Temerty Faculty of Medicine

Princess Margaret Cancer Centre

Cancer

University Health Network

A preclinical study is revealing new insights into the molecular machinery that drives the aggressiveness of pancreatic cancer.

The ability of pancreatic cancer to invade and spread to other parts of the body is a major factor in its poor prognosis, with an overall five-year survival rate of less than 10 per cent.

“Pancreatic cancer cells are known to be very metastatic and that’s a big problem,” says Leonardo Salmena, an associate professor of pharmacology and toxicology in the University of Toronto’s Temerty Faculty of Medicine.

Salmena is the senior author of a study, published in the Journal of Cell Biology, that investigates the role of a gene called INPP4B in pancreatic cancer’s ability to spread. Led by post-doctoral researcher Golam Saffi and former master’s student Lydia To, the team found that INPP4B exerts its tumour-promoting effects via a cellular organ called the lysosome.

“Classically, the lysosome is a garbage disposal organelle where old and tired proteins and other organelles get degraded to be used for energy and other building blocks for the cell,” says Salmena.

In most cells, lysosomes typically cluster around the nucleus. But in pancreatic cancer cells, the researchers found that INPP4B drove the lysosomes from the cell interior to the periphery, where these organelles fuse with the cell’s outer membrane. In doing so, the enzymes and other lysosomal factors responsible for breaking down cellular waste are dumped into the space surrounding the tumour cells.

This space contains a network of proteins and molecules that provides crucial structural support to cells and tissues while also restricting a cell’s ability to move. The release of the lysosome’s protein-degrading contents into this extracellular space causes the stabilizing network to fall apart, thus making it easier for pancreatic cancer cells to migrate and invade other tissues.

Crucially, Salmena and his team also identified the signalling pathway by which INPP4B drives the movement of lysosomes to the cell edge. INPP4B works with two other proteins – PIKfyve and TRPML-1 – to modify the lysosome’s surface structure and alter local calcium levels so that the organelle is propelled to the cell periphery.

Based on these findings, the researchers are testing two experimental drugs that target TRPML-1 and PIKfyve in a preclinical model of pancreatic cancer. They are also studying how the release of lysosomal contents can change the immunological environment of the cancer cells, and what effects that might have on the immune system’s ability to respond to the tumour.

Salmena first became interested in INPP4B when, during his post-doctoral research, he found that it was involved in breast cancer. Since then, he and his team have shown that the effects of INPP4B vary depending on the context.

For example, in some breast cancer types, INPP4B behaves as a tumour suppressor whereas it has an activating role in other aggressive cancers like pancreatic cancer – which the Canadian Cancer Society expects to be the third leading cause of cancer death in Canada in 2024, with an estimated 6,100 people dying from the disease.

Salmena and his colleagues later showed that among all cancers, INPP4B levels are highest in pancreatic tumours, and that high levels of the protein are associated with decreased overall survival in people with pancreatic cancer.

The study was a collaboration between Salmena’s group, Roberto Botelho, a professor of chemistry and biology at Toronto Metropolitan University, and Steven Gallinger, a hepatobiliary and pancreatic surgical oncologist and clinician-scientist at Princess Margaret Cancer Centre, University Health Network and a professor of surgery and laboratory medicine and pathobiology in Temerty Medicine. He is also director of the PanCuRx Translational Research Initiative at the Ontario Institute for Cancer Research.

The study was supported by the Cancer Research Society and the Canadian Institutes of Health Research.

Growing up with a dog may be good for your gut health: Study

rahul.kalvapalle — Thu, 26 Sep 2024 14:44:39 +0000

Growing up with a dog may be good for your gut health: Study

rahul.kalvapalle Thu, 09/26/2024 - 10:44

Cutline

Living with a dog between ages five and 15 is associated with reduced risk of developing Crohn’s disease, according to new research from Sinai Health and ��TV (photo by Kseniya Starkova/Getty Images)

Jovana Drinjakovic

Topic

Department of Immunology

Department of Medicine

Sinai Health

Lunenfeld-Tanenbaum Research Institute

Mount Sinai Hospital

Subheadline

Research from Sinai Health and ��TV found early exposure to dogs is linked to a healthier gut and reduced risk of developing Crohn's disease

Dog lovers can attest to the range of benefits that come with having a canine companion, but improved gut health likely isn’t one of them.

That may be about to change following research from Sinai Health and the University of Toronto that shows exposure to dogs during childhood is linked to beneficial changes in gut bacteria, gut permeability and blood biomarkers.

The study, published in Clinical Gastroenterology and Hepatology, found living with a dog between ages five and 15 is associated with a healthier gut microbiome and reduced risk of developing Crohn’s disease.

The research shines new light on how environmental factors influence the onset of Crohn’s – an inflammatory bowel condition – and could inform future prevention strategies.

For the study, researchers led by Kenneth Croitoru and Williams Turpin of Mount Sinai Hospital’s Centre for Inflammatory Bowel Disease (IBD) investigated how dozens of environmental factors impact the likelihood of developing Crohn’s as part of their overarching effort to be able to predict those at risk and potentially intervene early.

