A national research project has just launched to study the effectiveness and safety of COVID-19 vaccines in transplant recipients. The Government of Canada, through its COVID-19 Immunity Task Force (CITF) and Vaccine Surveillance Reference Group (VSRG), is investing over $2.84 million in this research program, based at University Health Network and called PREVenT COVID, short for Prospective Evaluation of COVID-19 Vaccine in Transplant Recipients: A National Strategy.
“Because people who have received a solid organ transplant and other immunosuppressed individuals are generally excluded from clinical trials of vaccines, little data exists to guide clinical best practices for these populations,” says Dr. Deepali Kumar, project lead, Clinician Investigator at the Toronto General Hospital Research Institute and Director of Transplant Infectious Diseases at the Ajmera Transplant Centre. “Our research will address this knowledge gap by revealing how transplant recipients—who are on immune-suppressing medications to prevent organ rejection—respond to COVID-19 vaccines. We will compare their immune responses to non-transplanted individuals as well as those who have contracted COVID-19.”
With this funding, Dr. Kumar’s team will launch this study across multiple transplant centres to examine short- and long-term antibody responses in transplant recipients following first and second doses of COVID-19 vaccines. The team will compare these responses to those of healthy individuals who have not undergone transplant and those of transplant recipients who naturally contracted COVID-19.
The team will also assess the short- and long-term safety profile of vaccines in transplant recipients, tracking the rates of local and systemic reactions, organ rejection and other transplant complications.
“People who have received an organ or stem cell transplant may have unique immunization needs. For example, we do not know whether the effectiveness of vaccines differ depending on the timing of immunization relative to transplant,” explains Dr. Kumar.
The researchers will then develop a national COVID-19 vaccination safety surveillance system for transplant recipients. This system will build upon the Canadian National Vaccine Safety Network—an ongoing Canada-wide vaccine safety surveillance initiative.
“Our goal is to help coordinate the efforts of provincial and national organizations that are involved in public health and vaccination research and facilitate information sharing among public health agencies and patient partners,” says Dr. Kumar. “This research will build on Canada’s leadership in transplant medicine and inform health policy to best protect transplant recipients from COVID-19.”
COVID-19 vaccination remains one of the most effective ways to protect ourselves and others from COVID-19. This is why vaccination is important for the general population around immunosuppressed individuals who may have a reduced immune response to any authorized COVID-19 vaccine series.
“It is imperative that we study the immune response and safety of vaccines not only in the general population, but in populations with specific health issues, such as persons having received organ transplants,” says Scott Halperin, Co-Chair of the VSRG. “We need to ensure that vaccines are working in vulnerable Canadians: studies like this will help to inform us whether a booster dose is needed in this specific population.”
The Government of Canada established the COVID-19 Immunity Task Force in April 2020 to lead nation-wide efforts to determine the extent of COVID-19 infection in Canada. The Vaccine Surveillance Reference Group was formed in December 2020 to support the monitoring of vaccine safety and effectiveness.
Findings from the Princess Margaret Cancer Centre showcase a new approach for treating acute myeloid leukemia—an aggressive cancer of the blood that is known to return following standard treatments.
Recurrence of this cancer is driven by leukemic stem cells. These cells are often resistant to current therapies and can survive when other cancer cells die—making them important treatment targets.
Led by Princess Margaret Cancer Centre Scientist Dr. Steven Chan, the research team conducted a screen of more than 100 drugs known to affect metabolism to find ones that selectively killed leukemic stem cells. Their findings revealed that drugs known as nicotinamide phosphoribosyltransferase (NAMPT) inhibitors were top candidates.
“Unlike normal blood stem cells, leukemic stem cells appear to rely heavily on the NAMPT enzyme to survive. The NAMPT inhibitors that we identified appear to kill leukemic stem cells by disrupting the pathways required for lipid metabolism,” says Dr. Chan.
When the research team treated two laboratory models of acute myeloid leukemia using cells derived from patients with NAMPT inhibitors, leukemia stem cells were much more susceptible to cell death than normal blood stem cells. “This is exciting because our data suggest that NAMPT inhibitors can be used to kill leukemic stem cells without affecting the normal blood system,” says Dr. Chan.
The team focused their experiments on a specific NAMPT inhibitor, known as KPT-9274, which is currently in clinical trials for other types of cancers. In three experimental models of acute myeloid leukemia, treatment with KPT-9274 was effective at killing leukemic stem cells; however, tumour growth in one model remained, suggesting that leukemic stem cells can become resistant to the treatment.
Dr. Chan and his colleagues analyzed the cells that had developed resistance and found that a protein, known as the sterol regulatory-element binding protein (SREBP) became activated when exposed to KPT-9274. Explains first author Amit Subedi, “When we silenced SREBP genes in these cells and treated them with KPT-927, we were able to overcome resistance.”
