Lung transplantation can be a lifesaving operation for diseases that threaten a patient’s ability to breathe. However, potentially fatal complications can still arise afterwards.
A research team, headed by Toronto General Hospital Research Institute Scientists Drs. Ana Konvalinka and Tereza Martinu, has identified molecular markers that can be measured to predict future complications. Specifically, the team discovered that the levels of a set of proteins can indicate which lung transplant recipients are most likely to develop chronic lung allograft dysfunction (CLAD)—a major long-term cause of death in these individuals.
CLAD affects around half of all transplant recipients at five years after the operation. While there are several types of CLAD, all are characterized by fibrosis in the lung—when normal tissue is gradually replaced with scar tissue.
“Effective treatments for CLAD do not yet exist, and our understanding of how it develops is limited,” says Dr. Martinu. “We wanted to find molecular targets of CLAD that will enable earlier diagnosis and the development of much-needed therapies.”
The research team took inspiration from existing knowledge of how fibrosis develops in kidney transplants. In previous work, Dr. Konvalinka’s team identified proteins that were altered in kidney cells in response to a peptide hormone called angiotensin II (Ang II). They then developed a mass spectrometry-based method to quantify proteins from kidney cells. Using this method, the team discovered that these potentially pro-fibrotic proteins were elevated in the urine and tissues of kidney transplant recipients.
The research fellows who led the current study, Drs. Gregory Berra and Sofia Farkona, proposed that similar mechanisms were at play in lungs and decided to investigate whether the same proteins are also relevant in lung transplants. “This project is a great illustration of how important cross-organ collaboration is and how we can learn from each other within our multi-organ transplant program,” comments Dr. Martinu.
By examining lung tissue samples from transplant recipients with CLAD and from healthy donors, the team identified differences in the levels of certain proteins. One protein receptor (angiotensin II receptor type 1) had a significantly greater presence in the CLAD samples, while two other proteins that are regulated by the hormone (thrombospondin 1 and glutamine synthetase) were linked with the amount of fibrosis.
The researchers then applied machine learning algorithms—a form of computer artificial intelligence—to large volumes of data on protein levels, teaching the algorithms how to identify which individuals have CLAD and which are likely to develop it.
When assessing all of the different protein levels in combination, the algorithms had an impressive near-perfect accuracy of 97% for predicting whether CLAD would develop.
“Our results could have exciting implications for clinical care,” says Dr. Konvalinka. “Understanding the common biochemical mechanisms involved in kidney and lung fibrosis may open new pathways for repurposing drugs and diagnostic tools for these conditions. We may be able to diagnose patients earlier and provide proactive care.”
This work was supported by the Canadian Donation and Transplantation Research Program, the Kidney Foundation of Canada, the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, the Kidney Research Scientist Core Education and National Training Program (KRESCENT), Les Hôpitaux Universitaires de Genève, the Ontario Research Fund, UHN’s Ajmera Transplant Centre, and UHN Foundation.
Berra G, Farkona S, Mohammed-Ali Z, Kotlyar M, Levy L, Clotet-Freixas S, Ly P, Renaud-Picard B, Zehong G, Daigneault T, Duong A, Batruch I, Jurisica I, Konvalinka A, Martinu T. Association between renin-angiotensin system and chronic lung allograft dysfunction. Eur Respir J. 2021 Apr 16. doi: 10.1183/13993003.02975-2020.
Everyone’s brain is unique, but are brains unique combinations of similar building blocks, or are the building blocks themselves—the brain cells—also unique? A study by UHN’s Krembil Brain Institute and the Centre for Addiction and Mental Health found a remarkably high degree of diversity of human brain cells.
Pyramidal neurons are one of the more common types of cells in the neocortex, the outermost region of the brain. Neurons in this region are organized into six distinct layers, and the physical and electrical properties of these neurons influence brain activity. Understanding the properties of these neurons is critical to understanding changes in brain function that underly disorders such as epilepsy.