“The idea behind predicting someone's risk of disease is that you can then also begin to understand who you might want to do something to try and prevent disease,” says Croitoru, a clinician-scientist at the Lunenfeld-Tanenbaum Research Institute (LTRI), part of Sinai Health, and a professor of medicine and immunology at ��TV’s Temerty Faculty of Medicine.

Croitoru notes the study doesn’t reveal why living with a dog makes someone less prone to Crohn’s disease. “We have established associations between environmental factors and Crohn’s and are now trying to understand how these environmental factors affect the triggering of the disease,” says Croitoru, who is also a gastroenterologist at Mount Sinai Hospital.

The study also found living with a large-sized family in the first year of life to reduce the likelihood of getting Crohn’s. It also found people who lived with a bird at the time of study were more likely to develop the disease.

Caused by inflammation in the gastrointestinal tract, Crohn’s disease can have far-reaching consequences on overall health and well-being. Its incidence among children under 10 has doubled since 1995, while the annual cost of inflammatory bowel disease to Canada is estimated at $5.4 billion per year, according to Crohn’s and Colitis Canada, a national non-profit.

The likelihood of getting Crohn’s is strongly influenced by genetics, but the environment also plays a role, says Croitoru, who holds the Canada Research Chair in Inflammatory Bowel Diseases. While we can’t change our genes, we can modify our surroundings and diet, for example, to potentially prevent the disease from occurring.

These findings come from the Genetic, Environmental and Microbial (GEM) Project, the largest study of its kind that seeks to identify potential triggers of Crohn’s disease.

Coordinated at Mount Sinai Hospital since 2008, the GEM Project has been collecting comprehensive medical and lifestyle data from over 5,000 healthy first-degree relatives of people who have Crohn’s and come from all over the world, including Australia, Canada, Israel, New Zealand, the U.K. and the U.S.

The project is funded by Crohn’s and Colitis Canada, the Canadian Institutes of Health Research and the Helmsley Charitable Foundation.

In the 15 years since the study began, over 120 people have developed the disease. “By understanding what is different about those who develop the disease, we should be able to predict who is at risk,” says Croitoru.

Previously, the group identified differences in the microbiome and other biomarkers in people who go on to develop Crohn’s and those who don’t.

In another recent report published in Gastroenterology, Sun-Ho Lee, a clinician-scientist at Mount Sinai Hospital’s IBD Centre and an assistant professor at the Institute of Medical Science at Temerty Medicine, used available data and machine learning to develop an “integrative risk score” that predicts the risk of Crohn’s with a high degree of accuracy.

But risk prediction is only the first step, says Croitoru, whose ultimate goal is to be able to intervene and prevent the disease from starting.

He and his team are now conducting research that seeks to devise and test strategies for prevention by, for example, adding supplements to the diet to promote a healthy microbiome.

“Sinai Health is committed to groundbreaking research and bringing those discoveries to patients," said Anne-Claude Gingras, director of LTRI and vice-president of research at Sinai Health.

“By integrating genetic, environmental, and microbial data, Dr. Croitoru and colleagues are paving the way towards personalized intervention strategies that could significantly reduce the incidence of Crohn’s disease.”

AI tool reduces risk of unexpected hospital deaths by 26 per cent: Study

Christopher.Sorensen — Mon, 23 Sep 2024 16:50:13 +0000

AI tool reduces risk of unexpected hospital deaths by 26 per cent: Study

Christopher.Sorensen Mon, 09/23/2024 - 12:50

Cutline

(photo by Tempura/Getty Images)

Adam Miller

Topic

Our Community

Unity Health

Artificial Intelligence

Lawrence Bloomberg Faculty of Nursing

St. Michael's Hospital

Subheadline

CHARTWatch, an artificial intelligence early warning system developed at Unity Health Toronto, alerts physicians when hospital patients face a high risk of unexpected death or transfer to an ICU

A new study by Toronto researchers evaluates the use of CHARTWatch, an artificial intelligence early warning system developed at Unity Health Toronto that monitors hospitalized patients in real-time, identifies those at high risk of unexpected death or transfer to an intensive care unit, and alerts doctors and nurses to intervene early.

The study, published in the Canadian Medical Association Journal, shows a 26 per cent reduction in unanticipated mortality after the tool was implemented in the general internal medicine ward of Unity Health Toronto’s St. Michael’s Hospital.

“As AI tools are increasingly being used in medicine, it is important that they are evaluated carefully to ensure that they are safe and effective,” says lead author Amol Verma, general internist at Unity Health and professor in the department of medicine in the University of Toronto’s Temerty Faculty of Medicine who led the development and implementation of CHARTWatch.

Amol Verma (L) and Muhammad Mamdani (supplied images)

“Our findings suggest that AI-based early warning systems are promising for reducing unexpected deaths in hospitals.”

One of the primary sources of unplanned admission to the ICU is the unexpected deterioration of hospitalized patients, which prompted the research team to develop this AI tool and study its effectiveness.

