Medical Research

Dalla Lana School of Public Health

Artificial Intelligence

machine learning

Space

Space exploration is often viewed as the realm of astronauts and engineers, but the ��Ƶ’s Farhan Asrar is using his expertise in public health to chart an extraterrestrial path in medicine.

Asrar, an associate professor in the department of family and community medicine in the Temerty Faculty of Medicine with a cross-appointment with the Dalla Lana School of Public Health, researches the physical and psychological effects of space travel on the human body, the challenges astronauts face during prolonged space missions and the potential implications for human health back here on Earth.

As a member of the International Space University, he recently travelled to Brazil to co-chair the department of human performance in space of the Space Studies Program, an annual nine-week program hosted in different locations around the world that provides participants professional development experience covering all aspects of space. As a co-chair, Asrar played a key role in developing curriculum for the program, organizing talks with astronauts and educational opportunities – including a trip to Brazil’s Paralympic training site to explore similarities between astronauts and elite athletes – and providing mentorship to attendees.

“I really appreciate that space brings everyone together – regardless of your background, culture or country,” the Mississauga-based physician and researcher says.

U of T News caught up with Asrar before he left for South America to ask him about his journey into space medicine, the challenges astronauts face and his role with the International Space University.

What is space medicine?

We are looking at what happens to astronauts and their health in space – we know that the microgravity has impacts on the body including bone and heart health. The space medicine side would introduce countermeasures that can maintain health and bone health in space, especially for someone who is staying for longer periods.

It also involves the preventive side because it is looking at individuals who might have medical conditions that would put them in a high-risk situation, and it examines whether their bodies would be able to withstand the strains of this extreme space environment.

What are some of the challenges astronauts encounter in space?

The distance and extreme environment can be stressful for anyone. When you are in space, you are away from your loved ones. You are in this really confined space with a select number of individuals for the next six months or so. Even simple tasks like going to the bathroom become more complex.

In order to prevent issues related to bone and heart health, astronauts have to exercise for two hours on a daily basis. They also have their regular schedule like keeping their premises clean and research projects – and working to meet all those tasks and needs in an extreme environment can be quite challenging.

With further distances away from Earth, the time delay creates challenges in communication. If someone has a medical emergency or needs mental health support, it can be difficult to communicate in a timely manner. These are the sorts of things we’re examining in space medicine: how do we train people to be better prepared for these challenges?

As a member of the Temerty Centre for AI Research and Education in Medicine (T-CAIREM), I know that there are developments in machine learning and artificial intelligence that are being explored for use in every aspect of medicine. This also has a role in space medicine and improving the response time from Earth to astronauts.

Farhan Asrar leads an introductory lecture on space medicine for Space Studies Program participants (supplied photo)

What sort of work will you be doing with the International Space University’s Space Studies Program?

This year, the space studies program is being held in Brazil and I was invited to co-chair the department of human performance and space along with Judith Hayes, NASA's chief science officer under the human health and performance directorate.

We helped develop curriculum for the program along with other chairs, directors and academics. We’ve organized talks, educational activities and different sessions that are related to human performance and health and medicine in space. We’ll be there to support and mentor the participants when necessary.

We’ve invited CSA’s flight surgeon and NASA’s Space psychologist to share their expertise on the health of astronauts, the training they do to prepare for missions and the challenges they face. We’ve also invited NASA astronaut Jessica Meir and Canadian astronaut David Saint-Jacques to talk about his experience in space. He has worked as a family doctor in the Arctic, so it’ll be interesting to hear about his experiences with extreme environments and challenges he’s had here on Earth, too.

I’ve also been researching the link between sports and space medicine – so we organized a visit to Brazil’s Paralympic training site. There are a lot of similarities between athletes and astronauts: they both have to be physically fit, train every day, and their training and professions put a physical strain on their bodies. In this session, we’ll also educate participants about Paralympic training and then get into physical barriers in space.

What excites you most about space?

I really appreciate that space brings everyone together, regardless of your background, culture or country. It’s great to have so many individuals working together – even the crew missions are now more diverse.

There’s also a lot of technology like GPS and infrared thermometers that originated from space programs before they became part of our everyday lives. Infrared thermometers, for example, were invented to measure the temperature of distant celestial objects and become very popular during the pandemic to check a person’s temperature.

Similarly, the isolation and extreme environments that astronauts feel on their missions is something we felt during COVID-19. And we used telemedicine during the pandemic, which originated from space and taking care of astronauts at a distance. With the pandemic, we were put in many situations we weren’t used to – but you could often look to the space world and say, “Yes, we’ve been doing this for decades and we can share our expertise.”

There’s so much that space introduced to our lives that we don’t even realize.

Research challenges long-held view of early-stage Alzheimer's disease

siddiq22 — Wed, 05 Jul 2023 03:12:54 +0000

Research challenges long-held view of early-stage Alzheimer's disease

siddiq22 Tue, 07/04/2023 - 23:12

Cutline

Gerold Schmitt-Ulms, a professor in the Temerty Faculty of Medicine's department of laboratory medicine and pathology, was one of the authors of the new study (supplied image)

Eileen Hoftyzer

Topic

Tanz Centre for Research in Neurodegenerative Diseases

Laboratory Medicine and Pathobiology

Faculty of Arts & Science

Subheadline

A new study by researchers from U of T's Tanz Centre for Research in Neurodegenerative Diseases examines how a hormone called somatostatin influences the earliest stages of the disease

Recent research from the Tanz Centre for Research in Neurodegenerative Diseases in the ��Ƶ's Temerty Faculty of Medicine is challenging long-held views of how a hormone called somatostatin influences the earliest stages of Alzheimer’s disease.