The research team, led by Krembil Scientist Dr. Taufik Valiante, studied brain tissue that was donated by patients who underwent brain surgery to treat epilepsy or cancer. With extreme care, Dr. Homeira Moradi, Krembil Scientific Associate, and the other researchers kept the delicate tissue alive after the surgery and studied various features of the neurons.
Little is known about the structure and function of adult human neurons because it is very rare to obtain living human brain tissue. “There are few opportunities beyond brain surgery for researchers to examine living human neurons," says Dr. Valiante. "This study was only possible because of the very large and active epilepsy program at UHN’s Krembil Brain Institute.”
The researchers used microscopic electrodes to characterize the electrical properties of over 200 neurons from 61 patients. This painstaking work was the product of almost a decade of collaboration from a multidisciplinary team including neurosurgeons and neuroscientists, patients who were willing to participate in the study and ethicists who ensured patient rights and safety.
The study revealed the impressive variability and distinct features of neurons located within different cortical layers. Specifically, neurons in deeper layers had unique electrical properties and shapes—and more variation in those shapes—compared to those in more superficial layers. These features suggest that deep layer neurons may drive communication across layers.
“Our findings are quite different from what we expected based on past studies that used pre-clinical models,” explains Dr. Valiante. “The findings provide further evidence for the unique physiology and specializations of the human brain.”
This study represents one of the largest studies of human neurons. The resulting data will serve as a valuable resource for improving computer simulations of brain function—simulations that will enable researchers to better model neocortical neurons and shed light on neurological disorders such as epilepsy.
This work was supported by the Centre for Addiction and Mental Health Discovery Fund, the National Institutes of Health, the Natural Sciences and Engineering Research Council, The Kavli Foundation and the UHN Foundation.
Chameh HM, Rich S, Wang L, Chen FD, Zhang L, Carlen PL, Tripathy SJ, Valiante TA. Diversity amongst human cortical pyramidal neurons revealed via their sag currents and frequency preferences. Nat Comm. 2021 May 3. doi: 10.1038/s41467-021-22741-9
UHN researchers have created a unique rehabilitation program that can help some of the 86,000 Canadians that live with a spinal cord injury achieve greater independence.
Spinal cord injuries can be ‘complete’—leading to the total loss of movement control at and below the site of injury—or ‘incomplete’—when some ability to move is retained.
Individuals living with an incomplete spinal cord injury can regain some standing and walking abilities; however, they often have trouble balancing, which makes it difficult for them to stand without support and puts them at a high risk of falling.
To address this issue, a team led by Drs. Kristin Musselman and Kei Masani, researchers at the KITE Research Institute, explored whether a new balance training program could improve perceived standing ability and confidence in individuals with an incomplete spinal cord injury.
This study builds on previous research in which the team evaluated the innovative four-week balance training program. The program involves balance exercises combined with performance feedback, which is displayed on a computer monitor. During the exercises, electrical stimulation is applied to the ankle muscles to induce contractions that help the participants maintain balance. Repeated exercise with muscle stimulation helps to retrain the nervous system to achieve greater balance control (Front Neurol., 2020).
“Our initial study showed that this program improves balance, but it did not give us any insights into whether the participants felt that the program was beneficial,” explains Dr. Musselman. “It is important to consider the perceived benefits of a training program to ensure that the programs we are developing are meaningful to patients. Patients are more likely to participate in rehabilitation if they find it valuable.”
To explore participants’ perspectives, the researchers interviewed five individuals who completed the training program. The participants answered questions about their goals and expectations, and how the program impacted their life, balance confidence and risk of falling.
Participants reported that the program increased their range of motion and muscle strength and decreased muscle spasms and pain. They also reported feeling more independent and better able to complete daily tasks such as cooking, self-dressing and using the washroom.
Importantly, participants gained confidence in their physical abilities and became more willing to try new activities. They also felt that they could continue to improve and were motivated to carry on with balance training.
“We knew that our balance training program benefits patients physically, but now we see that it also benefits them psychologically,” says Dr. Musselman. “This program can help individuals with an incomplete spinal cord injury gain the confidence needed to be more independent and carry out meaningful daily activities.”