“This important study evaluates the outcomes associated with the complex deployment of the entire AI solution, which is critical to understanding the real-world impacts of this promising technology,” says study co-author Muhammad Mamdani, vice president of data science and advanced analytics at Unity Health and director of ��TV’s Temerty Centre for Artificial Intelligence Research and Education in Medicine.

“We hope other institutions can learn from and improve upon Unity Health Toronto’s experiences to benefit the patients they serve.”

The study analyzed data from 13,649 patients aged 55 to 80 years old admitted to the general internal medicine unit (9,626 in the pre-intervention period and 4,023 using CHARTWatch) and 8,470 admitted to subspeciality units that did not use CHARTWatch.

Helping to prioritize patient needs

“The CHARTWatch project started at Unity Health when we asked patients, clinicians, hospital leaders, what would you want to use artificial intelligence for? If you could predict one thing that AI would tell you, what should that be?” says Verma, who is also the Temerty Professor of AI Research and Education in Medicine.

“And one of the leading priorities of everyone was to be able to predict in advance which patients might become so sick in hospital that they need ICU or might die.”

During the 19-month-long intervention period, 482 patients in the general internal medicine became high-risk, compared with 1,656 patients who became high risk in the 43-month-long pre-intervention period. There were also fewer non-palliative deaths in the CHARTWatch group than in the pre-intervention group (1.6 per cent versus 2.1 per cent).

“If I were a patient, I would be so relieved to know that we have this kind of system,” said co-author Yuna Lee, division head and general internist at St. Michael’s and professor in the department of medicine at ��TV.

“So, when the patient gets a high-risk alert, they’re going to be assessed by senior staff right away. Also, they’re going to have quite close monitoring by nursing staff, so they check on them every one to two hours.”

Expanding the impact of CHARTWatch

CHARTWatch inputs more than 100 aspects of a patient’s medical history and current health status that are routinely stored in the hospital’s electronic medical record. It analyzes the interactions between these inputs and how they change over time. With that information, it’s able to categorize each patient by their risk for deterioration and send an alert to prioritize treatment.

The study is one of the first to evaluate how CHARTWatch can benefit hospital patients in Canada and shows the potential real-world impact of AI on the health-care sector. Damian Jankowicz, Unity Health’s vice-president and chief information and AI officer, says he hopes AI tools such as CHARTWatch will continue to have a profound impact on patients.

“Hopefully with reduced administrative burden on our providers, they will have more time to spend with our patients and really focus on the patient needs,” he says.

“I hope that AI will be able to distill the incredible amounts of information that’s coming at our clinicians into important components and really bring their clinical judgment to the forefront.”

This story first was first published by Unity Health.

��TV receives $25-million gift from Myron and Berna Garron for Scarborough Academy of Medicine and Integrated Health

Christopher.Sorensen — Mon, 23 Sep 2024 13:58:19 +0000

��TV receives $25-million gift from Myron and Berna Garron for Scarborough Academy of Medicine and Integrated Health

Christopher.Sorensen Mon, 09/23/2024 - 09:58

Cutline

(Image supplied)

Advancement Staff

Topic

Our Community

David Palmer

Scarborough Academy of Medicine and Integrated Health

Leslie Dan Faculty of Pharmacy

Meric Gertler

��TV Scarborough

Subheadline

The donation supports the much-needed training of health professionals in the underserved Scarborough and Eastern GTA region

A $25-million gift from Myron and Berna Garron will contribute significantly to the construction of a new state-of-the-art facility at University of Toronto Scarborough that will house the Scarborough Academy of Medicine and Integrated Health (SAMIH). The gift will also support programming and faculty development – in collaboration with hospital partners such as Scarborough Health Network and Michael Garron Hospital – helping to ensure that SAMIH learners have access to a world-class education right in Scarborough and the Eastern GTA.

The University of Toronto will name the new building the Myron and Berna Garron Health Sciences Complex, in honour of the Garrons’ exceptional generosity.

“Myron and Berna Garron’s extraordinary benefaction will help us to realize our vision for the Scarborough Academy of Medicine and Integrated Health – to educate health-care professionals from the region, in the region and for the region,” said Meric Gertler, president of ��TV. “On behalf of the University of Toronto, I thank them for their leadership in the advancement of this crucial mission.”

Helping to revitalize the health-care landscape

SAMIH, the first hub for educating health professionals in Scarborough and the Eastern GTA and the only medical school in the region, was established to address the critical shortage of family physicians and specialists in the fast-growing area by training health providers who reflect the community. The training will take place in partnership with local hospitals, primary care centres and community agencies.

Once the program is fully up and running, SAMIH will have 160 medical students and a combined total of 252 physician assistants, physical therapists and nurse practitioners enrolled. Three top-ranked ��TV faculties – the Temerty Faculty of Medicine, the Lawrence Bloomberg Faculty of Nursing and the Leslie Dan Faculty of Pharmacy – will expand educational programming to this hub. These students will be based at the new Myron and Berna Garron Health Sciences Complex, which will also serve as a base for ��TV Scarborough undergraduates studying health sciences.