The team then searched for approved drugs that inhibit SREBP pathways, which led them to the discovery of dipyridamole, a drug used for preventing secondary stroke. The drug combination, when tested in experimental models, killed higher levels of leukemia stem cell than each drug alone and overcame drug resistance.
Comments Dr. Chan, “These results are promising. Future prospective clinical trials are an important next step to validating these findings and building out a more complete picture of the vulnerabilities of acute myeloid leukemia and ways to stamp it out.”
This work was supported by the Acute Leukemia Translational Research Initiative from the Ontario Institute for Cancer Research, the Leukemia Research Foundation, the Canadian Institutes of Health Research and The Princess Margaret Cancer Foundation. J Dick holds a Tier I Canada Research Chair in Stem Cell Biology.
Subedi A, Liu Q, Ayyathan DM, Sharon D, Cathelin S, Hosseini M, Xu C, Voisin V, Bader GD, D’Alessandro A, Lechman ER, Dick JE, Minden MD, Wang JCY, Chan SM. Nicontinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis. Cell Stem Cell. Epub Ahead of Print
The Krembil Research Institute is pleased to welcome Dr. Brian Ballios as its newest Clinician Scientist at the Donald K. Johnson Eye Institute.
Dr. Ballios’ research is focused on developing stem cell therapies for inherited and acquired retinal diseases, such as age-related macular degeneration and retinitis pigmentosa. These diseases result in progressive vision loss for which existing treatments can only slow progression.
“As a physician, I am struck by the immense personal toll of eye disease,” explains Dr. Ballios. “It is very motivating to conduct research that has the potential to make tremendous improvements in patients’ quality of life. I find inspiration in these patients’ journeys and share their eagerness for cures.”
Leveraging his background in engineering and medicine, Dr. Ballios developed the world’s first injectable biomaterial-based delivery system for transplanting stem cells into the retina. This work launched a new field of study into the use of biomaterials to improve cell transplantation in the retina. He also developed methods to efficiently generate light-sensitive cells from stem cells to replace the cells lost in retinal degeneration.
At Krembil, Dr. Ballios’ research program will bring together diverse fields that include retinal neurobiology, stem cell biology and bioengineering. He will continue to develop methods to generate light sensitive cells from stem cells and promote their survival and integration into the damaged eye. He will also develop accurate models of human inherited retinal disease and investigate the unique features of these conditions to improve the effectiveness of cell therapies.
“Coming to UHN is about joining an ecosystem of discovery. We have the best-of-the-best clinicians and vision science researchers,” says Dr. Ballios. “The Donald K. Johnson Eye Institute and the Krembil Research Institute bring together these leaders with a shared goal: to restore vision and improve the lives of patients.”
In 2017, Dr. Ballios was the inaugural recipient of Fighting Blindness Canada’s Clinician-Scientist Emerging Leader Award. His research has also been funded by the BrightFocus Foundation and the Retina Foundation of Canada. This year, he was awarded a Career Development Award from the Foundation Fighting Blindness U.S. He is currently the J. Ardeth Hill – Fighting Blindness Canada Professor in Ocular Genetics at the University of Toronto.
At the University of Toronto, Dr. Ballios completed his Doctor of Medicine and Doctor of Philosophy degrees through the combined MD/PhD program, a clinical residency in Ophthalmology and postdoctoral training in the Department of Ophthalmology and Vision Sciences. At Massachusetts Eye and Ear and Harvard University, he completed a clinical fellowship in Inherited Retinal Diseases.
Welcome to Krembil, Dr. Ballios!
Female ophthalmologists face a significant pay gap, despite being comparably productive to males, according to new research published in the journal Ophthalmology.
Several studies to date have suggested that female physicians earn less than men; however, most of these studies have been based on self-reported incomes or Medicare/Medicaid payments that capture only a subset of physician payments.
The new study looked at whether male and female ophthalmologists’ overall payments are different within the Ontario fee-for-service billing system. The research team was led by Dr. Tina Felfeli, a resident physician in the Department of Ophthalmology and Vision Sciences at the University of Toronto, and Dr. Yvonne Buys, a Clinician Investigator at the Donald K. Johnson Eye Institute.
“Fee-for-service systems, in which doctors are paid a set amount for each service they provide, are less susceptible to pay disparities,” explains Dr. Buys. “Nonetheless, we know that pay gaps still exist between male and female physicians. We wanted to determine whether male and female ophthalmologists have different incomes despite similar workloads, and how the pay gap in ophthalmology compares to other medical specialties.”