Although this rehabilitation program is not yet available in clinics, the researchers have recently received funding to develop a new version of it that is appropriate for clinical practice. They hope to test this new program in patients with spinal cord injury, as well as stroke, in the next few years.
This work was supported by the University of Toronto EMHSeed Program and the UHN Foundation.
Houston DJ, Unger J, Lee JW, Masani K, Musselman KE. Perspectives of individuals with chronic spinal cord injury following novel balance training involving functional electrical stimulation with visual feedback: a qualitative exploratory study. J Neuroeng Rehabil. 2021 Apr 1. doi: 10.1186/s12984-021-00861-z.
Congratulations to Dr. Gordon Keller who was named the co-recipient of the 2021 Scientific Grand Prize from the Lefoulon-Delalande Foundation of the Institut de France.
Each year, the Grand Prize is awarded to a world-leading researcher who has made significant contributions to cardiovascular research and medicine.
The award recognizes Dr. Keller’s revolutionary work on the directed differentiation of human pluripotent stem cells (hPSCs) into the different cell types found in the human heart. These advances have enabled the establishment of model systems to study human heart development and disease in a culture dish. Additionally, access to unlimited numbers of human heart cells from hPSCs has provided the basis for developing new cell-based therapies to treat heart disease.
Dr. Keller, who is the Director of the McEwen Stem Cell Institute and a Senior Scientist at the Princess Margaret Cancer Centre, will share this year’s prize with Dr. Christine Mummery, a prominent stem cell researcher at Leiden University Medical Center in the Netherlands. The prize is worth 600,000 Euros and will be split between the two winners.
“I am truly honored to be the co-recipient of this year’s Scientific Grand Prize from the Lefoulon-Delalande Foundation of the Institut de France along with my colleague Dr. Mummery,” says Dr. Keller. “I also extend my thanks to the extraordinary trainees in my lab who have contributed to this success and have helped move us closer to developing cell-based therapies for heart disease.”
Link to livestream (June 2, 2021 @ 9am EST): https://youtu.be/JPpn_Ugx-Uw.
Click here for the press release from the Institut de France.
Combining drugs is a common strategy for hard-to-treat cancers. Understanding how they work together is equally important and may lead to new and improved treatment strategies.
A study led by Dr. Aaron Schimmer, Research Director at the Princess Margaret Cancer Centre, and Dr. Li Zhang, Senior Scientist at Toronto General Hospital Research Institute, aimed to investigate why a new drug combination was effective at treating acute myeloid leukemia (AML) in patients who are not eligible for standard chemotherapy.
This powerful drug combination includes two next-generation therapies: Venetoclax, a drug that blocks a protein needed for cell survival, and Azacytidine, an epigenetic therapy that modifies gene expression.
Until now, little was known about how these two drugs work in combination to better target and destroy cancer cells by increasing the killing function of immune cells called T cells.
Using a subset of human T cells derived from healthy donors, the researchers treated the cells with Venetoclax. Treatment activated a group of T cells known to respond to threats and increased their ability to selectively kill AML cells in experimental models, without affecting their own survival. The researchers discovered that the drug did this by disrupting important mechanisms related to metabolism in T cells.
When looking at the effects of adding Azacytidine in combination with Venetoclax, they found that the Azacytidine primed AML cells for killing by T cells by inducing an immune response that mimicked a viral infection.
“Our findings reveal the biological mechanisms behind this drug combination, which were corroborated in patient samples,” says Dr. Schimmer. “More importantly, it highlights the potential of combining Venetoclax with adoptive T cell therapy—a technique where we can harvest and expand T cells from patients and better arm them to target and destroy cancer cells.”
This work was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, the Government of Ontario, the National Cancer Institute, the Cancer Prevention & Research Institute of Texas and The Princess Margaret Cancer Foundation. M Andreeff holds the Haas Chair in Genetics. L Zhang holds the Maria H. Bacardi Chair in Transplantation.