The Myron and Berna Garron Health Sciences Complex, currently under construction, will feature an anatomy lab for medical students, two large classrooms equipped with state-of-the-art technology, a 25-bed clinical skills lab and 10 instructional labs. To provide hands-on learning and serve the community directly, the facility will house three teaching clinics offering public services: a clinical psychology clinic, a nurse practitioner clinic and a satellite of ��TV’s Discovery Pharmacy.

SAMIH medical trainees will undertake clinical rotations at several area hospitals, including Scarborough Health Network, Lakeridge Health, Ontario Shores Centre for Mental Health Sciences and Michael Garron Hospital – named in memory of Myron and Berna Garron’s late son, who was born there and later died of cancer at the age of 13. The Garrons’ $50-million donation in 2015 to what was then Toronto East General Hospital has resulted in remarkable benefits for people in the region.

"We envision SAMIH as closing the circle on providing for total patient care, from educating professionals to delivering care bedside,” said Myron and Berna Garron. “In an era of extensive shortages of vital health practitioners, we are proud to help fill this educational and training gap, especially for the underserved area of Scarborough and the Eastern GTA."

SAMIH is expected to provide numerous benefits for the area. By increasing the number of health providers who will have received ��TV’s top-tier education, SAMIH will help improve access and care for patients who live in the region, extend the availability of various health-care services via its public clinics, provide opportunities for local students from diverse backgrounds to consider becoming a health professional and increase the likelihood of health professionals trained in Scarborough to practice locally.

Furthermore, the partnerships with Scarborough Health Network and Michael Garron Hospital will strengthen research and teaching links between the university and the hospitals.

“This generous investment from Myron and Berna Garron is a commitment to the future of health care; through their support of SAMIH and their partnership with Michael Garron Hospital, they’re enabling knowledge creation and sharing that will benefit our communities locally and more broadly,” said Melanie Kohn, president and CEO of Michael Garron Hospital. “The Garrons’ gift to our hospital will establish our first chair in education, in partnership with the University of Toronto, which will advance our ability to train tomorrow’s outstanding health-care leaders.”

A community of support

SAMIH was made possible by the Government of Ontario’s commitment to fund the expansion of medical education as part of its strategy to address the critical shortage of health professionals in the province.

“On behalf of Premier Doug Ford and our government, I want to thank Myron and Berna Garron for their generous donation to the Scarborough Academy of Medicine and Integrated Health,” said Sylvia Jones, Ontario’s deputy premier and minister of health. “Your support builds on the largest expansion of medical education that our government has undertaken in 15 years, training more doctors in the GTA than ever before to ensure people can access care in their communities for years to come.”

In a further boost for funding the building’s construction, Myron and Berna Garron’s donation triggers $10 million in matching funds from a $25-million gift to SAMIH from Orlando Corporation in 2022.

The five-storey, purpose-built Myron and Berna Garron Health Sciences Complex is located at U of T Scarborough at the intersection of Military Trail and Morningside Avenue, across from the Toronto Pan Am Centre, and is expected to open in the fall of 2026.

“This gift speaks to Myron and Berna Garron’s appreciation of how health-care education enables healthy lives – a key priority of Defy Gravity: The Campaign for the University of Toronto,” said David Palmer, vice-president of advancement at ��TV. “We are deeply grateful for this generous donation and the impact it will have on the health of those in Scarborough and the Eastern GTA. The Garron family’s generosity exemplifies how philanthropy can help address inequities and help shape the future of health care in our communities.”

��TV leaders react

“As home to the Scarborough Academy of Medicine and Integrated Health, the University of Toronto Scarborough is delighted for this opportunity to increase our impact on the community. SAMIH will attract a diverse pool of local talent and afford graduates the ability to establish their careers in Scarborough and the Eastern GTA – an asset for students with personal ties to the region and for a population in great need of more accessible health care.”

—Linda Johnston, ��TV vice-president and principal of ��TV Scarborough

“Building a new health sciences complex to house this region’s first medical academy is a historic undertaking. Creating an academy that is advancing health equity as a key priority is even more exceptional. This is a unique opportunity for Temerty Faculty of Medicine to expand the reach of our world-class programs, innovate teaching models and play a critical role in a pipeline that will infuse the health-care system with a steady stream of much-needed physicians and other health-care professionals.”

—Lisa Robinson, dean, Temerty Faculty of Medicine and vice-provost, relations with health-care institutions

“Thanks to the Garrons’ substantial support of the new Myron and Berna Garron Health Sciences Complex, students from the Lawrence Bloomberg Faculty of Nursing will have the opportunity to advance their nursing expertise in a clinic that is embedded within the community. This unique interprofessional environment will ensure graduates of our nurse practitioner program are well-equipped to meet the urgent need for primary health care in the region.”

