Year: 2015

Tracking the genomic footprints as predictive features of platinum refractory high-grade serous ovarian cancers

Michael Smith Foundation for Health Research/BC Cancer Foundation Post-Doctoral Fellowship Award

High-grade serous ovarian cancers (HGS) have a low five year survival rates at less than 40 percent. This is partly because of high relapse rates due to resistance to platinum-based therapies, which is the current standard of treatment. Although these therapies are effective at treating the primary tumour, cancers develop resistance to platinum drugs in almost all instances and the tumours recur.

How genomic instabilities evolve in HGS tumours and lead to platinum-resistance is poorly understood, and there are currently no biomarkers that give a reliable prognosis. We seek to identify effective genomic biomarkers for determining which HGS patients will respond more effectively to platinum-based chemotherapy.

This project will build on our research group's recent observations of differences in global genomic patterns between platinum-sensitive and platinum-resistant groups. We will analyze an HGS cohort of seventy cases composed of short- and long-term survivors with five year clinical follow-up data by:

  1. Comparing and contrasting the entire DNA sequence of tumours to the patient's normal DNA to identify global patterns of genomic instability
  2. Comparing and contrasting genomic profiles from the whole genome of the short-term and long-term survivors
  3. Studying diversity via deep-sequencing data of the tumours.

Ultimately, the results of this project and future work could allow for a long-term prognosis and optimized treatments for patients with HGS ovarian cancer.

Characterizing the interactions between attaching and effacing pathogens and the gastrointestinal microbiota

Diarrheal illnesses remain a major cause of sickness and death worldwide, killing approximately 760,000 children under the age of five each year. This project seeks to better understand one major cause: bacteria known as attaching and effacing (A/E) pathogens. This group includes several classes of pathogens: i) a class that causes death primarily among children in developing countries, and ii) a class with potentially life-threatening complications such as kidney failure in both developing and developed countries.

First, the normal community of microbes inhabiting the healthy mammalian digestive tract (the gut microbiota) represents a major challenge for A/E pathogens by competing for nutrients and possibly by producing molecules that inhibit the A/E pathogens. We will investigate how A/E pathogens sense and adapt to the presence of the gut microbiota with a view to gaining insights into their overall infection strategy.

Second, we will seek out species within the gut microbiota that inhibit A/E pathogens. Chemicals that they produce could form the basis of drug discovery programs for novel antibiotics.

Our final objective is to characterize one genetic system that A/E pathogens use to sense their surroundings: the Cpx envelope stress response. This system triggers production of damage-repair proteins when it senses damage to the envelope of the bacterial cell. We will study whether and how these repair proteins are required for A/E pathogens to infect mice. If so, they represent a potential target for developing novel antibiotics.

This project will yield a better understanding of a major cause of illness and death and might give rise to new avenues of research for novel antibiotics to counter it.

Exploring the mediating effect of parenting practices on the relationship between the neighbourhood environment and child physical activity

The neighbourhood environment has been found to affect the levels of physical activity among children. We are investigating the mediating effect of parenting practices on this relationship.

For example, some studies have found that children living in neighbourhoods that are more walkable or have more green space were more likely to be physically active. This may be related to parenting practices. For example, parents may restrict their children from playing outdoors if they feel that their neighbourhood is unsafe but may encourage outdoor play if they live near a park.

This study will address this gap by using survey data collected from two sample populations. First, data collected from a web-based survey of 500 parents across Canada and the USA will be used to describe the relationship between the neighbourhood environment (e.g. safety, crime, walkability) and physical activity parenting practices.

Second, one child from each of 88 living in Metro Vancouver will be provided with an accelerometer to record their physical activity patterns. Their parents will complete a questionnaire measuring their perception of the environment and the parenting practices they employ.

The goal of the project is to better understand how the environment can influence parenting practices, enabling recommendations on designing neighbourhoods to allow children to be more physically active.

Targeting the regulation of DNA repair by CDK12 for breast and ovarian cancer therapy

Human cells experience DNA damage every day, but DNA repair systems ensure that resulting mutation rates are extremely low. Two main pathways repair severe DNA damage in cells. The 'copying' pathway connects broken DNA ends by copying the missing sequence from the second DNA copy that is present before cells divide. The 're-joining' pathway simply re-joins the broken DNA ends irrespective of the missing sequence. Mutations in these pathways are frequently found in cancer cells, which can accumulate thousands of mutations.

