Why do females take longer to recover from concussions than males?
A team of researchers led by Dr. Angela Colantonio, Senior Scientist at KITE (formerly Toronto Rehabilitation Institute), has found a possible explanation: females are more likely to sustain a neck injury at the time of a concussion.
Concussions are the most common type of mild traumatic brain injury sustained by Canadians. However, the condition is not very well understood. Researchers have only recently begun to uncover the differences between the sexes in response to concussions.
To better understand these differences, Dr. Colantonio’s team examined the health records of over 90,000 female and male patients admitted to an emergency department in Ontario with a mild concussion.
“Females have more distinct and weaker necks which increases the risk of sustaining a neck injury along with a concussion. We suspected that additional neck injuries may contribute to why females take longer to recover,” describes Dr. Colantonio.
In analyzing the health records, the research team found that females with concussions were more likely to experience neck injury than males.
“Neck injuries can be missed during an initial screening in the emergency department because they have similar symptoms as concussions, such as dizziness, unsteadiness and headaches,” explains Dr. Colantonio.
“This research contributes to our understanding of how concussions may be experienced differently by the sexes which informs better care and prevention of injury.”
This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the US National Institutes of Health, the Canadian Institutes of Health Research, the Alzheimer’s Association and the Toronto Rehab Foundation.
Sutton M, Chan V, Escobar M, Mollayeva T, Hu Z, Colantonio A. Neck Injury Comorbidity in Concussion-Related Emergency Department Visits: A Population-Based Study of Sex Differences Across the Life Span. J Womens Health (Larchmt). 2018 Dec 28. doi: 10.1089/jwh.2018.7282.
A new program to support breast cancer survivors
Coping with cancer and receiving treatment can leave patients scarred and emotionally drained. Having lived through a combination of surgery, chemotherapy and radiotherapy, survivors often grapple with cancer’s emotional toll long after their physical recovery.
“Breast cancer survivors may have lost one or both of their breasts, have residual scars or swelling, and start menopause prematurely,” describes Dr. Mary Jane Esplen. “These effects often cause survivors to experience grief, lowered self-esteem and confidence, and shame about the appearance of their body.”
To improve the emotional well-being of breast cancer survivors, Dr. Esplen developed a program called Restoring Body Image after Cancer (ReBIC).
The program consists of eight group sessions where participants are encouraged to generate a series of images in their mind’s eye. These exercises help them to express their personal identity and self-image difficulties and to work through them. Factors that promote a negative body image and feelings of shame are also discussed.
In a study completed by Dr. Esplen to evaluate the impact of ReBIC, participants reported improvements in body image, their quality of life and ability to manage breast cancer-related symptoms. In light of its success, ReBIC is now being offered at University Health Network.
EsplenMJ, et al. J Clin Oncol. 2018 Mar; 36(8):749-756. Supported by the Canadian Breast Cancer Foundation (now part of the Canadian Cancer Society) and the Canadian Breast Cancer Research Alliance.
Performance Upgrade for Immune CellsEnhancing immunotherapy to treat a variety of cancers
When it comes to self-improvement, we have all sorts of tools at our disposal: glasses to improve our vision, treadmills to help us stay fit, and vaccines to ward off infectious diseases.
A research team led by Dr. Naoto Hirano has engineered a molecule with the potential to enhance the effectiveness of our immune system against cancer.
Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy currently approved in the United States to treat blood cancers. It involves extracting immune cells from the patient, genetically engineering them to recognize cancerous cells, and infusing them back into the patient where they are able to target and kill cancerous cells.
“The CAR molecule enables immune cells to recognize cancerous cells,” explains Dr. Hirano.
“We have engineered an improved CAR molecule
that imparts greater potency to immune cells against different cancers, including solid tumours, and showed that it did not worsen any potential side effects in experimental models.”
Future work will focus on validating these findings and translating them into clinical trials to improve the safety and efficacy of the CAR T cell therapy.
