Research Location: Vancouver Coastal Health Research Institute

Strategies to Promote Mobility and Physical Activity in Older Men in Assisted Living

Older men in assisted living spend up to 90 percent of their time in sedentary behavior. This lack of physical activity makes them more vulnerable to mobility-disability. Currently, 40 percent of Canadian men over the age of 75 already present some degree of mobility-disability. Mobility limitations lead to frailty, falls, and placement into higher levels of care. To promote mobility and physical activity in older men living in assisted living facilities, a better understanding of how they move is needed. This in turn helps assisted living facilities better customize programs that enhance their participation, and thus, improve their mobility.

To address the gaps, I will develop and evaluate strategies that promote mobility and physical activity (in older men who live in assisted living). More specifically, I will address the following two objectives:

  1. Examine how real-life measures from wearable sensors of the quality of movement (e.g. time required for transferring, gait speed) and quantity of movement (e.g. activity levels) associate with frailty and risk for falls in older men. I will use wearable sensors to measure mobility patterns during standard clinical tests and as residents go about their daily activities (e.g. walking, transferring, standing, seated, and lying).
  2. Examine how mobility and activity levels are influenced by a customized physical activity program and real-time feedback monitored by wearable sensors. I will conduct a 12-week randomized control trial of a customized physical activity intervention for older men in assisted living. Participants will be randomly assigned to either the program currently offered by a facility (control group) or to a physical activity program that is custom-designed based on the results under objective 1 (intervention group).

This project will be conducted in partnership with Fraser Health and the BC Care Providers Association. I hypothesize that participants in the intervention group will show greater improvement in measures of mobility, falls efficacy, and fall incidence. I will work with partners to refine my research objectives and disseminate results at the end of the trial. Findings will be shared through presentations, workshops and publications. By sharing best practices for mobility and physical activity promotion, I ultimately want to impact the older men who are in assisted living.

TEC4Home: Telehealth for Emergency-Community Continuity of Care Connectivity via Home telemonitoring

Health Research BC is providing match funds for this research project, which is funded by CIHR’s eHealth Innovation Partnership Program (eHIPP). Additional support is provided by the BC Ministry of Health and TELUS Health.

 

Health care for seniors can be challenging, especially for those with chronic illnesses like heart failure which is the third leading cause of hospital stays. After discharge, seniors are often vulnerable to their condition deteriorating, with one of four returning to hospital within one month of an emergency department visit or hospital stay.

 

Telehealth for Emergency-Community Continuity of Care Connectivity via Home-Telemonitoring (TEC4Home), is evaluating how home telemonitoring may improve care and increase patient safety during the transition from the emergency department to community care at home, and further, how it is best implemented to support patients with heart failure.

 

TEC4Home is led by Dr. Kendall Ho, a professor in the Department of Emergency Medicine at the University of British Columbia and an emergency department physician at Vancouver General Hospital. The aim is to improve patient outcomes and quality of life by reducing the number of emergency department revisits, hospitalizations and length of stay.

 

Patients enrolled in the TEC4Home project can monitor their health from the comfort of their homes and share information electronically with their physicians and health care providers. Using monitoring technology provided by TELUS Health, patients measure their own weight, blood pressure, pulse, and oxygen saturation daily over a 60-day period. The data is automatically sent to a TEC4Home monitoring nurse who can follow up as required.

 

Over the four years of the project, Ho’s team will conduct a number of studies and trials involving patients recruited from emergency departments and several health authorities across BC. Ho’s research is expected to inform the use and expansion of the home monitoring approach throughout BC and Canada and to other chronic diseases.

 

The use of technology like TEC4Home for patient self-management and monitoring of chronic illnesses can empower patients to become active participants in their care and recovery. Additionally, there is the potential to improve the quality of health care delivery and reduce health care costs while freeing up resources and hospital beds for other patients.

 

In 2017, Ho received an MSFHR Health Professional-Investigator Award related to this project.

Co-targeting Hsp27 and EGFR as a strategy to improve EGFR targeted therapies in EGFR dependent solid tumors

Epidermal Growth Factor Receptor (EGFR) is a key regulator of cell proliferation and a driver oncogene in several tumors. Many cancers have constitutively activated EGFR which leads to excessive signalling. Inhibition of EGFR using erlotinib or gefitinib significantly improves survival in patients with Non Small Cell Lung Cancer (NSCLC) while panitumumab and cetuximab are currently used in colorectal and head and neck cancer. Despite good initial responses to these drugs, the patients develop resistance and eventually die of recurrent disease. EGFR inhibitors induce stress responses that promote emergence of acquired resistance.