—Robyn Stremler, dean, Lawrence Bloomberg Faculty of Nursing

“We’re thrilled that ��TV pharmacy students will train on rotation at the Discovery Pharmacy within the new Myron and Berna Garron Health Sciences Complex. This additional location offering clinical training in an interdisciplinary setting will be a boon to the profession, given how the scope of practice for pharmacists continues to expand and evolve to better support the people and communities we serve.”

—Lisa Dolovich, dean, Leslie Dan Faculty of Pharmacy

Researchers develop new method for delivering RNA and drugs into cells

Christopher.Sorensen — Mon, 16 Sep 2024 15:02:15 +0000

Researchers develop new method for delivering RNA and drugs into cells

Christopher.Sorensen Mon, 09/16/2024 - 11:02

Cutline

PhD candidate Kai Slaughter, left, and University Professor Molly Shoichet are exploring how ionizable drugs can be used to co-formulate small interfering RNA (siRNA) for more effective intracellular delivery (supplied images)

Qin Dai

Topic

Institute of Biomedical Engineering

Princess Margaret Cancer Centre

Donnelly Centre for Cellular & Biomolecular Research

Faculty of Applied Science & Engineering

University Health Network

Subheadline

"This could be a game-changer for treating complex conditions where targeting multiple pathways is beneficial, such as cancer and viral infections"

Researchers at the University of Toronto and its hospital partners have developed a method for co-delivering therapeutic RNA and potent drugs directly into cells, potentially leading to a more effective treatment of diseases.

The research, published recently in the journal Advanced Materials, explores how ionizable drugs can be used to co-formulate small interfering RNA (siRNA) for more effective intracellular delivery.

The team – including Molly Shoichet, the study’s corresponding author and a University Professor in ��TV’s department of chemical engineering and applied chemistry in the Faculty of Applied Science & Engineering – specifically targeted drug-resistant cells with the delivery of a relevant siRNA. The siRNA was discovered study co-author and collaborator David Cescon, a clinician scientist at the Princess Margaret Cancer Centre, University Health Network, and an associate professor in ��TV’s Temerty Faculty of Medicine.

“We found that our co-formulation method not only potently delivered siRNA to cells but also simultaneously delivered active ionizable drugs,” said research lead author Kai Slaughter, a PhD candidate in Shoichet’s lab.

“This could be a game-changer for treating complex conditions where targeting multiple pathways is beneficial, such as cancer and viral infections.”

siRNA is a powerful tool in medicine, capable of silencing specific genes responsible for disease, but delivering these molecules into cells without degradation remains a significant challenge. While recent innovations in ionizable lipid design have led to efficiency improvements, traditional nanoparticle formulations are limited in the amount of small molecule drugs they can carry.

When therapeutic formulations are absorbed by cells, small molecule drugs and siRNA are often trapped in small compartments called endosomes, preventing them from reaching their target destination and reducing their effectiveness.

The research team discovered that combining siRNA with ionizable drugs – compounds that change their charge based on pH levels – enhances the stability and delivery efficiency of siRNA inside cells, helping both the siRNA and drug escape the endosome and more effectively reach their destination. This novel method utilizes the protective properties of lipids to safeguard siRNA during its journey through the body and ensure the release of RNA and the drug together within the target cells.

“One of the biggest hurdles in siRNA therapy has been getting these molecules to where they need to go without losing their potency,” Shoichet says.

“Our approach using ionizable drugs as carriers marks a significant step forward in overcoming this barrier, while also showing how drugs and RNA can be delivered together in the same nanoparticle formulation.”

Caution needed when drawing links between improving symptoms and unproven remedies: Study

Christopher.Sorensen — Fri, 06 Sep 2024 16:03:17 +0000

Caution needed when drawing links between improving symptoms and unproven remedies: Study

Christopher.Sorensen Fri, 09/06/2024 - 12:03

Cutline

(photo by Oleksandra Yagello/Getty Images)

Sunnybrook Staff

Topic

Sunnybrook Health Sciences Centre

Institute of Health Policy Management and Evaluation

Dalla Lana School of Public Health

Subheadline

"Post-hoc bias can play tricks on patients that can eventually lead to serious disappointments – and for health-care workers, it can ultimately lead to shortfalls in care"

People tend to continue with unproven treatments even if there’s no evidence to suggest an initial marginal improvement in symptoms is anything more than a potential coincidence, a new study has found.

"I've noticed many of my patients take unnecessary vitamins, pills or alternative remedies with little evidence to inform their choice, leading to a lot of distraction, wishful thinking and wasted money,” says senior study author Donald Redelmeier, a staff internist and senior scientist at Sunnybrook Health Sciences Centre, and professor in the department of medicine in the University of Toronto’s Temerty Faculty of Medicine.

“Perhaps even more concerning is a false belief that leads to a missed diagnosis that later becomes incurable.”

The study, published in the journal JAMA Network Open, explores “post-hoc bias” – a tendency in reasoning that causes many patients to continue taking dubious or unreliable treatments. The bias encourages a popular misconception: that because one action preceded another later event, the first must have caused the second since it occurred in sequence.

