A team of researchers led by Krembil Director and Senior Scientist Dr. Donald Weaver has shown that the diuretic medication furosemide can reduce inflammation in brain cells. This finding reveals that furosemide could serve as a new starting point for the design of innovative treatments for Alzheimer disease.
Alzheimer disease is the most common cause of dementia. Currently over 700,000 Canadians experience dementia—a number that is expected to double in the next decade. While current medications can slow the development of symptoms such as memory impairment, no treatment exists that can stop or reverse the progression of the disease.
“For patients battling Alzheimer disease and families watching their loved ones disappear, existing symptomatic treatments are not enough,” says Dr. Weaver.
To address the need for new treatments, Dr. Weaver’s research team is searching for ways to prevent or stop the brain changes that are known to cause disease symptoms.
In Alzheimer disease, one key change that occurs in the brain is the accumulation of a protein known as amyloid beta. The accumulated protein activates a type of immune cell known as microglia. Once activated, microglia release molecules that cause inflammation, which further damages brain cells.
Using an experimental model of inflammation, the team found that furosemide reduces the production of inflammation-causing molecules. They also found that the drug improves the ability of microglia to clear toxic debris.
Dr. Weaver adds, "Because furosemide is unable to cross the blood-brain barrier and get into the brain, our next focus will be to develop variants of the drug that can overcome this limitation. Because furosemide has been proven to be safe, it represents an exceptional starting point for the development of exciting therapies for this devastating disease.”
This work was supported by the Krembil Research Institute and the Toronto General & Western Hospital Foundation. Dr. Weaver holds a Tier 1 Canada Research Chair in Drug Design for Protein Misfolding Disorders.
Wang Z, Vilekar P, Huang J, Weaver DF. Furosemide as a Probe Molecule for the Treatment of Neuroinflammation in Alzheimer's Disease. ACS Chem Neurosci. 2020 Dec 16. doi: 10.1021/acschemneuro.0c00445.
The ability to repeat experiments is key to good science. This core principle, known as reproducibility, allows other laboratories to verify results and instill confidence in the findings.
Experimental models serve as unchanging frameworks in these experiments. Like goal posts, they enable the game to be played with the same rules each time. But what happens when the goal posts shift?
That is what Drs. Benjamin Haibe-Kains and Trevor Pugh asked in a recent study that explored how cancer cell lines—the most commonly used experimental model in biomedical research—change or ‘drift’ genetically.
“While genetic drift in cell lines is a concern for anyone using these experimental models, laboratories rarely measure genetic drift because it can be challenging to do from a logistics standpoint,” says Dr. Haibe-Kains. To address this, his team created an online Cancer Cell Line Identification toolkit (CCLid), which provides standards for a wide array of cell lines and streamlines the process of measuring genetic drift.
“To create CCLid, we used data from three existing large-scale studies. These pharmacogenomic studies genetically defined cancer cell lines and gauged the effect of anticancer drugs on these cells. Analysis of this data enabled us to measure genetic drift in 1,497 unique cell lines,” says Rene Quevedo, lead author of the study and a doctorate student in the laboratories of Drs. Haibe-Kains and Pugh.
The results revealed that genetic instability is prevalent in almost all cell lines with median genetic drift of 4.5-6.1% of the total genome size. The research team also found that 1.6% of all cell lines may be misidentified. "By misidentified, we mean that the genetics of the cell line were so distinct from the genetics of other cell lines of the same type, that they most likely had been mislabelled at some point,” says Dr. Pugh.
“Because genetic differences, including genetic drift, can influence how cells behave, we also explored how these differences affected response of the cells to different drugs,” says Dr. Haibe-Kains. “Although the association was weak, it was significant, which tells us that in certain situations genetic drift can affect drug response.”
By setting a new bar for the measurement of genetic drift, the CCLid toolkit will help cancer researchers track how genetic differences affect their findings—ultimately promoting scientific rigor and reproducibility.
This work was supported by the Gattuso Slaight Personalized Cancer Medicine Fund at the Princess Margaret Cancer Centre, the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, Stand Up To Cancer Canada, and The Princess Margaret Cancer Foundation. BHK is a Tier 2 Canada Research Chair (CRC) in Computational Pharmacogenomics. TJP is a Tier 2 CRC in Translational Genomics.
Quevedo R, Smirnov P, Tkachuk D, Ho C, El-Hachem N, Safikhani Z, Pugh TJ, Haibe-Kains B. Assessment of Genetic Drift in Large Pharmacogenomic Studies. Cell Syst. 2020 Oct 21;11(4):393-401.e2. doi: 10.1016/j.cels.2020.08.012.