We identified Heat Shock protein 27 (Hsp27), a stress induced chaperone protein correlated to treatment resistance in several tumors, as a mediator of resistance to erlotinib in NSCLC. Hsp27 becomes phospho-activated after erlotinib and helps stabilize EGFR. We developed the Hsp27 antisense inhibitor OGX427 which can block the adaptive survival response and enhance the activity of erlotinib and other anti-cancer drugs and now in phase II clinical trials in lung, pancreas, bladder and prostate cancers. While the activity of OGX427 is promising, a more potent and orally active inhibitor may improve cancer control; however small molecule inhibitors are difficult to develop because of the complex structure of Hsp27.

Using a series of drug screening assays, we identified a new drug, VPC27, that functionally inhibits Hsp27 with a good tolerability profile in mice studies. The aims of this project are: a) to compare the activity of VPC27 and OGX427 on tumor proliferation/survival in different EGFR dependent solid cancers alone or in combination with EGFR inhibitors; b) to define the molecular mechanisms that link Hsp27 with resistance to EGFR inhibitors, focusing on kinases and phosphatases proteins that regulate the phosphorylation and dephosphorylation of Hsp27 and EGFR.

These studies aim to build upon two strategies that are revolutionizing the treatment landscape in cancer: the use of molecular-targeted agents inhibiting driver oncogenes and the inhibition of adaptive responses that support development of resistance. Co-targeting treatment-induced adaptive responses mediated by Hsp27 can sensitize cancer cells to EGFR inhibitors and improve the efficacy of these drugs. Moreover, understanding mechanisms by which Hsp27 regulates EGFR activity is important to identify new molecules that could be used as new targets in cancer therapy.

How is the motor learning capacity of a skilled walking task affected after an incomplete spinal cord injury?

Many people who have an incomplete spinal cord injury (iSCI) have the potential to improve their ability to walk. Current training strategies are limited in their ability to target skilled walking tasks (e.g. stairs and obstacles).

Sensory function can be affected after iSCI. We believe that this could influence success at re-learning these tasks, because previous studies show that impaired sensory feedback from the leg muscles can influence how the foot moves while walking.

The goal of this work is to investigate how well people with an iSCI can re-learn a new skilled walking task, and to evaluate the impact of impaired sensory function in the lower limbs on this process.

Our findings will shed light on how reduced sensory function affects people re-learning skilled walking tasks after iSCI.

Targeting androgen receptor dimerization as a potential therapy for prostate cancer

Prostate cancer is a leading cause of death in men. Treatment involves reducing production of di-hydro-testosterone (DHT) or blocking the interaction of this hormone with the androgen receptor (AR), a transcription factor responsible to drive expression of genes responsible for tumour growth. This treatment is unfortunately temporary and tumours eventually undergo genetic changes to become castration-resistant and able to grow in the absence of DHT.

This research project aims to use drugs to block AR activity in castration-resistant prostate cancer. Within the nucleus, two androgen receptor molecules must self-associate (“dimerize”) before binding DNA and initiating transcription. Dr. Dalal hypothesizes that slowing tumour growth can be achieved by preventing the AR-DNA interaction directly or by interfering with AR dimerization.

Cell biology and biochemistry approaches will allow Dr. Dalal to study the molecular mechanism of DNA-blocking or dimer-interfering compounds. Several compounds targeting both processes have been optimized to show potent and specific inhibition of the androgen receptor in cultured prostate cancer cells. Gel shift assays, calorimetry methods and confocal microscopy are now being used to gauge the effects of drugs on both DNA binding and AR dimerization. Site-directed mutagenesis of amino acids on the AR protein surface will validate the binding location of inhibitors. Promising compounds will be tested in mice to show effects on the size of prostate tumours.

Targeting transcription factor dimerization and DNA binding is a novel strategy that holds great promise to treat advanced forms of prostate and other cancers.

Examining executive functions as mediators of a mental and social enrichment intervention for older adults with chronic stroke

Significant proportions of stroke survivors suffer long-term physical disability and are predisposed to sedentary lifestyles. This limits their performance of activities necessary for independent living in the community and contributes to increased risk for recurrent stroke and heart disease. Dr. John Best recognizes that intervention strategies are needed to motivate stroke survivors to engage in routine physical activity and to optimize their physical and motor functions.

Best’s research will examine executive functions (EFs) as mediators of a mental and social enrichment intervention for older adults with chronic stroke. Broadly speaking, EFs refer to the cognitive processes that allow for adaptive behavior and self-control.

One promising strategy targets EFs by engaging stroke survivors in complex mental and social activities. Best’s research will evaluate the importance of improving EFs within the context of a mental and social enrichment intervention in order to have a meaningful impact on physical and motor functions, the ability to perform daily activities, and routine engagement in physical activity.

