 20;115(11):1398-407. Epub 2007 Mar 12. [Pubmed abstract] Research was supported by the Heart and Stroke Foundation of Ontario, the Canadian Institutes of Health Research, the Team Research Program (CHENET) and Group Program (CIHR).

Hodgkin's Lymphoma: Earlier Screening Suggested in Survivors

Hodgkin's lymphoma (HL) survivors are at a higher risk of developing other cancers over the long term—a finding that has important implications for developing screening strategies for this group—according to an international study led by OCI researchers.

A team led by Dr. David Hodgson reviewed data from more than 18,000 survivors from 13 population-based cancer registries in North America and Europe to examine the risk of developing a second cancer after treatment for HL.  Risks were significantly elevated up to 30 years after the initial HL diagnosis for all cancer types evaluated except bladder and prostate.

Among young HL survivors, the absolute risk of colorectal cancer was comparable to an average 50-54 year-old by age 35-40, long before colorectal cancer screening would generally be recommended. Similarly the risk of breast cancer in young women was significantly elevated 5- 10 years after their lymphoma diagnosis, often years before the age when routine breast cancer screening would generally be recommended.

According to Dr. Hodgson, results suggest that, in HL survivors, breast and colorectal cancer screening should be performed earlier than in the general public. 

"This work reveals a need to develop individual risk assessment and screening strategies for early detection of second cancers in HL survivors.” says Dr. Hodgson.

J Clin Oncol. 2007 Mar 19; [Epub ahead of print]. [Pubmed abstract] Research was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics, and by the Ministry of Health and Long Term Care of Ontario.

Cancer: Targeting a New Approach for Treatment

A trial led by a researcher from PMH has revealed the potential efficacy of a new type of targeted drug in the fight against a cancer normally occurring in the elderly population.

Waldenstöm’s macroglobulinemia (WM) is a cancer of the immune system that can cause low blood counts, bleeding, and enlarged lymph nodes. The multi-site cooperative trial of 27 patients, led by UHN researcher Dr. Christine Chen in partnership with the National Cancer Institute of Canada Clinical Trials Group, shows that bortezomib—a biological agent disrupting the waste pathway of cancer cells—is effective in the treatment of WM.

“This finding identifies bortezomib as a promising compound for first-line treatment in WM,” says Dr. Chen. “Current studies are addressing some neurological complications of the treatment in some patients, and we’re exploring the potential for combination therapy to increase efficacy.”

J Clin Oncol. 2007 Mar 12; [Epub ahead of print]. [Pubmed abstract] Research was supported by the National Cancer Institute of Canada and the Canadian Cancer Society

Attention Deficit Hyperactivity Disorder: Paying Attention to Genetics

A TWRI research team has made a significant discovery that disentangles the relationship reading disability (RD) and attention deficit hyperactivity disorder (ADHD)—the two most common cognitive disorders of childhood.

ADHD is characterized by inattention, hyperactivity and impulsivity while RD children display difficulty in reading single words. The ability to concentrate is required for reading longer material and the current study led by TWRI researcher Dr. Cathy Barr, used various genetic tools to examine 232 families with reading problems.

Findings show that certain forms of the gene DRD1—a gene involved in receiving signals in the brain—contributes to inattention in children with ADHD and in children with reading disabilities but not to reading ability or reading skills.

“Our study is the first non-twin research in this area. We looked at children who have been identified by their teachers to have reading problems, along with their parents and siblings,” says Dr. Barr. “We’ve shown a genetic risk factor for inattentive behaviour exists and future studies will work towards solving this very complicated puzzle.”

Mol Psychiatry. 2007 Feb 20; [Epub ahead of print]. [Pubmed abstract] Research was supported by the Hospital for Sick Children Research Training Centre, the Ontario Mental Health Foundation and Canadian Institutes of Health Research.

Cardiovascular Disease: Staying on an Even Keel

Cardiovascular disease is a major concern worldwide and a recent study by UHN researchers Drs. Michael Sole, Denise Belsham, Peter Backx and post doctoral scholar Tami Martino sheds “light” on the importance of maintaining a regular 24-hour day/night routine.

Investigators altered the day/night cycle of hypertensive mice and found this disrupted critical processes affecting heart and blood vessel structure and function, markedly worsening the effects of blood pressure on target tissues. Although daily rhythms, such as sleep, are viewed mainly as affecting brain function, the authors conclude that rhythm disturbances may have a profound harmful effect on heart and blood vessel structure, function and response as targets to unfavorable factors such as high blood pressure. Of particular interest was the discovery that returning to a normal 24-hour day/night routine reverses these adverse effects.

“Shiftworkers and patients with sleep disorders are at an increased risk of cardiovascular disease,” says Dr. Sole. "These studies suggest that the disrupted day/night cycles often seen in critical care units may impair organ healing and patient recovery.“ "Fortunately, a normal 24-hour day/night routine reverses these effects and facilitates healing.”

Hypertension. 2007 Mar 5; [Epub ahead of print]. [Pubmed abstract] Research was supported by the Allen Ephriam and Shirley Diamond Cardiomyopathy Research Fund, the Heart and Stroke Foundation of Ontario, the Heart and Stroke Foundation and the Tailored Advanced Collaborative Training in Cardiovascular Science Initiative.

Architecture of Proteins in a Nerve Ending Complex

TWRI's Dr. Elise Stanley, research associate Rajesh Khanna and technician Qi Li developed a novel method to analyze the location of individual proteins within a large complex located in the ends of nerve cells (nerve terminals).

Synaptotagmin-1 is a protein located in the nerve terminal that is known to serve as a trigger for neurotransmission. The team led by Dr. Stanley has isolated a novel synaptotagmin-1 protein complex involved in nerve terminal recovery after transmission, which was analyzed by a novel fractional recovery method.

"We exposed the complex to high salt which caused some proteins to shed at different rates. We then ranked the proteins according to their interaction strengths. Data collected after several repeats of this process were used to determine the sequence of proteins and obtain a model of the entire synaptotagmin-1 complex," says Dr. Stanley.

Researchers believe that the syntaptotagmin-1 protein complex probably functions to signal the cell to initiate the recovery process and prepare for transmission of the next nerve impulse.

PLoS ONE. 2006 Dec 20;1:e67. [Pubmed abstract] Research was supported by the Canadian Institutes of Health Research, Canada Research Chair program and the Tenenbaum Chair in Neuroscience.

Breaking News from UHN Research

Treating Sleep Apnea

A recent report on the link between sleep apnea and heart failure by TGRI researcher Dr. Douglas Bradley was featured in the Globe and Mail. For the full story visit Globeandmail.com or [Pubmed abstract].

Upcoming Events

TWRI Research Day June 18th

TWRI research will be holding its annual Research Day on Monday June 18, 2007. The event will take place at 89 Chestnut and will include posters and abstracts from basic and clinical research area.