But medical science, the researchers note, stresses that the order of two events does not prove a cause-and-effect since coincidences are frequent. The implication for medical care is that a patient who improved after a treatment is not necessarily a patient who improved because of the treatment.

Instead, other potential explanations include withdrawal from an adverse activity, added rest or the body’s own healing powers.

To test bias across a variety of clinical cases, the researchers ran multiple experiments using hypothetical clinical scenarios administered by a randomized survey of pharmacists and members of the community.

The scenarios described a patient with fatigue or another vague symptom who feels a bit better after trying a vitamin, shampoo, sugar pill or other treatment.

“We found that most respondents suggested continuing the treatment indefinitely even though the change in symptoms might be pure random chance," says Redelmeier, who is also affiliated ICES and the Institute for Health Policy, Management and Evaluation in ��TV’s Dalla Lana School of Public Health.

"The post-hoc bias can play tricks on patients that can eventually lead to serious disappointments – and for health-care workers, it can ultimately lead to shortfalls in care."

While attributing an initial improvement in – or lack of – symptoms to a treatment is a quick and intuitive approach, the researchers say the study reinforces the need for both patients and clinicians to be cautious when drawing conclusions.

“An awareness of post-hoc bias will not make it disappear, however we suggest patients and clinicians need to think twice and stay mindful of alternative explanations.”

The study was supported by the Alfred P. Sloan Foundation, a Canada Research Chair in Medical Decision Sciences, Canadian Institutes of Health Research, the PSI Foundation of Ontario and the National Science Foundation.

This story was originally posted at Sunnybrook Research Institute

Researchers propose biologically based classification system for Parkinson’s disease

rahul.kalvapalle — Tue, 20 Aug 2024 16:17:45 +0000

Researchers propose biologically based classification system for Parkinson’s disease

rahul.kalvapalle Tue, 08/20/2024 - 12:17

Cutline

The "SynNeurGe" classification system for Parkinson's disease, proposed by researchers led by Professor Anthony Lang of the University Health Network and ��TV, is based on three key biomarkers (photo by FG Trade/Getty Images)

Eileen Hoftyzer

Topic

Department of Medicine

Tanz Centre for Research in Neurodegenerative Diseases

Parkinson's

University Health Network

Subheadline

The classification system could enable advancements in the development of tailored treatments for Parkinson's disease

A team of researchers led by Anthony Lang of the University Health Network and the University of Toronto have proposed a novel classification system for Parkinson’s disease that considers biological features and not just clinical symptoms.

The "SynNeurGe" system, described by Lang and collaborators in a paper published in The Lancet Neurology, classifies Parkinson’s disease based on three biomarkers: presence or absence of misfolded alpha synuclein protein, which is believed to cause or contribute to the underlying neurodegeneration; evidence of neurodegeneration using imaging techniques; and presence of gene variants that increase disease risk.

The researchers argue that such a classification system is necessary to advance the development of tailored treatments for Parkinson’s disease.

Professor Anthony Lang (supplied image)

“This is a complex group of disorders that may cause similar symptoms, but biologically they're very different,” says Lang, a senior scientist and Lily Safra Chair in Movement Disorders at UHN and a professor in the department of medicine and the Tanz Centre for Research in Neurodegenerative Disease at ��TV’s Temerty Faculty of Medicine, where he holds the Jack Clark Chair for Parkinson’s Disease Research

“If we cannot find ways to subdivide patients biologically, then applying a therapy designed to affect one biological pathway may not be effective in another group of patients that doesn't have that same pathway involved – and we won’t really have precision or personalized medicine for Parkinson’s disease.”

Currently, Parkinson’s disease is classified based on clinical presentation and symptoms, but the disease can affect the brain for years, possibly even decades, before symptoms appear. For future therapies to treat the underlying disease rather than just the symptoms, patients will need early intervention and treatments tailored to the biological features of the disease, researchers say.

Similar approaches are being used for other diseases – cancer treatments vary not only by the location of tumors but also their molecular features, and the development of drugs for Alzheimer’s disease is increasingly guided by the specific biological mechanisms involved in the disease.

The SynNeurGe classification system, while based on the three key biomarkers, also considers whether clinical features are present. The different combinations of biomarkers classify the disease into various sub-types.

Lang and co-authors note that such a classification should only be used for research at present, although it will almost certainly have clinical applications.

“Eventually we will see a biological approach influencing clinical care, particularly when we finally have effective disease-modifying therapies,” says Lang. “We currently don’t know how important these biomarkers actually are.

"We need large-scale prospective studies of biomarkers, imaging and clinical features to interpret the results, give patients accurate information about their diagnosis and provide appropriate treatment.”

Lang’s team plans to start conducting such studies of cerebrospinal fluid, skin and blood to look for biomarkers of different sub-types of Parkinson’s disease that will help inform the classification system and the development of tailored therapies.

“Now is the time to think about these diseases not solely based on their clinical manifestations, but to look at the biology and try to separate different biological subtypes so we can ultimately improve treatment for this disease,” Lang says.