“Importantly, for the first time, this research indicates the extent to which somatostatin could be important in Alzheimer’s disease,” says Gerold Schmitt-Ulms, co-author of the study published in Scientific Reports.

“The answer is that somatostatin has a significant effect, but it’s not black or white. It doesn’t prevent clumping of the amyloid beta protein, but slows it down. This is important, but we don’t know what this means for treatment yet,” says Schmitt-Ulms, an investigator at the Tanz Centre and professor in U of T’s department of laboratory medicine and pathology.

The dominant hypothesis of how Alzheimer's disease begins – the amyloid cascade hypothesis – says that too much amyloid beta protein is produced, which clumps together to form oligomers (small clumps of varying numbers of amyloid beta monomeric building blocks), which then continue to accumulate to form larger plaques that damage neurons.

As early as the 1970s, researchers observed that brains of people with Alzheimer’s disease had lower levels of the hormone somatostatin than people who did not have Alzheimer’s, and that the plaques of amyloid beta that are characteristic of the disease tend to form near neurons that produce somatostatin.

These observations suggested a relationship between somatostatin and amyloid beta aggregation, but researchers did not know what it was.

Then, in the early 2000s, a team from Japan published research describing that somatostatin drives production of an enzyme called neprilysin that can degrade amyloid beta. This finding suggested that if somatostatin was decreased, the levels of neprilysin would decrease – without neprilysin to degrade amyloid beta, the plaques would continue to grow, and Alzheimer's disease would progress.

This understanding of the role of somatostatin is where the field stood for more than a decade.

An image from the study summarizing its key findings (supplied image)

Several years ago, Schmitt-Ulms and his team investigated amyloid beta in its monomer and oligomer forms, specifically looking for molecules in the brain that would bind to the toxic oligomeric forms. They found that, of all proteins in the brain, somatostatin was the smallest to bind to amyloid beta – and the most selective, as it only interacted with the oligomers.

They then observed that somatostatin blocked the formation of oligomers, with higher concentrations of somatostatin having a greater effect. This earlier study provided the first evidence that somatostatin interacts directly with the oligomeric amyloid beta that are known to be the earliest stages of Alzheimer's disease, providing an alternative perspective on the impact of somatostatin on the disease.

“We didn’t actually intend to work on somatostatin, but these results made us very curious about what would happen if somatostatin was absent in an animal model that was genetically engineered to develop amyloid beta aggregations,” Schmitt-Ulms explains.

To answer this question, the research team crossed a somatostatin-deficient mouse line with an amyloidosis mouse model.

They found that when somatostatin was absent, there were more amyloid beta aggregates, consistent with what is seen in Alzheimer’s disease in humans.

Remarkably, the result did not seem to be caused by an effect of somatostatin on neprilysin levels, as there were no differences – a contradiction to the long-held understanding of the mechanism through which somatostatin impacts Alzheimer’s disease. Instead, the data suggested that somatostatin blocks oligomer formation independent of neprilysin by interacting with amyloid beta.

“There isn’t a lot of literature that explains how the environment in the brain can promote or inhibit amyloid beta forming into oligomers, so this is a nice vignette that shows that one molecule – somatostatin – seems to influence that first small oligomeric aggregation step,” Schmitt-Ulms says.

“And if you get fewer of these oligomeric forms, then you get fewer of the small clumps, which are the next step of amyloid beta aggregation – so the process made sense, and it was a striking finding.”

While the results have challenged the conventional view of somatostatin in Alzheimer’s and prompted discussions in the scientific community, what they mean for treatment is still uncertain.

Somatostatin plays important roles in the gastrointestinal, endocrine and nervous systems, so selectively promoting its role in blocking amyloid aggregation would be challenging. Schmitt-Ulms says that it is also unclear whether augmenting somatostatin, and thereby arresting the growth of amyloid beta aggregates, is beneficial.

Still, the results have shaken up the research field.

“The evidence speaks for itself, and we stand by our conclusions, but the data can’t answer what this means for therapeutics,” Schmitt-Ulms says.

“They do, however, indicate that somatostatin – one of the first-ever molecules that were biochemically linked to Alzheimer’s disease – may play a different role in the earliest stages of the disease than expected, and that in itself is important.”

The study was supported by Alberta Innovates Bio Solutions, Ontario Centres for Excellence/MaRS Innovation and the Borden Rosiak family.

From machine learning to mentorship, graduate Irene Fang showed leadership during her time at U of T

siddiq22 — Thu, 22 Jun 2023 17:43:55 +0000

From machine learning to mentorship, graduate Irene Fang showed leadership during her time at U of T

siddiq22 Thu, 06/22/2023 - 13:43

Cutline

Irene Fang graduated with an honours bachelor of science degree, working on research that could lead to new treatments and therapies for immunocompromised patients (supplied photo)

Topic

Artificial Intelligence

Immunology

machine learning

Subheadline

Even while undertaking complex research, the human biology and immunology student took the time to help her peers

While studying for her honours bachelor of science degree, new ��Ƶ graduate Irene Fang capitalized on opportunities both inside and outside the classroom.