The researchers examined sex differences in yearly income received by 807 ophthalmologists across nearly three decades, controlling for factors such as age and productivity. They then compared the pay differences observed in ophthalmology to those present in other physician specialty groups; surgical, medical non-procedural and medical procedural specialties.
The study revealed that representation of female physicians increased across specialties, from 17% in 1992 to 36% in 2018. Over this period, female representation in ophthalmology increased from 11% to 22%. Despite this 100% increase, ophthalmology continued to have the lowest proportion of female physicians. In the other three specialty groups, women comprised between 25% and 41% of physicians in 2018.
The team also found that females had lower incomes than males across specialties, despite being comparably productive. Amongst the top billers, the pay gap was most pronounced in ophthalmology, where males earned 17% ($161,900) more than females in 2018. By contrast, males earned only 8–12% more than females in other specialities.
The current findings suggest that the pay gap may be related to the proportionate representation of females within a specific medical specialty. Thus, ophthalmology, which has the lowest proportion of females, also has the largest sex difference in annual income.
“Moving forward, we need to determine the root causes of the pay gap in ophthalmology and other medical specialties. Previous studies have pointed to sex differences in practice patterns and opportunities to perform the most lucrative procedures, such as surgeries, but more research is needed,” says Dr. Buys. “Addressing sex-based inequities and systemic barriers to women’s success is essential for safeguarding inclusion in the medical profession.”
This study made use of de-identified data from the ICES Data Repository, which is managed by the ICES with support from its funders and partners: Canada’s Strategy for Patient-Oriented Research (SPOR), the Ontario SPOR Support Unit, CIHR and the Government of Ontario. The opinions, results and conclusions reported are those of the authors. No endorsement by ICES or any of its funders or partners is intended or should be inferred.
This work was supported by the UHN Foundation.
Felfeli T, Canizares M, Jin Y-P, Buys YM. Pay Gap Amongst Female and Male Ophthalmologists Compared to other Specialties. Ophthalmology. 2021 July 13. doi: 10.1016/j.ophtha.2021.06.015
A team of UHN researchers recently characterized how cells in four different brain regions respond to deep brain stimulation.
During deep brain stimulation, microelectrodes implanted in the brain emit pulses of electricity to change the activity of neurons. This procedure is currently approved for treating Parkinson disease, epilepsy and several other movement disorders. The electrical pulses can be adjusted in terms of their frequency, intensity and duration to reduce abnormal neuron activity, which eases the symptoms of the disorders.
“There are still many unknowns regarding how deep brain stimulation changes brain activity,” explains Dr. Luka Milosevic, the lead author of the study and a Scientist at the Krembil Brain Institute. “We wanted to understand how stimulation changes the activity of neurons in different brain regions. This understanding will enable us to improve the effectiveness of deep brain stimulation and apply the procedure to other conditions, such as addiction and depression.”
The researchers studied the activity of 115 neurons from four brain regions involved in movement control in patients with either Parkinson disease or essential tremor—a neurological disorder that causes involuntary shaking. They programmed the electrodes to deliver stimulation pulses at various frequencies, up to 200 pulses per second, and monitored whether this stimulation increased or decreased neuron activity. The team also developed a mathematical model to predict how neurons in each region would respond to electrical stimulation.
The findings revealed that how neurons respond to electrical stimulation depends on their location within the brain and the frequency of stimulation that they receive.
Electrical pulses had opposite effects in different regions, depending on the local concentration of chemicals that stimulate or suppress neuron activity. Low-frequency stimulation suppressed activity in regions with higher levels of inhibitory chemicals, but increased activity in regions with higher levels of excitatory chemicals. However, prolonged high-frequency stimulation suppressed activity in all regions. This was likely because neuronal communication could not keep up with stimulation impulses delivered at high frequencies (a phenomenon called “synaptic fatigue”).
Overall, the researchers concluded that both anatomical and physiological properties of the brain must be taken into consideration to be able to predict how electrical stimulation will change neuron activity in specific brain regions. Furthermore, it seems that high-frequency deep brain stimulation may elicit its beneficial therapeutic effect in Parkinson disease and essential tremor by disrupting the unhealthy signals generated by neurons in the areas of the brain known to be associated with these disorders.
“These findings have enabled us to gain a deeper understanding of how deep brain stimulation benefits patients and will help us fine-tune existing and future therapies. Moreover, our experimental findings and our computational model will support the development of new stimulation methods in other regions of the brain and for other neurological disorders,” says Dr. Milosevic.
This work was supported by the Natural Sciences and Engineering Research Council of Canada, donation from Dean Connor and Maris Uffelmann, donation from Walter and Maria Schroeder, the Dystonia Medical Research Foundation and the UHN Foundation.