Kagoya Y, et al. Nat Med. 2018 Mar; 24(3):352-359. Supported by Canadian Institutes of Health Research (CIHR), the Ontario Institute for Cancer Research, BioCanRx, Japan Society for the Promotion of Science, the Government of Ontario, the Natural Sciences and Engineering Research Council of Canada (NSERC), Takara Bio Inc. and The Princess Margaret Cancer Foundation (PMCF).
ittle Changes that MatterA single DNA letter variation in the genome can impact cancer risk
Just as a snowfall atop a mountain can mark the beginning of an avalanche, a single, often innocuous event can mark the beginning of a catastrophe.
Some of the most devastating cancers can also have an unremarkable beginning. Dr. Hansen He has discovered just such a seemingly innocuous event.
Tracing back the progression of prostate cancer, Dr. He and his team discovered that varying a single letter in an individual’s genetic code can increase the risk for a more aggressive form of prostate cancer.
“We found that this particular genetic variation is not in a functional region of the genome—such as a region that contains instructions for building cellular machinery or for housekeeping activities,” says Dr. He.
“Rather, it was in a region of the genome considered to have no useful information.”
“We need more studies at the genome level to understand how these single genetic variations can change the way cells regulate their activity,” adds Dr. He. “Then we can evaluate how they change the risk for cancer and take steps to prevent them from worsening outcomes.”
Hua JT, et al. Cell. 2018 Jul 26; 174(3):564-575.e18. Supported by NSERC; CIHR; the Movember Foundation; Prostate Cancer Canada; the U.S. Department of Defense; The Terry Fox Research Institute; the Ministry of Economic Development, Job Creation and Trade; and PMCF.
Immune cells in the heart work hard to eliminate viruses that damage heart muscle
Have you been sick with a cold recently? That sore and scratchy throat is caused by infection with a cold virus, which is typically eliminated by the immune system in a week or so.
In some cases, however, cold and other viruses can infect the heart, which could lead to much more serious consequences. Viral infection can cause myocarditis, inflammation of the heart muscle that can compromise its ability to pump blood. Little is known about how the immune system plays a role in this disease.
To address this gap in knowledge, Dr. Slava Epelman led a study to examine the role of dendritic cells, a type of immune cell, in viral myocarditis. His research team found that at least five types of dendritic cells reside in the heart, where they trigger immune responses to help eliminate infections.
The team noted that the two most abundant types of dendritic cells in the heart were crucial for eliminating viruses that infect the heart. The absence of these cells not only dampened the anti-virus response, but also led to significant heart damage that impaired the organ’s pumping action—an early warning sign for heart failure.
These results suggest that dendritic cells are important gatekeepers of heart health: they quickly eliminate viral infections before the infections can cause full-blown heart failure. Understanding the role that these immune cells play in this process could help with the development of new therapies to treat heart infections.
Clemente-Casares X et al. Immunity. 2017 Nov 21;47(5):974-989. Supported by the Canadian Institutes of Health Research (CIHR), the Heart and Stroke Foundation, the March of Dimes Canada, the Ted Rogers Centre for Heart Research, the Heart & Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research, the Peter Munk Cardiac Centre, the National Institutes of Health and the Toronto General & Western Hospital Foundation (TGWHF). M Cybulsky holds a Tier 1 Canada Research Chair (CRC) in Arterial Wall Biology and Atherogenesis.
Treatment for Two HIV drugs alter levels of a hormone that is critical to a healthy pregnancy
A healthy pregnant woman translates to a healthy baby. This is the reason that many women go to great lengths to improve their health once they become pregnant.
But as Dr. Lena Serghides discovered in two studies, women who are infected with the human immunodeficiency virus (HIV) face greater challenges when trying to ensure the health of their babies.
HIV-positive pregnant women are advised to take a drug regimen—commonly referred to as combination antiretroviral therapy (cART)—to prevent mother-to-child transmission of the virus. Unfortunately, these drug regimens are often associated with a number of adverse birth outcomes, including preterm delivery and low birth weight.
To better understand how these treatments affect birth outcomes, Dr. Serghides and her research team measured the levels of several different hormones in pregnant women, before and after they were randomly assigned to take two different cART regimens.