Lee J, Khan DH, Hurren R, Xu M, Na Y, Kang H, Mirali S, Wang X, Gronda MV, Jitkova Y, MacLean N, Arruda A, Alaniz Z, Konopleva MY, Andreeff M, Minden MD, Zhang L, Schimmer AD. Venetoclax enhances T cell-mediated anti-leukemic activity by increasing ROS production. Blood. 2021 Mar 16. doi: 10.1182/blood.2020009081.
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:
● Canada-Germany Research Partnership: Introducing the Max Planck–University of Toronto Centre for Neural Science and Technology.
● Embracing Emotions: Krembil celebrated Mental Health Week with online resources to promote emotional well-being.
● Taking the High Road: Study settles the dispute over whether low dose steroids are effective for lupus nephritis.
● An Eye for Innovative Treatments: Customized prosthetic device improves vision in individuals with corneal conditions.
● Snowflakes All the Way Down: A rare look at living human brain tissue reveals a high degree of cellular diversity.
● More Power to You: Study finds that the Manage My Pain app can engage and empower patients towards better health.
An estimated 1,950 women in Canada died of ovarian cancer in 2020. The most common and deadly type of ovarian cancer is called high-grade serous ovarian cancer (HGSOC), and the greatest risk factor for this disease is a cancer-causing genetic variation inherited from a parent.
Despite evidence that ovarian cancer risk can be passed from parents to children, historically, the majority of women with ovarian cancer never got genetic testing. Canadian guidelines do not advise first-degree relatives—parents, children and siblings—of a patient with ovarian cancer to receive genetic testing unless there is a strong family history or the person with ovarian cancer themselves tested positive. The high mortality of this disease, paired with low testing rates, suggests that many women may be unaware whether they have a genetic risk for ovarian cancer.
A multidisciplinary team at UHN, led by Clinician Investigator Dr. Marcus Bernardini, Scientific Associate Dr. Alicia Tone and genetic counsellor Jeanna McCuaig of the Princess Margaret Cancer Centre, used two unique approaches for finding and testing women with a first-degree relative who died from HGSOC: a public outreach campaign and a direct recruitment campaign.
The public campaign was conducted over a three-year period. It involved public engagement though television segments, newspaper articles, social media posts, an educational website as well as raising awareness among other health care professionals. This approach was successful and enabled them to engage with individuals from the public that were highly motivated to learn about their potential risk and receive genetic testing.
A direct recruitment campaign was also carried out to contact first-degree relatives of patients previously treated for ovarian cancer at UHN. It was particularly important to reach out to these individuals because if the patient’s ovarian cancer was caused by a genetic variation, the relative has a 50% chance of carrying the mutation.
The rate of genetic variation among participants recruited through both campaigns were similar. A variation on an ovarian cancer risk gene was identified in 6% of women and was more common in those whose relative was younger than 60 years old when they were diagnosed with ovarian cancer.
Of those with the disease-causing variation, 85% underwent gynecologic surgery to reduce the risk of developing cancer in the future; and undiagnosed cancer was discovered in three participants.
“None of the 11 women we identified would have qualified for the genetic testing based on Ontario’s current guidelines,” says Dr. Bernardini. “Our research supports modifying genetic testing criteria to include individuals whose relative was diagnosed with ovarian cancer prior to age 60 to ensure at-risk women are identified earlier.”
This work was supported by The Princess Margaret Cancer Foundation and Ovarian Cancer Canada.
Tone AA, McCuaig JM, Ricker N, Boghosian T, Romagnuolo T, Stickle N, Virtanen C, Zhang T, Kim RH, Ferguson SE, May T, Laframboise S, Armel S, Demsky R, Volenik A, Stuart-McEwan T, Shaw P, Oza A, Kamel-Reid S, Stockley T, Bernardini MQ. The Prevent Ovarian Cancer Program (POCP): Identification of women at risk for ovarian cancer using complementary recruitment approaches. Gynecol Oncol. 2021 Apr 13:S0090-8258(21)00321-8. doi: 10.1016/j.ygyno.2021.04.011.
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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