Drs. Heather Ross and Michael Jewett have been awarded the Order of Canada—one of the nation’s highest civilian honours. In addition, a previous recipient of the Order of Canada, Dr. Geoff Fernie, has been appointed to the Order of Ontario.
As pioneers in their respective fields, these researchers have altered the course of medical treatments, patient care and rehabilitation science. They have demonstrated dedication to the health of Canadians through their ground-breaking work, which has improved the lives of individuals across the country. See below for more details on these achievements.
Dr. Ross was appointed a Member of the Order of Canada. She is a Clinician Investigator at Toronto General Hospital Research Institute and world-leading cardiologist. The honour recognizes her innovative solutions to predicting, detecting and following cardiac events using artificial intelligence and digital technologies.
Dr. Jewett was appointed a Member of the Order of Canada. He is an Affiliate Scientist at Techna and Surgical Oncologist at Princess Margaret Cancer Centre. His appointment to the Order of Canada recognizes his ground-breaking work in surgical oncology, specifically for cancers of the urinary tract, and his dedication to patient-centred care.
Dr. Fernie was appointed a Member of the Order of Ontario. He is a Senior Scientist and the previous Director of the KITE Research Institute (the research arm of the Toronto Rehabilitation Institute). His membership in the Order of Ontario recognizes Dr. Fernie’s pioneering work in rehabilitation engineering. Dr. Fernie has developed a variety of innovative assistive technologies to help elderly people and people living with disabilities avoid injury, gain mobility and maintain independence. On commenting on the honour, Dr. Fernie said, “I think of this award as a ‘call to action’ for me to do even more. I must work harder to thank the people of Ontario by solving more problems to keep Ontarians healthy and safe.”
The Order of Canada was created in 1967 to recognize outstanding achievement, dedication to the community and service to the nation. The Order of Ontario was later established in 1986 and is the most prestigious provincial honour recognizing individual excellence in various fields.
A recent study led by Dr. Vincy Chan, Affiliate Scientist at The KITE Research Institute, examined how pre-existing health conditions affect inpatient rehabilitation outcomes after a traumatic brain injury. The team found that among adult patients in inpatient rehabilitation, conditions such as Alzheimer disease and dementia can reduce motor and cognitive recovery by up to 17%.
For the study, Dr. Chan and her team looked at de-identified data from all publicly funded hospitals in Ontario between April 2008 and March 2015. They discovered that close to 40,000 hospital visits during this time had a traumatic brain injury diagnosis. These injuries primarily result from a fall, motor vehicle collision, or being struck by an object or person.
Analyses of the data revealed that after receiving treatment, around one in six of patients were admitted to an inpatient rehabilitation bed. A third of these patients were females and on average, were 70 years of age.
The team looked for existing health conditions and events experienced by these individuals in the five years prior to their brain injury, then assessed the effect of these conditions on their motor and cognitive recovery during their rehabilitation stay.
Among male patients, ten categories of health status were found to be associated with reduced recovery, including Alzheimer disease and dementia (17% reduction), mental health disorders (5% reduction), and conditions and events commonly experienced by older adults such as osteoporosis and falls (5% reduction). All of these factors were common among male and female patients; however, only conditions and events commonly experienced by older adults significantly affected females (5% reduction).
“While our study shows that pre-existing health conditions reduce the extent of functional gain during rehabilitation, it is important to emphasize that patients with brain injuries still make significant progress during their rehabilitation stay,” says Dr. Chan.
The number of older adults experiencing traumatic brain injuries is rapidly increasing. In the coming decades, more patients with pre-existing health conditions will be admitted to a rehabilitation hospital after a brain injury, and providers need to be prepared for patients with these conditions.
“More research to understand how pre-existing conditions affect rehabilitation interventions will help us maximize the benefits of rehabilitation for all patients that experience brain injury,” says Dr. Chan.
This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD089106), the Canada Research Chairs Program, and the Toronto Rehab Foundation. V Chan holds an Early Career Research Award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R03HD104206). A Colantonio holds a Tier 1 Canada Research Chair in Traumatic Brain Injury in Underserved Populations.
Chan V, Sutton M, Mollayeva T, Escobar MD, Hurst M, Colantonio A. Data Mining to Understand How Health Status Preceding Traumatic Brain Injury Affects Functional Outcome: A Population-Based Sex-Stratified Study. Arch Phys Med Rehabil. 2020 Sep. doi: 10.1016/j.apmr.2020.05.017.