Recent studies show that tumours with mutations that inactivate the copying pathway can be effectively treated with drugs that inhibit the re-joining pathway. After drug treatment, both repair pathways are impaired in tumour cells, whereas normal cells still retain one functional pathway. As a result, doses can be adjusted so that side effects of chemotherapy are milder.

A protein named CDK12 appears to be a regulator of the copying pathway, and cells with abnormal CDK12 are sensitive to drugs that inhibit the re-joining pathway. Mutations in CDK12 have been found in many tumour types. Our preliminary results show that CDK12 regulates an essential cellular process termed 'alternative splicing,' where gene segments are assembled in different orders to create different versions of the same gene.

We will examine how CDK12 changes the alternative splicing of genes after DNA damage, and how this regulation is impaired by mutations in CDK12 that have been found in tumours. Ultimately, this work could lead to new research tools and help to define the population of cancers that can be treated with CDK12-based therapy.

Integrating HCV and addiction treatment to improve individual and population HCV outcomes among people who inject drugs

Hepatitis C (HCV) remains a significant challenge that affects an estimated 60,000 British Columbians. Many more, in particular, people who inject drugs (PWID), remain highly vulnerable to HCV infection. Recently, there have been dramatic developments in the treatment of HCV with the arrival of direct acting antivirals (DAAs). These drug regimens are highly effective, offering vastly superior cure rates over past HCV treatments. Interferon-free regimens with DAA-based regimens are also simpler and better tolerated. While there is immense optimism regarding future HCV treatment efforts, concerns remain regarding issues of access, treatment adherence, and potential reinfection following treatment. Further, recent evidence from phylogenetic analyses reveal that the core transmitters of HCV within British Columbia tend to be PWID with active addiction and who remain outside of conventional treatment programs.

Accordingly, there is now a pressing need to optimize the delivery of addiction treatment to ensure the success of HCV treatment in order to reduce HCV-associated morbidity and mortality, prevent forward transmission and protect valuable health resources. Vancouver offers an ideal setting in which to undertake research focused on identifying how to best integrate addiction and HCV treatment efforts. The BC Centre for Excellence in HIV/AIDS (BC CfE) is home to two large ongoing US National Institutes of Health-funded prospective cohort studies of PWID with a HCV prevalence of 90%. The BC CfE is also home to a CIHR and NIH-funded addiction clinical trials network, and is leading efforts to deliver DAAs to marginalized populations, including PWID.

Using prospective cohort methods, this postdoctoral program of research will seek to identify barriers to and facilitators of access and adherence to DAAs, as well as risk factors for HCV reinfection, with a focus on the role that addiction treatment plays in shaping HCV outcomes (e.g., sustained virological response). With the advent of safer and more efficacious HCV treatments, as well as the research infrastructure afforded by the BC CfE, I will be uniquely positioned to undertake innovative research with high potential to improve population health outcomes in British Columbia.

Wealthy and healthy: Socioeconomic status (SES) and syndemics

Co-infections with sexually transmitted infections and blood borne infections (STIBBI) are common among people living with HIV. They occur because of shared risk behaviours and common social conditions. It is a significant public health issue because groups of people at high risk of acquiring and transmitting infections can spread them more readily to the broader population.

This study proposes to examine neighbourhood-level characteristics (e.g. socio-behavioural groupings, geographic areas) to describe how contextual variables and socioeconomic status contribute to STIBBI co-infection trends. We will use provincial surveillance, laboratory, and healthcare utilization data linkages.

Our goal is to shed light on whether real-time data linkage could improve delivery of health services to core groups of people living with HIV. Ultimately, this work could inform health service policies and procedures that improve quality of life and reduce the spread of STIBBI among the general population.

A telehealth intervention to promote healthy lifestyles after stroke: The Stroke COACH

Stroke is often associated with low levels of physical activity and poor nutrition habits and with related conditions such as obesity, hypertension and diabetes. Within five years of the initial stroke, 30 percent of stroke survivors will suffer a recurrent stroke.