Professor Graham Collingridge, director of the Tanz Centre, says Lang and his team’s “landmark paper” is poised to have a significant impact on clinical practice around Parkinson's. “I am delighted that our researchers have played such a key role in this important biological classification,” Collingridge says.

Lang says research by Tanz Centre scholars has contributed significantly to the body of knowledge used to develop the proposed biological classification.

For example, Professor Ekaterina Rogaeva’s research on the genetics and epigenetics of Parkinson’s disease has shown that multiple genes and environments can influence Parkinson’s risk, highlighting the need to tailor therapies based on a patient’s genetic makeup.

Other researchers – including Anurag Tandon, Joel Watts, Martin Ingelsson and Gabor Kovacs – have been studying the role of misfolded alpha synuclein in neurodegeneration as well as cases of Parkinson’s disease where alpha synuclein is absent – which informed how Lang’s team included the protein in the classification.

��TV startup Honeybee acquired by global clinical trials firm Leapcure

rahul.kalvapalle — Fri, 16 Aug 2024 14:55:48 +0000

��TV startup Honeybee acquired by global clinical trials firm Leapcure

rahul.kalvapalle Fri, 08/16/2024 - 10:55

Cutline

(photo courtesy of Leapcure)

Rahul Kalvapalle

Topic

Our Community

Faculty of Applied Science & Engineering

��TV Entrepreneurship

Health Innovation Hub

Impact Centre

Innovation & Entrepreneurship

ONRamp

Startups

Subheadline

Co-founded by Catherine Chan and Weiwei Li, Honeybee Trials' platform helps clinical trial recruiters find, screen and manage patients for their research

Honeybee Trials, a University of Toronto startup that connects research teams with patients and study participants, has been acquired by global clinical trials company Leapcure in a deal that is poised to drive more inclusive and affordable trials that’s ultimately applicable to a broader population.

Co-founded by ��TV alumni Catherine Chan and Weiwei Li, Honeybee built a web and mobile platform to help clinical trial teams attract, screen, recruit and manage study participants. Since its founding in 2019, the startup has connected over 30,000 patients and participants to more than 1,000 clinical trials across North America.

Leapcure, headquartered in California, offers an array of solutions that combines people-backed services with data-driven technologies to fill clinical trials for global sponsors and CROs, but can now expand affordable patient recruitment to institutional sites, private sites and biotech firms. Moreover, their work alongside patients and advocacy groups has significantly helped to reach underrepresented communities – a focus that will receive a boost following the purchase of Honeybee.

Chan, who earned a master’s degree in the Temerty Faculty of Medicine’s department of nutritional sciences, says the deal grew out of a desire to partner strategically with a larger company that could provide access to broader sectors within the clinical research world.

Catherine Chan (L) and Weiwei Li (supplied image)

“At Honeybee, we offered competitive pricing for academic and hospital sites, local CROs [contract research organizations] and biotech firms,” Chan says. “With this partnership, we’re able to provide services across all of the different types of trial scopes and sizes.”

She adds that both Honeybee and Leapcure have placed a strong focus on diversity, equity, inclusion and accessibility by helping researchers attract study participants of different ethnicities, ages, genders and sexual orientations – helping make clinical trials more equitable and reflective of the wider population.

“It’s important to us that there's a mission and vision alignment between the companies... it couldn’t be a better fit,” Chan said.

The asset purchase deal for an undisclosed amount, which was announced in an Aug. 13 press release, will see Chan transition from CEO of Honeybee to senior director of product at Leapcure.

“We’re excited to join forces with Catherine and Honeybee. They’ve been really focused on the newest recruitment technologies that are most impactful for both patients and research,” said Leapcure CEO Zachary Gobst. “A big reason that things came together was our alignment on impact first. It’s a credit to how they’ve been approaching their business the right way from the beginning."

Honeybee evolved out of the frustrations that Chan faced in recruiting study participants for her master’s thesis. Motivated to explore solutions, Chan created a prototype that would help match participants with trials; she then enrolled in a one-week accelerator program in the Impact Centre (now the Centre for Entrepreneurship) in the Faculty of Arts & Science.

She soon teamed up with Li, who earned his bachelor’s and master’s of applied science degrees from the Faculty of Applied Science & Engineering, to co-found Honeybee. The startup later joined the Health Innovation Hub (H2i) accelerator and operated out of office space in ��TV Entrepreneurship’s ONRamp facility prior to the COVID-19 pandemic.

With COVID-19 measures encouraging the adoption of digital tools by clinical research teams, Honeybee found itself well-placed to play an important role. “The pandemic provided an opportunity for many tech companies to scale as the market became more open-minded and ready to adopt technologies to help connect them day-to-day," Chan says. "We saw a rapid adoption of Honeybee’s technology during this time where people moved away from traditional recruitment and patient communications to the current age.