Majoring in human biology and immunology in the Faculty of Arts & Science, Fang researched innovative methods in ultrasound detection driven by artificial intelligence (AI) and machine learning. She’s also working on research into cells and proteins in humans that could lead to new treatments and therapies for immunocompromised patients.

Even amid that busy schedule, Fang was determined to help others succeed. As a senior academic peer advisor with Trinity College, she was admired for her dedication to learning and the U of T community.

“I want to keep giving back because I am so appreciative of the upper-year mentors I connected with, starting in first year,” Fang says. “They continue to serve as an inspiration, motivating me to further develop personal and professional skills.”

Fang spoke with Faculty of Arts & Science writer David Goldberg about what she learned during her undergraduate studies, the importance of peer support and her post-graduation plans.

Why was U of T the right place for you to earn your undergraduate degree?

U of T provided a plethora of academic, research and experiential learning opportunities alongside a world-class faculty to help cultivate my curiosity and consolidate my knowledge. In conjunction with an unparalleled classroom experience, I gained a real-world perspective with international considerations through the Research Opportunities Program.

I would be remiss if I didn’t also mention how extracurricular activities enhanced and enriched my university experience. The many clubs at U of T helped me focus on my passions and make meaningful connections with like-minded peers who became my support network, enabling me to reach my full potential.

How is your area of study going to improve the life of the average person?

It is absolutely fascinating that AI has already revolutionized the medical field. Specifically, AI possesses the potential to aid in the classification of ultrasound images, enhancing early detection and diagnosis of internal bleeding because of injuries or hemophilia. Overall, AI may lead to more efficient care for patients, thereby improving health outcomes.

In terms of my immunology research, since the memory B cells expressing the specific receptor are dysregulated in people suffering from some autoimmune disorders and infectious diseases, a better understanding of how memory B cells are regulated could provide valuable insight into the underlying mechanisms of such diseases so we can enable scientists to develop new therapies that alleviate patients’ symptoms.

What are you hoping to do after graduation?

I aspire to pursue a career in the medical field, conduct more research and nurture my profound enthusiasm for science while interacting with a diverse group of people. I hope to devote my career to improving human health outcomes while engaging in knowledge translation to make science more accessible to everyone.

Why was working as a peer advisor at U of T important to you?

I remember feeling overwhelmed as a first-year student until I reached out to my academic peer advisors. Had I not chatted with them, I would not have known about – let alone applied for – my first research program. Looking back, it opened the door to many more new, incredible possibilities and opportunities.

This experience made me realize the significance and power of mentorship, inspiring me to become an academic peer advisor. Seeing my mentees thrive and achieve their goals has made this role so rewarding – so much so that I am determined to engage in mentorship throughout my career after graduation.

What advice do you have for current and incoming students to get the most out of their U of T experience?

Ask all questions – because there are no silly questions. Get involved, whether it be volunteering, partaking in work-study programs, sports or joining a club. Meeting new people and talking to strangers can be daunting, but the undergraduate career is a journey of exploration, learning and growth.

Be open-minded and don’t be afraid to try something new. Immersing yourself in distinct fields enables you to discover your interests and passions, which can lead you to an unexpected but meaningful path.

Also, be kind to yourself because failures are a normal part of the learning process – what’s important is that you take it as an opportunity to learn, grow and bolster your resilience.

And finally, although academia and work can keep you busy, remember to allocate time for self-care. Exercise, sleep and pursue hobbies because mental health is integral for success in life.

U of T researchers find vulnerability in COVID-19 variants that reduces transmissibility

Christopher.Sorensen — Mon, 12 Jun 2023 20:45:36 +0000

U of T researchers find vulnerability in COVID-19 variants that reduces transmissibility

Christopher.Sorensen Mon, 06/12/2023 - 16:45

Cutline

(illustration by NIAID)

Anika Hazra

Topic

COVID-19

Donnelly Centre for Cellular & Biomolecular Research

Biochemistry

Molecular Genetics

Researchers at the ��Ƶ have found that Omicron variants of the COVID-19-causing virus can be hindered in their ability to infect people by mutations in the spike protein that prevent the virus from binding to and entering cells.

The spike protein is a distinctive feature of viruses, found on their outside surface. The researchers found that mutations in this protein influence the sensitivity of Omicron variants to chemical reduction – a process that can prevent Omicron variants from spreading and could potentially be delivered to patients through aerosol therapy.

“While infection by the Omicron variant usually leads to milder symptoms, this variant is unique in how easily it can spread,” said Zhong Yao, lead author on the study and senior research associate in the lab of Igor Stagljar, a professor at U of T’s Donnelly Centre for Cellular and Biomolecular Research.

“Our study clearly demonstrates a significant vulnerability of Omicron to chemical reduction – one that is either not found or is much less potent in previous variants of coronavirus.”

The team's findings were published in the Journal of Molecular Biology.