All living things have a tendency to develop their own way of surviving in an unfavourable environment. Cancer cells are no different when they are faced with cancer-fighting drugs.
A new study, led by clinician and Scientist Dr. Catherine O’Brien at the Princess Margaret Cancer Centre, shows that cancer cells become dormant and enter a ‘drug tolerant persister (DTP)’ state when exposed to anticancer therapies such as chemotherapy and targeted agents.
While DTPs have been shown to exist in several cancers, there is little understanding of the mechanisms that drive this state in response to chemotherapy and targeted therapies.
To further characterize the DTP state in cancer cells, the research team developed experimental models of colon cancer. “When treated with chemotherapy, we found that all cells within the tumour were capable of entering a DTP state and that this phenomenon was not limited to a subpopulation of cells,” explains Dr. O’Brien. “Once treatment ended, the cells began growing again.”
The researchers were interested in examining which biological mechanisms were responsible for driving this response. Using high-throughput genetic sequencing technologies, they found that during the DTP state, cancer cells displayed gene expression profiles similar to what certain animals use during development when faced with unsuitable environmental conditions, called diapause. During diapause, development and growth of an embryo is suspended until the threat is removed.
The authors also found that slow-growing DTP cancer cells are functionally similar to embryos in diapause where both are dependent on a cellular mechanism called autophagy—a process by which cells self-digest themselves during periods of starvation in order to survive.
They went further, showing that by treating tumours with inhibitors of autophagy, cancer cells were less likely to enter the DTP state and escape chemotherapy.
“Here we demonstrate for the first time how cancer cells have adopted an evolutionary-conserved mechanism to survive cancer treatment,” says Dr. O’Brien. “New therapeutic strategies that target cancer cells in the DTP state, or hamper the ability of the cells to enter this slow-cycling state, will be essential for addressing treatment failure and relapse of this devastating disease.”
This work was supported by the Canadian Institutes of Health Research, the Terry Fox Research Institute, the Natural Sciences and Engineering Research Council of Canada and The Princess Margaret Cancer Foundation. M Ramalho-Santos holds a Canada 150 Research Chair in Developmental Epigenetics, TJ Pugh holds a Tier 2 Canada Research Chair in Translational Genomics, B Haibe-Kains holds a Tier 2 Canada Research Chair in Pharmacogenomics and CA O’Brien holds a Tier 2 Canada Research Chair in Translational Research in Colorectal Cancer.
Rehman SK, Haynes J, Collignon E, Brown KR, Wang Y, Nixon AML, Bruce JP, Wintersinger JA, Mer AS, Lo EBL, Leung C, Lima-Fernandes E, Pedley NM, Soares F, McGibbon S, He HH, Pollet A, Pugh TJ, Haibe-Kains B, Morris Q, Ramalho-Santos M, Goyal S, Moffat J, O'Brien CA. Colorectal cancer cells enter a diapause-like DTP state to survive chemotherapy. Cell. 2021 Jan 7. doi: 10.1016/j.cell.2020.11.018.
The nerves that run through the spinal cord exchange messages between the brain and the rest of the body. Traumatic injuries to the spinal cord can damage these nerves and cause paralysis, numbness or loss of bladder or bowel control.
A treatment called surgical decompression alleviates compressed nerves in the spinal cord and can help patients regain some sensory and motor function. Krembil Senior Scientist Dr. Michael Fehlings and a team of neurosurgeons including Dr. Jetan Badhiwala sought to find out the optimal time to perform this surgery.
“We’ve identified a critical window within which surgical decompression should take place.” Dr. Fehlings explains, “Patients who had surgical decompression within 24 hours of their injury had the greatest neurological recovery after one year. Furthermore, we discovered that motor recovery plateaus with surgeries performed after 36 hours.”
The team analyzed data from four multicentre studies for 1,548 patients. The patients were split into two groups based on the time from injury to surgery: individuals who received surgery within 24 hours, and those who received surgery at or after 24 hours. At one year after surgery, those who received surgery within 24 hours showed greater improvement in all motor scores tested. Moreover, even within 24 hours, the earlier patients received surgery, the better their recovery.
Using the data, the team also discovered that at 36 hours after the injury there was a plateau in recovery. This suggests that at this point the nerves and tissue become irreversibly damaged and surgery is no longer beneficial.
“This study demonstrates that ‘time is spine’—timely surgical decompression, specifically within 24 hours, can provide patients the greatest chance for recovery,” says Dr. Fehlings.