We developed the telehealth Stroke COACH programme, a lifestyle modification intervention comprised of a self-management manual for stroke survivors, a self-monitoring kit (including a blood pressure monitor, pedometer, and health report card), and telephone-coaching sessions by trained ‘lifestyle coaches’. In this six month program, seven sessions of 30-60 minutes are delivered by the coaches who use motivational interviewing techniques to facilitate active patient engagement and enhance chronic disease self-management skills of problem solving, decision making, action planning, and resource utilization.

One hundred twenty-five community-dwelling individuals who have had a stroke of mild to moderate severity within the last twelve months will be enrolled in this single-blind randomized controlled trial. They will be randomly assigned to either: 1) Stroke COACH with a lifestyle coach, or 2) control group (memory training program with a memory coach).

We predict that the Stroke COACH will improve a global measure of lifestyle behaviour in community-dwelling stroke survivors compared to the control group. This will be measured at zero, six, and 12 months using the Lifestyle Profile II, a global lifestyle behaviour measure that considers physical activity, stress management, nutrition, health advocacy, interpersonal support, and spirituality.

We also predict improvement in physical activity and cardiovascular health outcomes, which we will measure using the StepWatch Activity Monitor and bloodwork results.

If testing is successful, the low-cost and remote delivery of the Stroke COACH would enable a large number of Canadians in both urban and rural regions to improve health behaviours of people living with stroke, potentially reducing the risk of subsequent stroke.

The key bacterial species and mechanisms by which they modulate allergic disease development

Michael Smith Foundation for Health Research/AllerGen Post-Doctoral Fellowship Award

A major focus for mucosal immunology research has been on the types of bacteria that reside in the mammalian intestinal tract. These bacteria are collectively referred to as the microbiota. Disrupting the microbiota composition by antibiotic use has been linked to the development of allergic disease in both human populations and mouse models.

Mice treated with antibiotics early in life acquire an altered microbiota and signs of asthma in a mouse model of allergy. We seek to identify key bacterial species within the microbiota that affect allergy in this mouse model.

Additionally, we plan to explore whether antibiotic treatment affects cells of the immune system. A high level of one particular kind of antibodies (IgE) is associated with allergic asthma development in humans, and treating mice with antibiotics results in high levels of IgE. We will test whether changing IgE levels in mice changes their sensitization to allergens.

If antibiotic use is linked to allergy development, understanding how could allow researchers to develop strategies to soften this effect.

Don’t sugar coat it: Cardiac consequences of developing Type 2 diabetes after spinal cord injury

Michael Smith Foundation for Health Research/Rick Hansen Institute (RHI)/International Collaboration on Repair Discoveries (ICORD) Post-Doctoral Fellowship Award

People with spinal cord injury (SCI) are at an increased risk of developing type 2 diabetes. Currently, no studies have investigated type 2 diabetes in people with SCI. We believe it may contribute to the high rate of heart disease among people with SCI.

The aim of the present study is to develop an animal model of SCI combined with type 2 diabetes. We will then use this model to see whether type 2 diabetes progresses more quickly after SCI, whether developing type 2 diabetes after SCI impairs function of the heart, and possible causes of the negative impact of type 2 diabetes on heart function.

Should we find that type 2 diabetes impairs heart function, this will lead to further studies aimed at preventing and treating type 2 diabetes in people with SCI. Our findings could aid in the clinical management and treatment of people with SCI and significantly improve their health and quality of life.

Influence of community rehabilitation services on community reintegration and health utilization after stroke

Stroke is a leading cause of long-term disability in adults, and community reintegration is the pivotal outcome of successful rehabilitation.

Physical and cognitive impairments after stroke impact reintegration of patients into the community and place a burden on caregivers. The current system seeks to address this with health care services aimed at improving physical and cognitive functioning, as well as providing access to information and resources to facilitate improvement. These services are costly, and it is not known if such services benefit community reintegration or could potentially reduce the usage and cost of other health and social services.

The primary purpose of this study is to determine the impact of rehabilitation services on community reintegration and health after stroke.

This study will include 100 community-dwelling stroke patients and their caregivers. They will be assessed at several timepoints following stroke, and the hours and type of community rehabilitation services will be documented within this 12-month period. We will use the framework from the World Health Organization International Classification of Functioning to assess impairments and activity. We will compare the extent of the use and cost of health and social services, community services, and medications used by the patient with their degree of community reintegration.

The study protocol has been reviewed and approved by the local Clinical Research Ethics Board.

The results from this research could help to inform the effective delivery of health care services for stroke survivors.