The researchers found that Omicron-specific mutations in the virus’s spike protein reduce its ability to bind to a key receptor in host cells, called ACE2. The spike protein’s receptor-binding domain, the surface of which comes into contact with the ACE2 receptor, consists of multiple disulfide bonds. Two of these bonds, involving the C480-C488 and C379-C432 disulfides, are highly susceptible to cleavage through chemical reduction, the team showed.

Researchers Zhong Yao, left, and Igor Stagljar (supplied images)

The internal environment of a cell is in a naturally reduced state compared to the surface, and does not usually support disulfides bonds. In contrast, extracellular proteins and protein domains contain disulfide bonds that are oxidized, creating a structural conformation that helps them bind to receptors.

Breaking disulfide bonds changes the conformation of the proteins, so they can no longer fit into their receptors. Treating the Omicron spike protein with a reducing agent breaks the disulfide bonds at the surface, inhibiting the spike protein from binding to the ACE2 receptor.

“While mutations, in general, have increased the transmissibility of Omicron subvariants, as well as their ability to evade the immune system, this vulnerability to disulfide cleavage presents potential target areas for treating Omicron infections,” said Stagljar, who is also a professor of biochemistry and molecular genetics at U of T’s Temerty Faculty of Medicine.

One potential treatment method that takes advantage of Omicron’s structural vulnerability is aerosol therapy. Reducing agents can be toxic to the body at higher levels and can potentially harm non-target proteins. Aerosol therapy overcomes this obstacle by delivering the reducing agent directly to the lungs, which can tolerate a higher concentration level of the reducing agent than the rest of the body.

The researchers found that Omicron variants were particularly sensitive to an antioxidant called bucillamine, which is in a Phase 3 clinical trial by Revive Therapeutics to evaluate its safety and efficacy.

“While Omicron is less deadly overall, it still poses a threat to older, immunocompromised and unvaccinated groups,” Yao said.

“It’s helpful to understand the mechanism through which Omicron variants are transmitted between people, so that we can harness it for therapeutic treatments and be more prepared.”

The research was supported by the PRiME COVID-19 Task Force, COVID Relief, the Toronto COVID-19 Action Fund and the Temerty Knowledge Translation grant.

Researchers discover new protein needed for rapid wound repair

siddiq22 — Wed, 07 Jun 2023 20:35:11 +0000

Researchers discover new protein needed for rapid wound repair

siddiq22 Wed, 06/07/2023 - 16:35

Cutline

Katheryn Rothenberg, a postdoctoral researcher in U of T's Quantitative Morphogenesis Lab, was lead author on the new study (photo by Qin Dai)

Qin Dai

Topic

Institute of Biomedical Engineering

Cell and Systems Biology

Faculty of Applied Science & Engineering

Lawrence S. Bloomberg Faculty of Nursing

Subheadline

A new study by researchers from U of T's Faculty of Applied Science & Engineering examines the mechanisms underlying collective cell migration

Researchers from the ��Ƶ's Faculty of Applied Science & Engineering have made progress in understanding the intricate cellular processes involved in tissue development and repair.

The findings, published in the journal Current Biology, shed light on the mechanisms underlying collective cell migration – a fundamental behaviour that plays a crucial role in both normal embryo development and pathological conditions such as cancer metastasis.

“This study advances our understanding of the molecular signals that coordinate cellular behaviours, in embryonic development and tissue repair, and likely also in tumour invasion,” says Rodrigo Fernandez-Gonzalez, a professor in the department of cell and systems biology and the Institute of Biomaterials and Biomedical Engineering who heads the Quantitative Morphogenesis Laboratory.

Researchers found that Rap1 – a molecular switch that regulates cell adhesion and signalling when turned on – plays a role in the formation and remodelling of adherens junctions (protein complexes that occur at cell–cell junctions and cell–matrix junctions in epithelial and endothelial tissue) and the cytoskeleton during the collective cell movements that drive the rapid, scar-less wound healing response in embryos, making it an attractive therapeutic target in the future.

In embryonic wound healing, the cells around the wound move together to seal the lesion. To that end, cells undergo a series of intricate molecular changes. At the centre of these changes, a unique structure called tricellular junction (TCJ) is formed. The TCJ acts as a hub that hosts a series of proteins that are essential in coordinating cell movements.

When researchers tagged the Rap1 protein with a sensor that could be detected by a microscope, they were able to visualize large concentrations of the protein accumulating around the wound, and specifically at the TCJs.

Upon establishing the localization of Rap1 in the hub of wound repair, the researchers set out to find its role in this complex process. By inactivating or reducing the amount of Rap1 in the embryo, they observed a significant reduction in the wound closure rate compared to normal embryos. Conversely, by activating Rap1, the wound closure rate was dramatically accelerated.

“The fact that collective migration speed can be modulated by Rap1 activity provides a potential pathway for either promoting cell migration – for example, to heal chronic wounds or stopping undesired migration like cancer metastasis,” says Katheryn Rothenberg, a postdoctoral researcher in Fernandez-Gonzalez’s lab who led the study.

Researchers also found that Rap1 plays a crucial role in interacting with cell-cell adhesion proteins necessary to maintain cells together as they move to close the wound, and cytoskeletal proteins that cells use to pull on each other and move collectively. They observed that any disruption to Rap1 can greatly impede the speed at which wounds close.