“Although digital adoption across other industries has grown quite rapidly, healthcare has lagged behind, rightfully so and for many reasons, but we’re glad the transformation is happening. Just five years ago, clinical trial coordinators were still using paper handouts to recruit on the street and paper calendars to schedule patients.

“The pandemic expedited researchers being able to meet people where they are.”

Chan says the acquisition by Leapcure will enable the rollout of tiered services ranging from low-cost, self-serve tiers – targeting research teams with more modest budgets – to higher levels of service that include dedicated management.

“I’m really excited about the solutions we now have to offer together as well as the next steps in how we’re going to disrupt clinical trials.”

Professor Paul Santerre, co-founder and director of H2i, hailed Chan as "a model outcome" of the accelerator's mission to empower innovators in translating their ideas into products and companies that tackle important problems.

“Catherine and her team’s achievements are transformative in terms of democratizing the recruitment of patients for clinical study cohorts," said Santerre, the Baxter Chair for Health Technology and Commercialization at the University Health Network and professor in the Faculty of Dentistry and Institute of Biomedical Engineering who is cross-appointed to the department of chemical engineering and applied chemistry.

"She has much to still teach us about the power of digital tools and their ethical use to achieve impact in clinical research trials – and this acquisition will accelerate that outcome."

��TV researchers develop AI model to predict 'very dynamic' peptide structures

Christopher.Sorensen — Thu, 15 Aug 2024 12:54:41 +0000

��TV researchers develop AI model to predict 'very dynamic' peptide structures

Christopher.Sorensen Thu, 08/15/2024 - 08:54

Cutline

PhD Graduate Osama Abdin and Professor Philip M. Kim developed a deep-learning model that can predict all possible shapes of peptides, which are are of keen interest to researchers who are developing therapeutics (supplied image)

Anika Hazra

Topic

Donnelly Centre for Cellular & Biomolecular Research

Alumni

Artificial Intelligence

Computer Science

Subheadline

The new model expands on the capabilities of Google DeepMind's AlphaFold, the leading AI system for predicting protein structures

Researchers at the University of Toronto have developed a deep-learning model that can predict all possible shapes of peptides – chains of amino acids that are shorter than proteins, but perform similar biological functions.

Called PepFlow, the model combines machine learning and physics to model the range of folding patterns that a peptide can assume based on its energy landscape.

Peptides, unlike proteins, are dynamic molecules that can take on a range of conformations. They are involved in many biological processes that are of keen interest to researchers who are developing therapeutics.

“We haven’t been able to model the full range of conformations for peptides until now,” said Osama Abdin, first author on the study and recent PhD graduate of molecular genetics at ��TV’s Donnelly Centre for Cellular and Biomolecular Research. “PepFlow leverages deep-learning to capture the precise and accurate conformations of a peptide within minutes.

“There’s potential with this model to inform drug development through the design of peptides that act as binders.”

The study was recently published in the journal Nature Machine Intelligence.

A peptide’s role in the human body is directly linked to how it folds since its 3D structure determines the way it binds and interacts with other molecules.

“Peptides were the focus of the PepFlow model because they are very important biological molecules and they are naturally very dynamic, so we need to model their different conformations to understand their function,” said Philip M. Kim, the study’s principal investigator and a professor at the Donnelly Centre. “They’re also important as therapeutics, as can be seen by the GLP1 analogues, like Ozempic, used to treat diabetes and obesity.”

Peptides are also cheaper to produce than their larger protein counterparts, said Kim, who is also a professor of computer science in ��TV’s Faculty of Arts & Science and a professor of molecular genetics in the Temerty Faculty of Medicine.

The new model expands on the capabilities of AlphaFold, the leading Google DeepMind AI system for predicting protein structure. It does this by generating a range of conformations for a given peptide. Taking inspiration from highly advanced physics-based machine learning models, PepFlow can also model peptide structures that take on unusual formations, including the ring-like structure that results from a process called macrocyclization. Peptide macrocycles are currently a highly promising venue for drug development.

“It took two-and-a-half years to develop PepFlow and one month to train it, but it was worthwhile to move to the next frontier beyond models that only predict one structure of a peptide,” Abdin said.

There are, however, limitations given that PepFlow represents the first version of a new model. The study authors noted a number of ways in which PepFlow could be improved, including training the model with explicit data for solvent atoms, which would dissolve the peptides to form a solution, and for constraints on the distance between atoms in ring-like structures.

Yet, even as a first version, the researchers say PepFlow is a comprehensive and efficient model with potential for furthering the development of treatments that depend on peptide binding to activate or inhibit biological processes.

“Modelling with PepFlow offers insight into the real energy landscape of peptides,” said Abdin.

The research was supported by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada.

Common antibiotics carry small but serious risks of life-threatening drug reactions: Study

Christopher.Sorensen — Wed, 14 Aug 2024 12:51:57 +0000

Common antibiotics carry small but serious risks of life-threatening drug reactions: Study

Christopher.Sorensen Wed, 08/14/2024 - 08:51

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(photo by vorDa/Getty Images)

Misty Pratt

Topic

Sunnybrook Health Sciences