In a separate clinical trial, Dr. Fehlings and his team, including Dr. Badhiwala, assessed whether the drug riluzole could help enhance sensorimotor recovery if taken prior to surgical decompression. While the drug did not improve motor recovery, researchers found evidence that it might reduce neck pain after decompression in patients with degenerative cervical myelopathy, or compression of the spinal cord.
Dr. Fehlings comments, “We hope that our findings help inform existing clinical guidelines for the treatment of spinal cord injuries, and put in motion more research into therapeutic strategies that can be rapidly deployed after injury to help improve the recovery of patients with spinal cord injuries.”
Badhiwala JH, Wilson JR, Witiw CD, Harrop JS, Vaccaro AR, Aarabi B, Grossman RG, Geisler FH, Fehlings MG. The influence of timing of surgical decompression for acute spinal cord injury: a pooled analysis of individual patient data. Lancet Neurol. 2020 Dec 21. doi: 10.1016/S1474-4422(20)30406-3.
Supported by the Canadian Institutes of Health Research, and the Toronto General & Western Hospital Foundation.
Fehlings MG, Badhiwala JH, Ahn H, Farhadi HF, Shaffrey CI, Nassr A, Mummaneni P, Arnold PM, Jacobs WB, Riew KD, Kelly M, Brodke DS, Vaccaro AR, Hilibrand AS, Wilson J, Harrop JS, Yoon ST, Kim KD, Fourney DR, Santaguida C, Massicotte EM, Kopjar B. Safety and efficacy of riluzole in patients undergoing decompressive surgery for degenerative cervical myelopathy (CSM-Protect): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial. Lancet Neurol. 2020 Dec 22. doi: 10.1016/S1474-4422(20)30407-5.
Sponsored by AOSpine North America, and the Toronto General & Western Hospital Foundation.
This surgical decompression research also benefits from the support of the DeGasperis Family Foundation. Dr. Fehlings holds the Gerald and Tootsie Halbert Chair in Neural repair and Regeneration.
Starting chemotherapy after a cancer diagnosis can be daunting and distressing for individuals and their caregivers.
“The time between a diagnosis and the initiation of chemotherapy is often the most stressful,” says Dr. Janet Papadakos, a Scientist at The Institute for Education Research at UHN. “Anxiety can impair a patient’s ability to cope and retain information, which can affect how well they manage the side effects of chemotherapy and their quality of life.”
A recent study led by Dr. Papadakos revealed that patient education classes preceding chemotherapy can alleviate anxiety and improve preparedness. The study also revealed that tailoring the information in these classes to specific cancer groups is key to their success.
The study evaluated UHN’s GyneChemo class, which is offered to individuals diagnosed with gynecologic cancers and their family, friends and caregivers. The class was introduced in 2011 and, as well as answering participant questions, provides information on what to expect during chemotherapy, managing side effects, coping with emotions, seeking medical assistance and acting as a caregiver.
By surveying attendees before and after the class, Dr. Papadakos’ team assessed the impact of the class on participants.
Prior to the class, the majority of the participants stated that they felt unprepared. Afterwards, the participants reported feeling more prepared. In addition, patients’ scores for anxiety decreased and scores for coping ability increased. Caregivers similarly experienced an increase in their preparedness to engage in caregiving activities.
Moreover, 96% of patients agreed that new patients should take the class and over 90% of participants agreed that the class is an important part of the treatment journey.
Dr. Papadakos’ results will enable further refinements to the GyneChemo class. In the near future, an online version of the class will launch as part of the Princess Margaret Cancer Classes, a new web resource for UHN patients and caregivers. This online version will increase accessibility and is especially timely given the on-going COVID-19 pandemic.
By boosting confidence and feelings of control, the class is helping improve treatment compliance and, ultimately, treatment outcomes. It is critical that clinicians continue to assess the informational needs of patients and caregivers so that education can be tailored to those needs without compromising the quality and comprehensiveness of the information that each person receives.
This work was supported by The Princess Margaret Cancer Foundation.
Samoil D, Abdelmutti N, Gallagher LO, Jivraj N, Quartey NK, Tinker L, Giuliani M, Trang A, Ferguson SE, Papadakos J. Evaluating the effect of a group pre-treatment chemotherapy psycho-education session for chemotherapy-naive gynecologic cancer patients and their caregivers. Gynecol Oncol. 2020 Oct 16. doi: 10.1016/j.ygyno.2020.10.007.
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