“By unravelling the intricate molecular mechanisms involved, we have uncovered potential targets for therapeutic interventions in various conditions that rely on collective cell migration,” Fernandez-Gonzalez says.

“We are now keen on understanding the upstream signals that turn Rap1 on during wound healing. This understanding would facilitate the development of tools to activate Rap1 in congenital disorders associated with deficient collective cell behaviour, or to inhibit Rap1 when it contributes to spread disease.”

Nursing PhD graduate creates toolkit to improve communication for ICU patients

Christopher.Sorensen — Tue, 06 Jun 2023 17:02:11 +0000

Nursing PhD graduate creates toolkit to improve communication for ICU patients

Christopher.Sorensen Tue, 06/06/2023 - 13:02

Cutline

Laura Istanboulian, a new graduate of the Lawrence S. Bloomberg Faculty of Nursing, created a “communication bundle” to help solve a decades-old problem in hospital ICUs (supplied photo)

Topic

Nursing

PhD

Subheadline

Nurse practitioner Laura Istanboulian worked with patients, families and health-care professionals to co-design new tools that can better support patients

Already juggling a career as a nurse practitioner, marriage, two kids and aging parents, Laura Istanboulian wondered if she was too old – or if it was too late – to pursue her doctorate in nursing science.

Yet it had been her dream to complete her PhD – and as a nurse, she was motivated to situate her research around her patients. She was specifically interested in addressing a decades-old problem in hospital intensive care units (ICUs) that makes it difficult for individuals who require a ventilator to communicate with their health-care providers.

Istanboulian decided to pursue her doctorate, making it her objective to reframe communication as something essential to a quality patient experience.

While in the program, she co-designed and implemented a bundled communication toolkit for ICU patients as part of her PhD at the Lawrence S. Bloomberg Faculty of Nursing.

The bundle is a portable, multi-modal set of tools that Istanboulian co-designed with nurses, patients and their families. Each item in the bundle is evidence-based in supporting the communication needs of patients – including alphabet boards, blank boards for writing on, writing tools like markers and pencils, a pain scale, a basic needs scale and some pre-translated boards in multiple languages.

Istanboulian using tools from the bundle to communicate with a patient in the ICU (supplied photo)

The bundle also contains six short education modules for staff to gain a better understanding of how to use each tool option to best support a patient.

“I was not trying to invent something brand-new – these tools existed already, but it became necessary to have them contained in one convenient and accessible location, and to also make providers aware of the need to make an effort to communicate with ventilated patients,” Istanboulian explains.

When a patient is on a ventilator, no air can pass over their vocal cords – meaning that they cannot speak. They might make efforts to communicate – but that requires both interpretation and time from the health-care provider, which is not always available, Istanboulian says.

Some patients may also have cognitive impairments or brain dysfunction from their illness or medical condition, making communication that much harder – and their fear from not knowing what is going on even more palpable.

Istanboulian notes that limited communication with a patient can also affect care providers.

“It can be intimidating caring for someone when you cannot explain what it is happening to them or understand what they are trying to say,” she says.

Istanboulian recounts a moment when she used the new communication tools to try to understand one of her clients, who could not speak or hear.

“On the blank board, he wrote, ‘Thank you so much for taking the time.’ I took a photo of that and it hangs by my desk, because it is a reminder that this effort to communicate really mattered to this person – and it also tells me that this doesn’t happen as a rule,” she says.

“As nurses and physicians, we might be doing the best for them medically, but if patients don’t understand what is happening to them, they can feel very unsafe and alone.”

Developing the communication bundle was not without its challenges, especially as Istanboulian began her PhD just as the COVID-19 pandemic began to unfold.

The bundled toolkit in a central location on a hospital unit (supplied photo)

“Laura overcame significant obstacles posed by the global pandemic to complete her doctoral research,” says Istanboulian’s supervisor Craig Dale, an associate professor in the Lawrence S. Bloomberg Faculty of Nursing.

“She designed, implemented and evaluated this communication-support intervention for mechanically ventilated adult patients in the ICU and the outcome of her research has the potential to be implemented in ICUs worldwide – a positive impact that extends well beyond the pandemic.”

Despite the constantly shifting policies around visitors and isolation requirements for the ICU, Istanboulian found most families, patients and nurses were more than willing to help her design the new tools.

“They really wanted to engage in this process – which was so profound to me, because it showed how much everyone wanted to see this issue of communication addressed,” Istanboulian says.

Families and caregivers offered helpful tips for nurses on providing phone updates on loved ones, and nurses were able to speak to what they would find most helpful in using the bundle, including how to easily share some of the online tools using the internal hospital intranet.

Following the initial success of the tools, Istanboulian is keen to scale up the bundle so that it is accessible to larger units in the hospital – and eventually available across multiple hospital sites within the health-care system.

Istanboulian says one of the key lessons she learned from the project was that the toolkit does require tailoring to local environments in order to meet the needs of the end users. She is currently working with an international group of researchers who are developing core outcomes for communications research in critical care and recommendations that will assist in scaling up the bundle.