Milosevic L, Kalia SK, Hodaie M, Lozano AM, Popovic MR, Hutchison WD, Lankarany M. A theoretical framework for the site-specific and frequency-dependent neuronal effects of deep brain stimulation. Brain Stimul. 2021 May 12. doi: 10.1016/j.brs.2021.04.022.
The Ontario government is providing over $70.4 million to support the development of homegrown ideas, products and technologies. Of these funds, $3.8 million has been provided to help advance research and innovation at UHN.
The funds were provided through two competitive programs from the Ontario Research Fund: the Early Researcher Award, which helps exceptional early career researchers to build their research teams, and the Research Infrastructure program, which enables the acquisition of advanced research infrastructure to conduct world-leading research. The projects that received funding are described below.
Early Researcher Awards
Three early career researchers at UHN received awards to build their research teams and enable the following projects:
Dr. Faiyaz Notta will elucidate the cellular and molecular mechanisms that regulate the development of pancreatic cancer using three-dimensional culture systems.
Dr. Sonya MacParland will define and target autoimmune liver disease.
Dr. Mamatha Bhat will identify new drug targets and therapeutic strategies to prevent long-term complications in liver transplant recipients.
Research Infrastructure Program
Funds were provided for the cutting-edge research required conduct the following two UHN-led projects:
Dr. Sara Vasconcelos will explore new regenerative medicine techniques for repairing damaged hearts using stem cells and engineered blood vessels.
“Driving research excellence and innovation is crucial as Ontario continues to defeat COVID-19 and lay the groundwork for a robust and long-term economic recovery,” said Jill Dunlop, Minister of Colleges and Universities. “Our government will continue to support ground-breaking research to advance new discoveries and innovation, while fostering a skilled labour force and promoting new business opportunities across the province.”
Thank you to the Ontario Government for supporting these innovative research projects, which have strong potential to bring new health technologies and treatments to Ontarians.
Most of us try to live a balanced life while trying to meet all of our demands. Processes inside our body, such as the formation of new blood cells, also strike a similar balance.
The continuous supply of new blood cells throughout our lifetime relies on a rare population of stem cells known as long-term hematopoietic stem cells. These cells must find a balance between making new blood cells and preserving their population.
Researchers have shown that these blood stem cells generally exist in a dormant state. When new blood cells are needed—such as during blood loss—the body sends signals that ‘activate’ some of them to produce blood cells. Others remain dormant, possessing a property known as latency that enables their numbers to be maintained. Until now, the processes that govern latency have remained largely unknown.
Given the similarity between blood stem cells and leukemia stem cells, the team investigated whether the same mechanisms are involved in controlling normal blood production. These more recent results were published Nature Immunology.
In this latest study, postdoctoral fellow Dr. Kerstin Kaufmann and the research team were able to use advanced molecular techniques to confirm their guess. Their findings revealed that expression of INKA1 in long-term hematopoietic stem cells kept the cells in a latent state. They further identified two subsets of long-term stem cells that were linked to pathways controlled by INKA1: one that responds quickly to generate new blood cells and eventually becomes depleted; and another that remains dormant and maintains the ability to self-renew.
“Here we have identified that there are two types of long-term blood stem cells: one that can respond quickly to repopulate blood cells when the body desperately needs them, and another type that plays the slow game and remains dormant in order to preserve and maintain the population of stem cells,” says Dr. Dick.
“While these findings could have implications for the development of cell therapies, they also shed light on our fundamental understanding of how new blood cells are made and maintained in the body.”
This work was supported by the German Research Foundation, the University of Toronto’s Medicine by Design initiative, the Canada First Research Excellence Fund, the Canadian Institutes of Health Research, the International Development Research Centre, the Canadian Cancer Society, the Terry Fox Research Institute, the Ontario Institute for Cancer Research, the Government of Ontario and The Princess Margaret Cancer Foundation. J Dick holds a Tier 1 Canada Research Chair in Stem Cell Biology.
Kaufmann KB, Zeng AGX, Coyaud E, Garcia-Prat L, Papalexi E, Murison A, Laurent EMN, Chan-Seng-Yue M, Gan OI, Pan K, McLeod J, Boutzen H, Zandi S, Takayanagi SI, Satija R, Raught B, Xie SZ, Dick JE. A latent subset of human hematopoietic stem cells resists regenerative stress to preserve stemness. Nat Immunol. 2021 Jun 22. doi: 10.1038/s41590-021-00925-1.
Research conducted at UHN's research institutes spans the full spectrum of diseases and disciplines, including cancer, cardiovascular sciences, transplantation, neural and sensory sciences, musculoskeletal health, rehabilitation sciences, and community and population health.
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