The information garnered from Best’s research will be crucial for improving stroke rehabilitation for older Canadians who suffer chronic disability from stroke.

Practice experiences of rural GP surgeons in British Columbia

The recruitment and retention of health care professionals is one of the most pressing challenges currently facing the Canadian health care system. In rural communities, the number of obstetricians and general surgeons is diminishing for a number of reasons, including difficulties in recruitment, an aging workforce, resistance to a demanding call schedule, and an increase in sub-specialization resulting in fewer ‘general’ surgeons. In some rural communities, maternity care is provided by general surgeons with enhanced obstetrical skills.

There are approximately 4,000 pregnant women in BC living in rural communities whose maternity care comes from these general practice (GP) surgeons. Despite the important role these practitioners play in sustaining rural maternity care in BC, to date, there has been no systematic research into their current experiences, and no official policy regarding guidelines for the practice, training, and maintenance of skills. Dr. Jude Kornelsen is investigating the role of these practitioners in rural health care in BC and their contribution to sustainable maternity care in these communities from a multi-disciplinary perspective.

Primarily through in-depth interviews, she will detail the experiences of GP surgeons in providing obstetrical care to rural communities including understanding their motivation, the nature of support received, and identifying any barriers to practice. She will describe the relationship between GP surgeons and specialists in their local community and in referral facilities, and determine how they receive ongoing training, mentoring and education. Ultimately, this research will provide a greater understanding of the culture of GP surgeons’ role in rural maternity service delivery in rural BC, and will help to inform policy guidelines regarding the practice, training, and maintenance of skills.

Elucidating the functions of MCL-1 in DNA repair

Mammalian cells have developed elaborate DNA damage response (DDR) and DNA repair systems in order when to protect and repair their DNA encountering toxic agents. In tumour cells, activation of these molecular events can make tumour cells resistant to chemotherapy or radiotherapy-induced DNA damage. Therefore, decoding how the DDR and DNA repair mechanisms are controlled is very important for understanding how cells become resistant to chemotherapy and to find ways to improve conventional cancer therapies. MCL-1 is a pro-survival protein that has multiple roles within the cell and has been shown to protect cells from death. It can interact with multiple important nuclear proteins involved in DDR response. Loss of MCL-1 increases genome instability after DNA damage. These studies indicate that MCL-1 may be an important component of the DDR machinery to regulate the repair of DNA lesions. Dr. Yemin Wang is investigating how MCL-1 regulates DDR and DNA repair. He is taking an intracellular approach to understand how MCL-1 is delivered into the nucleus after DNA damage and will also use this approach to investigate how MCL-1 regulates crucial events in DDR and DNA repair machinery. Dr. Wang will also examine whether the presence of MCL-1 in the nucleus affects how the cell responds to chemotherapy and whether the role of MCL-1 in DDR affects tumor development. The results of Dr. Wang’s work will provide us with a better understanding of MCL-1 in DDR and DNA repair processes, explain its essential function in vertebrate development, and help us to design improved therapeutic interventions for cancer treatment.

Air pollution and asthma: Modifying factors in a public health context

In reaction to air pollutants, asthmatics may experience an “”asthma exacerbation”” characterized by the narrowing of their airways. This may lead to a shortness of breath that may require urgent medical attention. One source of air pollution associated with asthma exacerbations is diesel exhaust. How and why diesel exhaust causes exacerbations is unclear, but one hypothesis is that it causes “”oxidative stress””, which is damage to cells and body tissues due to certain chemical characteristics. Ongoing exposure to traffic-related air pollution can also result in new asthma in previously healthy individuals. Dr. Christopher Carlsten is working to understand how different air pollutants, particularly diesel exhaust, influence asthma. He is trying to determine whether diesel exhaust creates oxidative stress, and, if so, if that stress is responsible for airway narrowing in human asthmatics. In his laboratory, diesel exhaust is generated in concentrations typically found in mining operations or in busy bus terminals. Volunteer subjects inhale the exhaust for two hours – a short exposure time has no permanent effects but does produce mild, temporary changes – and changes in oxidative stress and airway narrowing are measured. In some subjects, other typical environmental allergens such as tree and grass pollen are added to see if they worsen the effect of diesel exhaust. In addition to this work, Dr. Carlsten and colleagues are following a group of more than 20,000 children from birth to see how their exposure to such pollution may lead to new asthma. Dr. Carlsten’s research will lead to a better understanding of diesel exhaust-related airways disease and will lead to measures to protect Canadians exposed to traffic-related pollution. This research aims to inform recommendations for or against changes in fuel composition and/or personal measures to bolster anti-oxidant levels. Dr. Carlsten’s work to understand the effects of air pollution on asthma development should inform interventions regarding pollutant exposure in children.