Her team found that levels of the hormone estradiol were decreased in women taking one type of cART regimen and increased in those taking the other. These changes were linked to significantly lower birth weight, suggesting that hormonal changes may contribute to the adverse birth outcomes for women taking cART.
Says Dr. Serghides, “The results of our study underscore the need for more research on the long-term effects of these regimens as they may affect fetal development by differentially altering hormone levels.”
McDonald CR et al. Clin Infect Dis. 2018 Jan 18;66(3):428-436 & Balogun KA et al. Clin Infect Dis. 2018 Jan 18;66(3):420-427. Supported by CIHR; the Ontario HIV Treatment Network G655; the Canadian Foundation for AIDS Research; the Global Alliance to Prevent Prematurity and Stillbirth; and Grand Challenges in Global Health: Preventing Preterm Birth Initiative. KC Kain holds a Tier 1 CRC in Molecular Parasitology.
Tools of the TradeA new method enables scientists to better control the production of cell types
Jack of all trades, master of none. It can be nice to have many skills, but sometimes it’s better to focus on building expertise in one key area.
The same may be true when developing cell therapies with iPS and iPL cells, as Dr. Thomas Waddell and his graduate student Li Guo found. iPS cells are stem cells that can be used to make a wide variety of cell therapies; however, their use is limited because they could grow into unwanted cell types, including tumours.
To address these limitations, the research team (along with Dr. Andras Nagy from the Lunenfeld-Tanenbaum Research Institute) used an approach called ‘interrupted reprogramming’ to make iPL cells. In contrast to iPS cells, iPL cells can be coaxed into becoming only a restricted number of different cell types, depending on the type of cell that was used to make the iPL cell.
This method makes it easier to control which cell types can be produced and to create batches of cells that are more pure.
To explore the potential use of iPL cells to treat respiratory disease, the research team focused on a type of cell—known as a club cell—that is found on the inner surface of the lungs. They used their approach to convert club cells into iPL cells; then, they coaxed the iPL cells into becoming other types of lung cells, such as goblet cells, which produce a thick fluid that traps foreign substances in the lungs.
This method could be used to develop new cell-based therapies to speed up the healing process after lung injury or to repair donor lungs before transplantation.
Guo L et al. Stem Cell Reports. 2017 Dec 12;9(6):1780-1795. Supported by the Hospital for Sick Children Transplant and Regenerative Medicine Program, CIHR, the Ontario Research Fund and TGWHF. TK Waddell holds the Pearson-Ginsberg Chair in Thoracic Surgery and the Thomson Family Chair in Translational Research. A Nagy holds a Tier 1 CRC in Stem Cells and Regeneration.
Findings published in Cell have revealed that a rarely studied type of genetic material—known as circular RNA—is prevalent in prostate cancer and some of this genetic material is essential for growth of the cancer.
The work was carried out in the labs of Drs. Housheng Hansen He at the Princess Margaret Cancer Centre and Paul Boutros at the University of California, Los Angeles (formerly at the Ontario Institute of Cancer Research).
“Novel sequencing approaches have opened up a new realm of research. By studying this circular genetic material in prostate cancer, we’ve uncovered a wealth of insight into how the cancer grows and spreads, while uncovering potential new strategies to target and kill it,” says Dr. He, lead author of the study.
The main type of genetic material in the cell—known as genomic DNA—serves as the ‘source book’ that holds the information required by cells to carry out chemical reactions required for life. DNA is also used by the cell to create or ‘code for’ other forms of genetic material, including RNA, which is thought of as the ‘working copy’ of the genetic code.
Much of the DNA and RNA found in the cell resembles a string or rope of varying lengths; however, some of it can be joined end to end to create a circular molecule.
Dr. He and his collaborators began to suspect that circular RNA may be important for prostate cancer growth because previous studies have suggested that various distinct forms of RNA are present in prostate cancer cells. As well, circular RNA has been implicated in other types of cancers, such as colon and breast cancer.