Her work with researcher Dr. Kelly Smith – a specialist in health-care quality and patient safety who is an associate professor and co-lead for outcomes and evaluation at U of T's Institute of Health Policy, Management & Evaluation – will also help to determine how patients and family members interpret communication as a safety issue and help reframe communication as something that many see as simply "nice to have," Istaboulian says, to something essential to a patient's experience.

As Istanboulian embarks on life after her PhD, which includes ongoing research and a new position as an assistant professor at Toronto Metropolitan University, she's grateful for the many people that helped her on her path to graduating with her doctorate.

“My wife was my No. 1 – she was always making space for me to be able to write or research. My supervisor and clinical supervisor were so supportive of me not only conducting the research, but maintaining my clinical practice; and my parents were so proud of me,” Istanboulian says.

“I’m not sure everyone is as fortunate to have that level of support – and I think that was really the recipe for this dream becoming a reality.”

Novel treatment for recurrent glioblastoma shows promising results

siddiq22 — Wed, 17 May 2023 14:50:56 +0000

Novel treatment for recurrent glioblastoma shows promising results

siddiq22 Wed, 05/17/2023 - 10:50

Cutline

Researchers Farshad Nassiri, left, and Gelareh Zadeh found that a new therapy for glioblastoma can prolong patient survival (photos courtesy of UHN)

Topic

Cancer

partnerships

An international clinical trial led by researchers at University Health Network (UHN) and the ��Ƶ has shown that a new therapy for recurrent glioblastoma prolongs patient survival, in some cases by several years.

The novel therapy involves the combination of an oncolytic virus, engineered to selectively infect and kill cancer cells, and type of a targeted immunotherapy called immune checkpoint inhibition.

“The initial clinical trial results are promising,” said the study's principal investigator Gelareh Zadeh, a neurosurgeon-scientist at UHN, where she is co-director of the Krembil Brain Institute.

“We are cautiously optimistic about the long-term clinical benefits for patients," said Zadeh, a professor in the department of surgery at the Temerty Faculty of Medicine who also holds the Dan Family Chair in Neurosurgery and the Wilkins Family Chair in Brain Tumour Research.

The study's findings were published in the journal Nature Medicine.

Imaging from the study following infusion of the oncolytic immunotherapy DNX-2401 (supplied image)

Glioblastoma is a notoriously difficult-to-treat primary brain cancer. Despite aggressive treatment, which typically involves surgical removal of the tumour and multiple chemotherapy drugs, the cancer often returns – at which point further treatment options are scarce.

To meet the urgent need for new therapies, Zadeh and her colleagues evaluated the new treatment in 49 patients with recurrent disease from 15 hospital sites across North America. University Health Network was the only Canadian site and treated most of the patients enrolled in the trial.

First, the team slowly injected the virus directly into the tumour using stereotactic techniques, which are minimally invasive and guided by imaging and other technologies. Patients then received a common immune checkpoint inhibitor intravenously once every three weeks, starting one week after surgery.

Immune checkpoint inhibitors are effective treatments for a variety of cancers, but have had limited success in treating recurrent glioblastoma.

“These drugs work by preventing cancer’s ability to evade the body’s natural immune response, so they have little benefit when the tumour is immunologically inactive, as is the case in glioblastoma,” Zadeh said.

“Oncolytic viruses can overcome this limitation by creating a more favourable tumour microenvironment, which then helps to boost anti-tumour immune responses."

The combination of these viruses and immune-checkpoint inhibitors results in a “double hit” to tumours: the virus directly kills cancer cells and stimulates local immune activity that makes the cancer cells more vulnerable to targeted immunotherapy.

The therapy had no major unexpected adverse effects and yielded a median survival of 12.5 months – considerably longer than the six to eight months typically seen with existing therapies.

“We’re very encouraged by these results,” said Farshad Nassiri, first author on the study and a senior neurosurgery resident at U of T.

“Over half of our patients achieved a clinical benefit – stable disease or better – and we saw some remarkable responses with tumours shrinking, and some even disappearing completely. Three patients remain alive at 45, 48 and 60 months after starting the clinical trial.”

The researchers also performed experiments to define mutations, gene expression and immune features of each patient’s tumour. They discovered key immune features that could eventually help clinicians predict treatment responses and understand the mechanisms of glioblastoma resistance – the first study of its kind for brain tumours.

Zadeh said that in general, the drugs used in cancer treatments do not work for every patient, but that a subpopulation of glioblastoma patients that will likely respond well to the new treatment. She also said that this kind of translational research, which combines basic bench science and clinical trials, is key to moving personalized treatments for glioblastoma forward.

“The trial would not have been possible without our incredible OR teams, research safety teams and researchers – including Dr. Warren Mason at Princess Margaret Cancer Centre – and our brave patients and their families. We’re also grateful to the Wilkins Family for providing the funds to enable us to complete trials that advance care for our patients,” Zadeh said.

The next steps for the researchers are to test the effectiveness of the combination therapy against other treatments in a larger, randomized clinical trial.

The research was supported by DNATrix Inc., Merck & Co. Inc., the Princess Margaret Cancer Centre Foundation and the UHN Foundation.