The researchers used a technique known as ultra-deep sequencing to define the circular RNA present within 144 tumours from patients with prostate cancer. They identified over 76 thousand circular RNAs—more than 30 thousand of which had not been previously described.
The researchers then compared the genetic data to patient outcomes, revealing that tumours from individuals with the most aggressive types of prostate cancer tended to have aberrant production of circular RNAs.
The researchers took this work one step further by targeting and inhibiting specific circular RNA molecules in experimental models of prostate cancer. They found that around 11% of the circular RNA was important for driving cancer growth—emphasizing its potential to serve as a new anticancer target.
This work was supported by the Princess Margaret Cancer Foundation, the Princess Margaret Genomic Centre, the Ontario Institute for Cancer Research, Prostate Cancer Canada, Terry Fox Research Institute, the Canada Foundation for Innovation, the Ontario Research Fund, the Natural Sciences and Engineering Research Council of Canada, the Canadian Cancer Society, the Canadian Institutes of Health Research, the Shanghai Committee of Science and Technology, University of Toronto and The Center for Translational Molecular Medicine.
Chen S, et al. Widespread and Functional RNA Circularization in Localized Prostate Cancer. Cell. 2019 Feb 7. doi: https://doi.org/10.1016/j.cell.2019.01.025.
Using artificial intelligence to optimize treatment in Parkinson disease
Artificial intelligence (AI) has blurred the lines between science fiction and reality with self-driving cars, humanoid robots and virtual assistants. Researchers are also harnessing its power to improve treatments for diseases, like Parkinson disease.
Parkinson disease is characterized by slowed and stiff movements and tremors. Although these symptoms can be controlled through medications like levodopa, many patients who take levodopa experience side effects such as muscle spasms and involuntary movements.
A major challenge for neurologists is adjusting levodopa’s dosage, so that the disease symptoms are reduced without worsening the drug’s side effects. Moreover, evaluating the side effects’ severity is subjective and varies by neurologist.
To remedy this, a research team led by Dr. Babak Taati is using a form of AI known as deep learning.
The researchers captured short videos of patients receiving infusions of levodopa and used the deep learning algorithm to measure the severity of the patients’ spasms and involuntary movements. Their findings revealed that the AI algorithm performed as well as or better than neurologists at gauging treatment response.
“Our AI algorithm was able to accurately detect the onset and the remission of side effects in response to levodopa infusion. We hope to turn our algorithm into a clinical tool that helps doctors prescribe more effective treatments,” says Dr. Taati.
Li MH et al. Parkinsonism Relat Disord. 2018 Aug;53:42-45. Supported by the Natural Sciences and Engineering Research Council, Toronto Rehab Foundation (TRF) and the Toronto General & Western Hospital Foundation.
Shock Your Socks offElectrical stimulation could alleviate symptoms of sleep apnea
Electricity is a powerful treatment for many conditions. It can keep the heart beating at a healthy pace and restore movement in paralyzed limbs.
Dr. Azadeh Yadollahi discovered that electricity could also be used to prevent the accumulation of excess fluid in legs.
During prolonged periods of inactivity, fluid tends to pool in the legs. This can lead to a variety of complications including painful swelling and increased risk of leg ulcers and blood clots. While sleeping, the excess leg fluid can also move into the neck, where it can worsen the symptoms of sleep apnea, a disorder in which breathing slows or stops for minutes at a time during sleep.
In a recent study, Dr. Yahollahi tested whether electrical stimulation of calf muscles could reduce leg fluid buildup.
She measured fluid buildup in the legs of 13 patients with sleep apnea while they sat for 1.5 hours during two separate sessions. In one session, the electrical therapy was applied through a custom-made sock; whereas in the other session, participants received a mock therapy. She found that electrical stimulation reduced fluid buildup by 43% and leg swelling by almost 90%.
“Our findings show that electrical stimulation of the calf is a promising strategy to prevent leg fluid accumulation. The improvements that we observed suggest that our approach has the potential to ease the symptoms of sleep apnea,” says Dr. Yadollahi.
Vena D, et al. Sci Rep. 2017 Jul 20;7(1):6055. Supported by TRF.
Setting a High Bar for SafetyDefining the features of the best handrails to prevent falls
A massive, one-of-a-kind research facility is located underneath Toronto Rehab, and researchers are using it to help make the world a safer and more accessible place for everyone.
Known as the Challenging Environment Assessment Laboratory (CEAL), this facility houses a cutting-edge hydraulic motion simulator that can be used to mimic everyday environmental challenges, such as driving with headlight glare or walking on an icy, inclined surface.
Dr. Alison Novak and her team recently used CEAL to improve the design of handrails to help prevent falls in healthy adults.
The research team asked study participants wearing safety harnesses to stand next to a handrail within the advanced motion simulator (illustrated below). The platform was then programmed to deliver quick and sudden movements to make participants fall. The resulting falls were recorded with motion capture cameras, while handrail sensors recorded forces applied to the rail.
The team found that participants’ ability to recover their balance and control during a fall increased as the height of the handrail increased, and that higher handrails might provide greater stability with reduced physical demands.
“Given that the handrail heights that we tested are within the range required by the International Building Code, our findings could be used to improve current building standards,” explains Dr. Novak.
“Future research will determine the handrail features to prevent falls in older adults and people with mobility or balance impairments, as these individuals are at high risk of falls and fall-related injuries.”
Komisar V et al. Gait Posture. 2017 Dec 14(60);209-216. Supported by Canadian Institutes of Health Research, AGE-WELL (Aging Gracefully across Environments using Technology to Support Wellness, Engagement and Long Life), Toronto Rehabilitation Institute, the University of Toronto and TRF.
Welcome to the latest issue of The Krembil.
The Krembil is the official newsletter of the Krembil Research Institute (formerly the Toronto Western Research Institute). Research at Krembil is focused on finding innovative treatments and cures for chronic debilitating disorders, including arthritis and diseases of the brain and eyes.
Stories in this month’s issue include:
● THE YEAR IN REVIEW: A message from Dr. Donald Weaver, Director of the Krembil Research Institute.
● PITCHING LIKE A PRO: Krembil will host a competition to help researchers better showcase their work to the public.
● ONE MUTATION SPANNING TWO COUNTRIES: What do Finns and Canadians have in common? A gene mutation that causes Parkinson disease.
● PUTTING LABELS ON PROTEIN BEHAVIOUR: UHN researchers expand database of interactions between proteins to accelerate drug discovery.
● LOCATION IS EVERYTHING: Better brain treatment targeting improves outcomes for individuals with essential tremor.
● SPARKING CURIOSITY: Research study provides new insight on what makes us more open to new experiences.
Read these stories and more online here. To read previous issues, see the newsletter archive.
Enlisting tiny nanoparticles to deliver a new kind of therapy for lung cancer
They say good things come in small packages. A recent therapy developed by Dr. Kazuhiro Yasufuku epitomizes this phrase. Measuring less than a thousand times the width of a single hair, it promises to transform the way that lung cancer is treated.
The approach uses a technology known as small interfering RNA (siRNA), which can be used to target and silence the genes that drive lung cancer cell growth.
However, delivering this promising drug to cancer cells has been a challenge because the siRNAs are just as likely to kill a healthy cell as a cancer cell.
To overcome this challenge, Dr. Yasufuku linked an siRNA molecule to a tiny nanoparticle that specifically infiltrates lung cancer cells. These newly designed nanoparticles dramatically slowed the growth of lung cancer cells in an experimental model of disease without affecting healthy cells.
Explains Dr. Yasufuku “Our study demonstrates that it is possible to develop siRNAs that target cancer cells more precisely. We are refining this technique in hopes of developing customized siRNA treatments for patients with advanced lung cancer who currently have little to no therapeutic options and high rates of mortality.”
Kato T, et al. Mol Cancer Res. 2017 Oct 9. pii: molcanres.0341.2016. Supported by The Princess Margaret Cancer Foundation.