Read the original story at the UHN website

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How AI could help doctors predict cardiac problems in critically ill children

Christopher.Sorensen — Fri, 12 May 2023 19:40:27 +0000

How AI could help doctors predict cardiac problems in critically ill children

Christopher.Sorensen Fri, 05/12/2023 - 15:40

Cutline

U of T professors Mjaye Mazwi, left, and Sebastian Goodfellow are training AI to recognize the warning signs of impending arrhythmia (Diogenes Baena/Hospital for Sick Children)

Phil Snell

Topic

Our Community

Faculty of Applied Science & Engineering

Pediatrics

Artificial Intelligence

Hospital for Sick Children

A unique collaboration between U of T Engineering researchers and hospital physicians is pioneering the use of artificial intelligence – similar to an AI that helps detect earthquakes – to diagnose heart rhythm abnormalities at Toronto’s Hospital for Sick Children.

The innovative approach, which combines specially trained AI with the expertise of SickKids clinicians, could lead to significantly better health outcomes for critically ill children by providing faster and more accurate diagnosis of heart problems, the researchers say, as well as easing demands on clinicians’ time.

“This could help some of our most vulnerable patients, while also reducing stress on the health-care system,” says Mjaye Mazwi, a staff physician at SickKids, associate professor in the department of paediatrics at U of T’s Temerty Faculty of Medicine and research co-lead at the Temerty Centre for Artificial Intelligence Research and Education in Medicine.

When the heart is functioning as it should, it beats to a regular rhythm – the familiar vertical spike followed by ripples that appear on a heart monitor. A heartbeat that is too fast, too slow or chaotic can cause severe complications and death.

Almost one in three children admitted to an intensive care unit experience a heart rhythm anomaly – at SickKids, this affects as many as 700 children a year. These patients require constant monitoring, which places a high demand on hospital staff who are typically caring for other patients at the same time.

“The challenge is that clinicians cannot continuously monitor every bedside,” says Sebastian Goodfellow, an assistant professor in U of T’s department of civil and mineral engineering and a principal investigator at the Lassonde Institute of Mining. This can lead to a delay in detecting or diagnosing an abnormal heart rhythm, resulting in a worse outcome for the patient.

He and Mazwi, who is SickKids’ director of translational engineering in critical-care medicine, are developing what they believe will be a game-changing solution.

Prior to joining the Faculty of Applied Science & Engineering, Goodfellow worked at a mining startup where he helped build AI models to scan geological data for certain patterns. In 2017, he was invited to enter a “computing in cardiology” challenge with a team from Laussen Labs, a research group at SickKids. There, he met Mazwi, who was interested in using AI to detect heart arrhythmias and was looking for help with the complex challenge of deploying it in the hospital. Goodfellow’s experience made him a natural collaborator.

The AI they are developing is being trained to recognize the warning signs of impending arrhythmia based on clinicians’ expertise and more than 10,000 electrocardiogram readings – a far greater number than even the most experienced clinicians would encounter during their career. Before being deployed with patients, the AI needs to be able to match or exceed the performance of a clinician, and accurately sound the alarm when one of these arrhythmia warning signs appears.

“We want this AI to partner with the best of human intelligence in a kind of collaborative intelligence,” Mazwi says. “We don’t believe that AI will replace clinicians, but we do believe that clinicians who use AI will outperform and replace clinicians who do not.”

The researchers are initially focusing on a specific type of irregular cardiac activity called Junctional Ectopic Tachycardia, or JET, that is especially tricky to detect because it involves subtle changes in the patient’s electrocardiogram. In those who have recently had corrective heart surgery, JET poses a significant risk of injury or death.

Detecting and treating JET early reduces this risk and also helps shorten the patient’s hospital or ICU stay, benefiting the entire health-care system, Mazwi says. Eventually, the researchers hope to develop AI models for detecting every kind of heart rhythm anomaly.

Although AI is making rapid inroads into many areas of life, including medicine, Mazwi says the process in health care is necessarily slower and more careful. An AI model must be tested and retested to ensure it will improve both patient outcomes and overall performance in the health-care system before it is used on actual patients.

“We’re held to a much higher standard,” he says. “You don’t deploy an AI until you are perfectly sure it will provide gains over the current process.”

The research team at U of T and SickKids is collaborating with clinicians and researchers at other pediatric hospitals in England, Israel and Australia to test the AI models being developed in Toronto. Their two goals: to ascertain if the models work as well on similar patient populations in other hospitals and to sow the seeds for expanding far beyond Canada.

“The timely detection and diagnosis of heart arrhythmias is a challenge – it’s an even greater challenge for hospitals that do not have the funding and expertise that SickKids does,” Goodfellow says. “The real impact will be when we take this technology to underserved communities.”

Researchers identify a potential new therapeutic target in Parkinson’s disease

siddiq22 — Mon, 24 Apr 2023 13:50:47 +0000

Researchers identify a potential new therapeutic target in Parkinson’s disease

siddiq22 Mon, 04/24/2023 - 09:50

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A new study by researchers from UHN and U of T examined how to prevent the accumulation in the brain of a protein that contributes to Parkinson's disease (photo by Christian Wiediger via Unsplash)

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Tanz Centre for Research in Neurodegenerative Diseases

Donnelly Centre for Cellular & Biomolecular Research

University Health Network

Neurology

Parkinson's

A team of researchers from the Krembil Brain Institute (KBI) and the ��Ƶ have identified a protein-protein interaction that contributes to Parkinson’s disease.

In a study published in Nature Communications, KBI scientists Lorraine Kalia and Suneil Kalia and U of T researcher Philip M. Kim examined a protein called alpha-synuclein (a-syn) that accumulates in the brain in patients with Parkinson's and leads to cell death.

Much research is currently focused on clearing a-syn with antibodies or using small molecules to prevent a-syn from aggregating. In their study, the researchers took an alternate approach by looking for protein-protein interactions that may be promoting the accumulation of a-syn in Parkinson’s disease.

Protein-protein interactions govern most inner workings of the cell, including breaking down disease-causing proteins. Inhibiting certain interactions has emerged as a promising approach to treat diseases such as stroke and cancer.

“Identifying a particular interaction that contributes to a disease, and then finding ways to disrupt it, can be a painstaking and incredibly slow process,” says Lorraine Kalia, who is also a staff neurologist at University Health Network, a scientist at U of T’s Tanz Centre for Research in Neurodegenerative Diseases and an assistant professor in the division of neurology and in the department of laboratory medicine and pathobiology in the Temerty Faculty of Medicine.

“We all started out a bit skeptical that we would have something useful at the end, and so the fact that we do have something that warrants further work is much more than we anticipated.”

Kim, who is a professor in U of T’s Donnelly Centre for Cellular and Biomolecular Research and in the department of molecular genetics in the Temerty Faculty of Medicine, notes the team took an approach they hoped would expedite the discovery of potential therapies.

“We developed a platform to screen molecules called peptide motifs – short strings of amino acids that can disrupt protein-protein interactions – for their ability to protect cells from a-syn,” Kim says. “Once we identified candidate peptides, we determined which protein-protein interactions they target.”

Through this approach, the team identified a peptide that reduced a-syn levels in cells by disrupting the interaction between a-syn and a protein subunit of the cellular machinery called “endosomal sorting complex required for transport III” (ESCRT-III).

“ESCRT-III is a component of a pathway that cells use to break down proteins, called the endolysosomal pathway. We discovered that a-syn interacts with a protein within ESCRT-III – CHMP2B – to inhibit this pathway, thereby preventing its own destruction,” Lorraine Kalia says.

“We were impressed that the platform worked. But I think what was more interesting is that by doing this kind of screening, we were able to find an interaction that was really not previously characterized, and we also found a pathway that’s not yet been targeted for therapeutics.”

Once the group identified this interaction, they confirmed that they could use their peptide to disrupt it – preventing a-syn from evading the cell’s natural clearance pathways, notes Suneil Kalia, who holds the R.R. Tasker Chair in Stereotactic and Functional Neurosurgery at UHN and is an associate professor in the division of neurosurgery in the Temerty Faculty of Medicine.

“We tested the peptide in multiple experimental models of Parkinson’s disease, and we consistently found that it restored endolysosomal function, promoted a-syn clearance and prevented cell death,” he says.

These findings indicate that the a-syn-CHMP2B interaction is a potential therapeutic target for the disease, as well as other conditions that involve a buildup of a-syn, such as dementia with Lewy bodies (another disease associated with abnormal deposits of a-syn in the brain).

The next steps for this research are to clarify exactly how a-syn and CHMP2B interact to disrupt endolysosomal activity. Ongoing studies are also determining the best approach for delivering potential therapeutics to the brain.

“This research is still in its early stages – more work is definitely needed to translate this peptide into a viable therapeutic,” cautions Lorraine Kalia. “Nonetheless, our findings are very exciting because they suggest a new avenue for developing treatments for Parkinson’s disease and other neurodegenerative conditions.”

This study also highlights the value of multidisciplinary collaborations in health research.

“We simply could not have conducted this study in a silo. The endolysosomal pathway is underexplored, so it was not an obvious place to look for potential disease-related protein-protein interactions. Dr. Kim’s screening platform was critical for pointing us in the right direction,” Suneil Kalia points out.

“It is really extraordinary to see this platform – which we initially used to find potential therapeutics for cancer – yielding advances in brain research. The pathways that cells use to stay healthy are fundamentally very similar across tissues, so the insights that we gain about one organ system or disease could have important implications in other contexts,” Kim says.

“It’s really brand-new science and targets that haven’t been a focus for drug development for Parkinson’s," Lorraine Kalia adds. "We hope this changes the landscape for treatment of this disease, which is so in need of new therapies.”

The research was supported by the Canadian Institutes of Health Research, the Michael J. Fox Foundation for Parkinson’s Research, Parkinson’s UK, the Canada Foundation for Innovation, the Ontario Research Fund, the Krembil Research Institute and the UHN Foundation.

This story was originally published on the website of the Krembil Brain Institute, University Health Network.

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Neurodegenerative Diseases

Biomolecular Research

U of T biostatistician uses big data to shed new light on chronic diseases

Christopher.Sorensen — Thu, 27 Sep 2018 18:25:22 +0000

U of T biostatistician uses big data to shed new light on chronic diseases

Christopher.Sorensen Thu, 09/27/2018 - 14:25

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Nathalie Moon recently joined U of T's department of statistical sciences as an assistant professor in the teaching stream (photo by Diana Tyszko)

Dee Keilholz

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Big Data

Faculty of Arts & Science